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Sivabharathi RC, Rajagopalan VR, Suresh R, Sudha M, Karthikeyan G, Jayakanthan M, Raveendran M. Haplotype-based breeding: A new insight in crop improvement. PLANT SCIENCE : AN INTERNATIONAL JOURNAL OF EXPERIMENTAL PLANT BIOLOGY 2024; 346:112129. [PMID: 38763472 DOI: 10.1016/j.plantsci.2024.112129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/09/2024] [Accepted: 05/15/2024] [Indexed: 05/21/2024]
Abstract
Haplotype-based breeding (HBB) is one of the cutting-edge technologies in the realm of crop improvement due to the increasing availability of Single Nucleotide Polymorphisms identified by Next Generation Sequencing technologies. The complexity of the data can be decreased with fewer statistical tests and a lower probability of spurious associations by combining thousands of SNPs into a few hundred haplotype blocks. The presence of strong genomic regions in breeding lines of most crop species facilitates the use of haplotypes to improve the efficiency of genomic and marker-assisted selection. Haplotype-based breeding as a Genomic Assisted Breeding (GAB) approach harnesses the genome sequence data to pinpoint the allelic variation used to hasten the breeding cycle and circumvent the challenges associated with linkage drag. This review article demonstrates ways to identify candidate genes, superior haplotype identification, haplo-pheno analysis, and haplotype-based marker-assisted selection. The crop improvement strategies that utilize superior haplotypes will hasten the breeding progress to safeguard global food security.
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Affiliation(s)
- R C Sivabharathi
- Department of Genetics and Plant breeding, CPBG, Tamil Nadu Agricultural University, Coimbatore 641003, India
| | - Veera Ranjani Rajagopalan
- Department of Plant Biotechnology, Centre for Plant Molecular Biology and Biotechnology, Tamil Nadu Agricultural University, Coimbatore, 641003, India
| | - R Suresh
- Department of Rice, CPBG, Tamil Nadu Agricultural University, Coimbatore 641003, India
| | - M Sudha
- Department of Plant Biotechnology, Centre for Plant Molecular Biology and Biotechnology, Tamil Nadu Agricultural University, Coimbatore, 641003, India.
| | - G Karthikeyan
- Department of Plant Pathology, CPPS, Tamil Nadu Agricultural University, Coimbatore 641003, India
| | - M Jayakanthan
- Department of Plant Molecular Biology and Bioinformatics, Centre for Plant Molecular Biology and Biotechnology, Tamil Nadu Agricultural University, Coimbatore 641003, India
| | - M Raveendran
- Directorate of research, Tamil Nadu Agricultural University, Coimbatore 641003, India.
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Li Y, Qiu S, Zhong W, Li Y, Liu Y, Cheng Y, Liu Y. Association Between DCC Polymorphisms and Susceptibility to Autism Spectrum Disorder. J Autism Dev Disord 2020; 50:3800-3809. [PMID: 32144606 DOI: 10.1007/s10803-020-04417-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Autism spectrum disorder (ASD) represents a group of childhood-onset lifelong neuro-developmental disorders. However, the association between single nucleotide polymorphisms (SNPs) in the deleted in colorectal carcinoma (DCC) gene and ASD susceptibility remains unclear. We investigated the association between ASD susceptibility and seven SNPs in DCC on the basis of a case-control study (231 ASD cases and 242 controls) in Chinese Han. We found that there was no association between ASD susceptibility and the seven SNPs in DCC; however, T-A haplotype (rs2229082-rs2270954), T-A-T-C haplotype (rs2229082-rs2270954-rs2292043-rs2292044), C-G-T-C-T haplotype (rs934345-rs17753970-rs2229082-rs2270954-rs2292043), C-G-T-C-T-G haplotype (rs934345-rs17753970-rs2229082-rs2270954-rs2292043-rs2292044), and G-G-T-C-C-C-C haplotype (rs934345-rs17753970-rs2229082-rs2270954-rs2292043-rs2292044-rs16956878) were associated with ASD susceptibility. Our results indicate that the haplotypes formed on the basis of the seven SNPs in DCC may be implicated in ASD.
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Affiliation(s)
- Yan Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Shuang Qiu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Weijing Zhong
- Chunguang Rehabilitation Hospital, Changchun, 130021, China
| | - Yong Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China
| | - Yunkai Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yi Cheng
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Yawen Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, 130021, China.
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Mishra A, Sundaravadivel P, Tripathi SK, Jha RK, Badrukhiya J, Basak N, Anerao I, Sharma A, Idowu AE, Mishra A, Pandey S, Kumar U, Singh S, Nizamuddin S, Tupperwar NC, Jha AN, Thangaraj K. Variations in macrophage migration inhibitory factor gene are not associated with visceral leishmaniasis in India. J Infect Public Health 2019; 12:380-387. [PMID: 30611734 DOI: 10.1016/j.jiph.2018.12.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 11/24/2018] [Accepted: 12/17/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The host genetic factors play important role in determining the outcome of visceral leishmaniasis (VL). Macrophage migration inhibitory factor (MIF) is an important host cytokine, which is a key regulator of innate immune system. Genetic variants in MIF gene have been found to be associated with several inflammatory and infectious diseases. Role of MIF is well documented in leishmaniasis diseases, including Indian visceral leishmaniasis, where elevated level of serum MIF has been associated with VL phenotypes. However, there was no genetic study to correlate MIF variants in VL, therefore, we aimed to study the possible association of three reported MIF gene variants -794 CATT, -173G > C and non-coding RNA gene LOC284889 in Indian VL phenotype. METHODS Study subjects comprised of 214 VL patients along with ethnically and demographically matched 220 controls from VL endemic regions of Bihar state in India. RESULTS We found no significant difference between cases and controls in allelic, genotypic and haplotype frequency of the markers analysed [-794 CATT repeats (χ2=0.86; p=0.35; OR=0.85; 95% CI=0.61-1.19); -173 G>C polymorphism (χ2=1.11; p=0.29; OR=0.83; 95% CI=0.59-1.16); and LOC284889 (χ2=0.78; p=0.37; OR=0.86; 95% CI=0.61-1.20)]. CONCLUSION Since we did not find any significant differences between case and control groups, we conclude that sequencing of complete MIF gene and extensive study on innate and adaptive immunity genes may help in identifying genetic variations that are associated with VL susceptibility/resistance among Indians.
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Affiliation(s)
- Anshuman Mishra
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India; Vinoba Bhave Research Institute, Allahabad, India; Institute of Advanced Materials, Linkoping, Sweden
| | | | | | - Rajan Kumar Jha
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India
| | | | - Nipa Basak
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India; Academy of Scientific and Innovative Research, India
| | - Isha Anerao
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Akshay Sharma
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Ajayi Ebenezer Idowu
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India; Osun State University, Oshogbo, Nigeria
| | | | | | - Umesh Kumar
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Sakshi Singh
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India
| | | | | | - Aditya Nath Jha
- CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India; Sickle Cell Institute Chhattisgarh, Raipur, India
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Abstract
In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network's collaborative informatics and neuroimaging suite (COINS).
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Carignano HA, Beribe MJ, Caffaro ME, Amadio A, Nani JP, Gutierrez G, Alvarez I, Trono K, Miretti MM, Poli MA. BOLA-DRB3gene polymorphisms influence bovine leukaemia virus infection levels in Holstein and Holstein × Jersey crossbreed dairy cattle. Anim Genet 2017; 48:420-430. [DOI: 10.1111/age.12566] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2017] [Indexed: 12/11/2022]
Affiliation(s)
- H. A. Carignano
- Instituto de Genética; Centro de Investigaciones en Ciencias Veterinarias y Agronómicas - INTA; Hurlingham B1686 Argentina
| | - M. J. Beribe
- Estación Experimental Agropecuaria Pergamino - INTA; Pergamino B2700 Argentina
| | - M. E. Caffaro
- Instituto de Genética; Centro de Investigaciones en Ciencias Veterinarias y Agronómicas - INTA; Hurlingham B1686 Argentina
| | - A. Amadio
- Estación Experimental Agropecuaria Rafaela - INTA; Rafaela S2300 Santa Fe Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Ciudad Autónoma de Buenos Aires C1033AAJ Argentina
| | - J. P. Nani
- Estación Experimental Agropecuaria Rafaela - INTA; Rafaela S2300 Santa Fe Argentina
| | - G. Gutierrez
- Instituto de Virología; Centro de Investigaciones en Ciencias Veterinarias y Agronómicas - INTA; Hurlingham B1686 Argentina
| | - I. Alvarez
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Ciudad Autónoma de Buenos Aires C1033AAJ Argentina
- Instituto de Virología; Centro de Investigaciones en Ciencias Veterinarias y Agronómicas - INTA; Hurlingham B1686 Argentina
| | - K. Trono
- Instituto de Virología; Centro de Investigaciones en Ciencias Veterinarias y Agronómicas - INTA; Hurlingham B1686 Argentina
| | - M. M. Miretti
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Ciudad Autónoma de Buenos Aires C1033AAJ Argentina
- Grupo de Investigación en Genética Aplicada; Instituto de Biología Subtropical (GIGA - IBS); Universidad Nacional de Misiones; Posadas N3300 Argentina
| | - M. A. Poli
- Instituto de Genética; Centro de Investigaciones en Ciencias Veterinarias y Agronómicas - INTA; Hurlingham B1686 Argentina
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Zheng J, Rodriguez S, Laurin C, Baird D, Trela-Larsen L, Erzurumluoglu MA, Zheng Y, White J, Giambartolomei C, Zabaneh D, Morris R, Kumari M, Casas JP, Hingorani AD, UCLEB Consortium, Evans DM, Gaunt TR, Day INM. HAPRAP: a haplotype-based iterative method for statistical fine mapping using GWAS summary statistics. Bioinformatics 2017; 33:79-86. [PMID: 27591082 PMCID: PMC5544112 DOI: 10.1093/bioinformatics/btw565] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 04/29/2016] [Accepted: 08/26/2016] [Indexed: 11/21/2022] Open
Abstract
MOTIVATION Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients ([Formula: see text]) of the variants. However, haplotypes rather than pairwise [Formula: see text], are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel. RESULTS Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N < 2000) while other methods become suboptimal. Moreover, HAPRAP's performance is not affected substantially by single nucleotide polymorphisms (SNPs) with low minor allele frequencies. We applied the method to existing quantitative trait and binary outcome meta-analyses (human height, QTc interval and gallbladder disease); all previous reported association signals were replicated and two additional variants were independently associated with human height. Due to the growing availability of summary level data, the value of HAPRAP is likely to increase markedly for future analyses (e.g. functional prediction and identification of instruments for Mendelian randomization). AVAILABILITY AND IMPLEMENTATION The HAPRAP package and documentation are available at http://apps.biocompute.org.uk/haprap/ CONTACT: : jie.zheng@bristol.ac.uk or tom.gaunt@bristol.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Jie Zheng
- MRC Integrative Epidemiology Unit, School of Social and Community Medicine, Bristol, UK
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Santiago Rodriguez
- MRC Integrative Epidemiology Unit, School of Social and Community Medicine, Bristol, UK
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Charles Laurin
- MRC Integrative Epidemiology Unit, School of Social and Community Medicine, Bristol, UK
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Denis Baird
- MRC Integrative Epidemiology Unit, School of Social and Community Medicine, Bristol, UK
| | - Lea Trela-Larsen
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Mesut A Erzurumluoglu
- School of Social and Community Medicine, University of Bristol, Bristol, UK
- Department of Health Sciences, Genetic Epidemiology Group, University of Leicester, Leicester, UK
| | - Yi Zheng
- Dedman College of Humanities and Sciences, Southern Methodist University, Dallas, TX, USA
| | - Jon White
- Department of Genetics, Environment and Evolution, University College London Genetics Institute, London, UK
| | - Claudia Giambartolomei
- Department of Genetics, Environment and Evolution, University College London Genetics Institute, London, UK
| | - Delilah Zabaneh
- Department of Genetics, Environment and Evolution, University College London Genetics Institute, London, UK
| | - Richard Morris
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Meena Kumari
- Department of Genetics, Environment and Evolution, University College London Genetics Institute, London, UK
| | - Juan P Casas
- Department of Genetics, Environment and Evolution, University College London Genetics Institute, London, UK
- Department of Primary Care & Population Health, University College London, Royal Free Campus, London, UK
| | - Aroon D Hingorani
- Department of Genetics, Environment and Evolution, University College London Genetics Institute, London, UK
- Centre for Clinical Pharmacology, University College London, London, UK, Division of Medicine
| | | | - David M Evans
- MRC Integrative Epidemiology Unit, School of Social and Community Medicine, Bristol, UK
- University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia, QLD
| | - Tom R Gaunt
- MRC Integrative Epidemiology Unit, School of Social and Community Medicine, Bristol, UK
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Ian N M Day
- School of Social and Community Medicine, University of Bristol, Bristol, UK
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Varshney RK, Singh VK, Hickey JM, Xun X, Marshall DF, Wang J, Edwards D, Ribaut JM. Analytical and Decision Support Tools for Genomics-Assisted Breeding. TRENDS IN PLANT SCIENCE 2016; 21:354-363. [PMID: 26651919 DOI: 10.1016/j.tplants.2015.10.018] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 09/01/2015] [Accepted: 10/23/2015] [Indexed: 05/18/2023]
Abstract
To successfully implement genomics-assisted breeding (GAB) in crop improvement programs, efficient and effective analytical and decision support tools (ADSTs) are 'must haves' to evaluate and select plants for developing next-generation crops. Here we review the applications and deployment of appropriate ADSTs for GAB, in the context of next-generation sequencing (NGS), an emerging source of massive genomic information. We discuss suitable software tools and pipelines for marker-based approaches (markers/haplotypes), including large-scale genotypic and phenotypic, data management, and molecular breeding approaches. Although phenotyping remains expensive and time consuming, prediction of allelic effects on phenotypes opens new doors to enhance genetic gain across crop cycles, building on reliable phenotyping approaches and good crop information systems, including pedigree information and target haplotypes.
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Affiliation(s)
- Rajeev K Varshney
- International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), Patancheru, India; School of Plant Biology, University of Western Australia, 35 Stirling Highway, Crawley, Australia.
| | - Vikas K Singh
- International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), Patancheru, India
| | - John M Hickey
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush, UK
| | - Xu Xun
- Beijing Genomics Institute (BGI) Shenzhen, Shenzhen, China
| | - David F Marshall
- Information and Computational Sciences, The James Hutton Institute, Invergowrie, Dundee, UK
| | - Jun Wang
- Beijing Genomics Institute (BGI) Shenzhen, Shenzhen, China
| | - David Edwards
- School of Plant Biology, University of Western Australia, 35 Stirling Highway, Crawley, Australia
| | - Jean-Marcel Ribaut
- Generation Challenge Program/Integrated Breeding Platform, c/o CIMMYT, Apdo. Postal 6-641, DF Mexico, Mexico
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Lim JSL, Sutiman N, Muerdter TE, Singh O, Cheung YB, Ng RCH, Yap YS, Wong NS, Ang PCS, Dent R, Schroth W, Schwab M, Chowbay B. Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients. Br J Clin Pharmacol 2016; 81:1142-52. [PMID: 26799162 DOI: 10.1111/bcp.12886] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 01/05/2016] [Accepted: 01/19/2016] [Indexed: 12/25/2022] Open
Abstract
AIM The aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer. METHODS Sixty-six CYP2C19 polymorphisms were identified in healthy Asians (n = 240), of which 14 were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17. These 17 SNPs were further genotyped in Asian breast cancer patients receiving tamoxifen (n = 201). Steady-state concentrations of tamoxifen and its metabolites were quantified using liquid chromatography–mass spectrometry. Non-parametric tests and regression methods were implemented to evaluate genotypic–phenotypic associations and haplotypic effects of the SNPs. RESULTS CYP2C19 functional polymorphisms and their linked SNPs were not significantly associated with plasma concentrations of tamoxifen and its main metabolites N-desmethyltamoxifen, (Z)-4-hydroxytamoxifen and (Z)-Endoxifen. However, CYP2C19*2 and its seven linked SNPs were significantly associated with lower NorEND concentrations, MRNorEND/NDDM and MRNorEND/(Z)-END. Specifically, patients carrying the CYP2C19*2 variant allele A had significantly lower NorEND concentrations [median (range), GG vs. GA vs. AA: 1.51 (0.38–3.28) vs. 1.28 (0.30–3.36) vs. 1.15 ng ml−1 (0.26–2.45, P = 0.010)] as well as significantly lower MRNorEND/(Z)-END [GG vs. GA vs. AA: 9.40 (3.27–28.35) vs. 8.15 (2.67–18.9) vs. 6.06 (4.47–14.6), P < 0.0001] and MRNorEND/NDDM [GG vs. GA vs. AA: 2.75 (0.62–6.26) vs. 2.43 (0.96–4.18) vs. 1.75 (1.10–2.49), P < 0.00001]. CYP2C19 H2 haplotype, which included CYP2C19*2, was also significantly associated with lower NorEND concentrations (P = 0.0020), MRNorEND/NDDM (P < 0.0001) and MRNorEND/(Z)-END (P < 0.0001), indicating significantly lower formation rates of NorEND. CONCLUSION These data highlight the potential relevance of CYP2C19 pharmacogenetics in influencing NorEND concentrations in tamoxifen-treated patients, which may influence treatment outcomes.
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Affiliation(s)
- Joanne Siok Liu Lim
- Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
| | | | - Thomas E Muerdter
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University Tubingen, Germany
| | - Onkar Singh
- Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore
| | - Yin Bun Cheung
- Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore.,Department of International Health, University of Tampere, Finland
| | | | - Yoon Sim Yap
- Division of Medical Oncology, National Cancer Centre, Singapore
| | - Nan Soon Wong
- OncoCare Cancer Centre, Mount Elizabeth Novena Medical Centre, Singapore
| | | | - Rebecca Dent
- Division of Medical Oncology, National Cancer Centre, Singapore
| | - Werner Schroth
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University Tubingen, Germany
| | - Matthias Schwab
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and Department of Clinical Pharmacology, University Hospital, Tubingen, Germany
| | - Balram Chowbay
- Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.,Clinical Pharmacology, SingHealth, Singapore.,Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore
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Rodríguez-Castillo JA, Arce-Mendoza AY, Quintanilla-Siller A, Rendon A, Salinas-Carmona MC, Rosas-Taraco AG. Possible association of rare polymorphism in the ABCB1 gene with rifampin and ethambutol drug-resistant tuberculosis. Tuberculosis (Edinb) 2015; 95:532-7. [PMID: 26067842 DOI: 10.1016/j.tube.2015.04.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 03/30/2015] [Accepted: 04/08/2015] [Indexed: 01/13/2023]
Abstract
Human P-glycoprotein (P-gp) is a membrane transporter encoded by ABCB1 (also known as MDR1) that plays a critical role in pharmacokinetics of many unrelated drugs. Rifampin (RMP) and ethambutol (ETB), two anti-tubercular agents, are substrates of P-gp. Single nucleotide polymorphisms (SNPs) in ABCB1 have been associated with resistance to several drugs; however, their association with RMP and ETB resistance in tuberculosis patients has not yet been studied. Genotype/allele frequencies in C1236T, G2677T/A and C3435T SNPs of ABCB1 were obtained from 99 tuberculosis patients susceptible or resistant to RMP and ETB (NoRER or RER). 2677G>A allele prevalence was found to be significantly higher in the RER group compared to NoRER (5 resistant vs 2 non-resistant patients, P < 0.01; OR, 11.0; 95% CI, 2.00-56.00). No differences were found in genotype/allele frequencies in C1236T and C3435T SNPs of ABCB1 and resistance to RMP and ETB in tuberculosis patients (P > 0.05). The present study suggests the 2677G>A allele of ABCB1 could be associated with simultaneous resistance to RMP and ETB in pulmonary tuberculosis patients. Further studies with larger sample sizes are needed to confirm this association and explore its nature.
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Affiliation(s)
- José Alberto Rodríguez-Castillo
- Departamento de Inmunología, Facultad de Medicina y Hospital Universitario, Universidad Autonoma de Nuevo León, Monterrey 64460, Mexico
| | - Alma Y Arce-Mendoza
- Departamento de Inmunología, Facultad de Medicina y Hospital Universitario, Universidad Autonoma de Nuevo León, Monterrey 64460, Mexico
| | - Armando Quintanilla-Siller
- Departamento de Inmunología, Facultad de Medicina y Hospital Universitario, Universidad Autonoma de Nuevo León, Monterrey 64460, Mexico
| | - Adrian Rendon
- CIPTIR (Centro de Investigación, Prevención y Tratamiento de Infecciones Respiratorias) Hospital Universitario, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Mario C Salinas-Carmona
- Departamento de Inmunología, Facultad de Medicina y Hospital Universitario, Universidad Autonoma de Nuevo León, Monterrey 64460, Mexico
| | - Adrian G Rosas-Taraco
- Departamento de Inmunología, Facultad de Medicina y Hospital Universitario, Universidad Autonoma de Nuevo León, Monterrey 64460, Mexico.
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Catanzaro D, Rancan S, Orso G, Dall'Acqua S, Brun P, Giron MC, Carrara M, Castagliuolo I, Ragazzi E, Caparrotta L, Montopoli M. Boswellia serrata Preserves Intestinal Epithelial Barrier from Oxidative and Inflammatory Damage. PLoS One 2015. [PMID: 23209806 DOI: 10.1371/journal] [Citation(s) in RCA: 512] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aminosalicylates, corticosteroids and immunosuppressants are currently the therapeutic choices in inflammatory bowel diseases (IBD), however, with limited remission and often serious side effects. Meanwhile complementary and alternative medicine (CAM) use is increasing, particularly herbal medicine. Boswellia serrata is a traditional Ayurvedic remedy with anti-inflammatory properties, of interest for its usefulness in IBDs. The mechanism of this pharmacological potential of Boswellia serrata was investigated in colonic epithelial cell monolayers exposed to H2O2 or INF-γ+TNF-α, chosen as in vitro experimental model of intestinal inflammation. The barrier function was evaluated by the transepithelial electrical resistance (TEER) and paracellular permeability assay, and by the tight junction proteins (zonula occludens-1, ZO-1 and occludin) immunofluorescence. The expression of phosphorylated NF-κB and reactive oxygen species (ROS) generation were determined by immunoblot and cytofluorimetric assay, respectively. Boswellia serrata oleo-gum extract (BSE) and its pure derivative acetyl-11-keto-β-boswellic acid (AKBA), were tested at 0.1-10 μg/ml and 0.027 μg/ml, respectively. BSE and AKBA safety was demonstrated by no alteration of intestinal cell viability and barrier function and integrity biomarkers. H2O2 or INF-γ+TNF-α treatment of Caco-2 cell monolayers significantly reduced TEER, increased paracellular permeability and caused the disassembly of tight junction proteins occludin and ZO-1. BSE and AKBA pretreatment significantly prevented functional and morphological alterations and also the NF-κB phosphorylation induced by the inflammatory stimuli. At the same concentrations BSE and AKBA counteracted the increase of ROS caused by H2O2 exposure. Data showed the positive correlation of the antioxidant activity with the mechanism involved in the physiologic maintenance of the integrity and function of the intestinal epithelium. This study elucidates the pharmacological mechanisms mediated by BSE, in protecting intestinal epithelial barrier from inflammatory damage and supports its use as safe adjuvant in patients affected by IBD.
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Affiliation(s)
- Daniela Catanzaro
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, 35131, Padova, Italy
| | - Serena Rancan
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, 35131, Padova, Italy
| | | | - Stefano Dall'Acqua
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, 35131, Padova, Italy
| | - Paola Brun
- Department of Molecular Medicine, University of Padova, via Gabelli 63, 35121, Padova, Italy
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, 35131, Padova, Italy
| | - Maria Carrara
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, 35131, Padova, Italy
| | - Ignazio Castagliuolo
- Department of Molecular Medicine, University of Padova, via Gabelli 63, 35121, Padova, Italy
| | - Eugenio Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, 35131, Padova, Italy
| | - Laura Caparrotta
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, 35131, Padova, Italy
| | - Monica Montopoli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, 35131, Padova, Italy
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11
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Wen SH, Tsai MY. Haplotype association analysis of combining unrelated case-control and triads with consideration of population stratification. Front Genet 2014; 5:103. [PMID: 24860592 PMCID: PMC4028876 DOI: 10.3389/fgene.2014.00103] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 04/09/2014] [Indexed: 12/27/2022] Open
Abstract
Combining data when data are collected under different study designs, such as family trios and unrelated case-control samples, gains more power and is cost-effective than analyzing each data separately. However, a potential concern is population stratification (PS) among unrelated case-control samples and analyses integrating data should address this confounding effect. In this paper, we develop a simpler method, haplotype generalized linear model (HGLM), that tests and estimates haplotype effects on disease risk and allows for modification against PS for combining data. We proposed to combine information across aggregations of haplotype weighted-counts estimated from population case-control data and trio data separately, and to perform subsequent GLM analysis. Furthermore, we present a framework of analysis of variance based on haplotype weighted-counts for detecting whether it is appropriate to combine two data sources, as well as the modified HGLM with clustering methods for addressing PS. We evaluate the statistical properties in terms of the accuracy, false positive rate (FPR) and empirical power using simulated data with regard to various disease risks, sample sizes, multi-SNP haplotypes and the presence of PS. Our simulation results indicate that HGLM performs comparably well with the likelihood-based haplotype association analysis, particularly when the haplotype effects are moderate, but may not perform well when dealing with lengthy haplotypes for small sample sizes. In the presence of PS, the modified HGLM remains valid and has satisfactory nominal level and small bias. Overall, HGLM appears to be successful in combining data and is simple to implement in standard statistical software.
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Affiliation(s)
- Shu-Hui Wen
- Department of Public Health, College of Medicine, Tzu-Chi University Hualien, Taiwan
| | - Miao-Yu Tsai
- Institute of Statistics and Information Science, National Changhua University of Education Chang-Hua, Taiwan
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12
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Guthridge JM, Lu R, Sun H, Sun C, Wiley GB, Dominguez N, Macwana SR, Lessard CJ, Kim-Howard X, Cobb BL, Kaufman KM, Kelly JA, Langefeld CD, Adler AJ, Harley ITW, Merrill JT, Gilkeson GS, Kamen DL, Niewold TB, Brown EE, Edberg JC, Petri MA, Ramsey-Goldman R, Reveille JD, Vilá LM, Kimberly RP, Freedman BI, Stevens AM, Boackle SA, Criswell LA, Vyse TJ, Behrens TW, Jacob CO, Alarcón-Riquelme ME, Sivils KL, Choi J, Joo YB, Bang SY, Lee HS, Bae SC, Shen N, Qian X, Tsao BP, Scofield RH, Harley JB, Webb CF, Wakeland EK, James JA, Nath SK, Graham RR, Gaffney PM. Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. Am J Hum Genet 2014; 94:586-98. [PMID: 24702955 DOI: 10.1016/j.ajhg.2014.03.008] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 03/12/2014] [Indexed: 11/15/2022] Open
Abstract
Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.
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Affiliation(s)
- Joel M Guthridge
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
| | - Rufei Lu
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Harry Sun
- Immune and Tissue Growth and Repair and Human Genetics Department, Genentech, South San Francisco, CA 94080, USA
| | - Celi Sun
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Graham B Wiley
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Nicolas Dominguez
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Susan R Macwana
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Christopher J Lessard
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Xana Kim-Howard
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Beth L Cobb
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Kenneth M Kaufman
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA
| | - Jennifer A Kelly
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Carl D Langefeld
- Department of Biostatistical Sciences, Wake Forest University, Winston-Salem, NC 27106, USA
| | - Adam J Adler
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Isaac T W Harley
- Division of Molecular Immunology and Graduate Program in Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA
| | - Joan T Merrill
- Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Gary S Gilkeson
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Diane L Kamen
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Timothy B Niewold
- Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN 55902, USA
| | - Elizabeth E Brown
- Department of Epidemiology, University of Alabama-Birmingham, Birmingham, AL 35294, USA; Department of Medicine, University of Alabama-Birmingham, Birmingham, AL 35294, USA
| | - Jeffery C Edberg
- Division of Clinical Immunology and Rheumatology, University of Alabama-Birmingham School of Medicine, Birmingham, AL 35294, USA
| | - Michelle A Petri
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Rosalind Ramsey-Goldman
- Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - John D Reveille
- Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, TX.77030, USA
| | - Luis M Vilá
- Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan 00921, Puerto Rico
| | - Robert P Kimberly
- Division of Clinical Immunology and Rheumatology, University of Alabama-Birmingham School of Medicine, Birmingham, AL 35294, USA
| | - Barry I Freedman
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27106, USA
| | - Anne M Stevens
- Division of Rheumatology, Department of Pediatrics, University of Washington Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Susan A Boackle
- Division of Rheumatology, University of Colorado Denver, Aurora, CO 80045, USA
| | - Lindsey A Criswell
- Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA 94143, USA
| | - Tim J Vyse
- Division of Medicine, Imperial College of London, London SW7 2AZ, UK
| | - Timothy W Behrens
- Immune and Tissue Growth and Repair and Human Genetics Department, Genentech, South San Francisco, CA 94080, USA
| | - Chaim O Jacob
- Department of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Marta E Alarcón-Riquelme
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Centro de Genómica e Investigaciones Oncológicas (GENYO). Pfizer-Universidad de Granada-Junta de Andalucía, Granada 18016, Spain
| | - Kathy L Sivils
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Jiyoung Choi
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea
| | - Young Bin Joo
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea
| | - So-Young Bang
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea
| | - Hye-Soon Lee
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea
| | - Sang-Cheol Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-791, Korea
| | - Nan Shen
- Molecular Rheumatology Laboratory, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiaoxia Qian
- Molecular Rheumatology Laboratory, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Betty P Tsao
- Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - R Hal Scofield
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73105, USA; United States Department of Veterans Affairs Medical Center, Oklahoma City, OK 73105, USA
| | - John B Harley
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA
| | - Carol F Webb
- Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Cell Biology and Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Edward K Wakeland
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA
| | - Judith A James
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73105, USA
| | - Swapan K Nath
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| | - Robert R Graham
- Immune and Tissue Growth and Repair and Human Genetics Department, Genentech, South San Francisco, CA 94080, USA
| | - Patrick M Gaffney
- Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
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13
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Kim-Howard X, Sun C, Molineros JE, Maiti AK, Chandru H, Adler A, Wiley GB, Kaufman KM, Kottyan L, Guthridge JM, Rasmussen A, Kelly J, Sánchez E, Raj P, Li QZ, Bang SY, Lee HS, Kim TH, Kang YM, Suh CH, Chung WT, Park YB, Choe JY, Shim SC, Lee SS, Han BG, Olsen NJ, Karp DR, Moser K, Pons-Estel BA, Wakeland EK, James JA, Harley JB, Bae SC, Gaffney PM, Alarcón-Riquelme M, on behalf of GENLES, Looger LL, Nath SK. Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. Hum Mol Genet 2014; 23:1656-68. [PMID: 24163247 PMCID: PMC3929085 DOI: 10.1093/hmg/ddt532] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Collaborators] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 10/18/2013] [Accepted: 10/22/2013] [Indexed: 12/22/2022] Open
Abstract
Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (P(EA) = 1.01 × 10(-54), PHS = 3.68 × 10(-10), P(AA) = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (PAA = 1.49 × 10(-9)), and rs13306575 in HS and KR (P(HS) = 7.04 × 10(-7), P(KR) = 3.30 × 10(-3)). In KR, a 3-SNP haplotype was significantly associated (P = 4.20 × 10(-7)), implying that SLE predisposing variants were tagged. Significant SNP-SNP interaction (P = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance ('missing heritability') of complex diseases like SLE.
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Affiliation(s)
- Xana Kim-Howard
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Celi Sun
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Julio E. Molineros
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Amit K. Maiti
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Hema Chandru
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Adam Adler
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Graham B. Wiley
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Kenneth M. Kaufman
- Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA
| | - Leah Kottyan
- Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA
| | - Joel M. Guthridge
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Astrid Rasmussen
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Jennifer Kelly
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Elena Sánchez
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Prithvi Raj
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Quan-Zhen Li
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - So-Young Bang
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Hye-Soon Lee
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Tae-Hwan Kim
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Young Mo Kang
- Kyungpook National University Hospital, Daegu, Korea
| | | | | | - Yong-Beom Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | | - Seung Cheol Shim
- Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, Korea
| | - Shin-Seok Lee
- Chonnam National University Hospital, Gwangju, Korea
| | - Bok-Ghee Han
- Korea National Institute of Health, Osong, Korea
| | - Nancy J. Olsen
- Division of Rheumatology, Department of Medicine, Penn State Medical School, PA, USA
| | - David R. Karp
- Rheumatic Diseases Division, Department of Medicine, University of Texas Southwestern Medical Center, TX, USA
| | - Kathy Moser
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | | | - Edward K. Wakeland
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Judith A. James
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - John B. Harley
- Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA
| | - Sang-Cheol Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Patrick M. Gaffney
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Marta Alarcón-Riquelme
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | | | - Loren L. Looger
- Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, VA, USA
| | - Swapan K. Nath
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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Collaborators
Eduardo Acevedo, Eduardo Acevedo, Ignacio García-De La Torre, Marco A Maradiaga-Ceceña, Mario H Cardiel, Jorge A Esquivel-Valerio, Jacqueline Rodriguez-Amado, José Francisco Moctezuma, Pedro Miranda, Carlos Perandones, Buenos Aires, Cecilia Castel, Hugo A Laborde, Paula Alba, Jorge Musuruana, Annelise Goecke, Carola Foster, Lorena Orozco, Vicente Baca,
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14
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Arja C, Ravuri RR, Pulamaghatta VN, Surapaneni KM, Raya P, Adimoolam C, Kanala KR. Genetic determinants of chronic obstructive pulmonary disease in South Indian male smokers. PLoS One 2014; 9:e89957. [PMID: 24587150 PMCID: PMC3933698 DOI: 10.1371/journal.pone.0089957] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 01/25/2014] [Indexed: 11/18/2022] Open
Abstract
The development of chronic obstructive pulmonary disease, upon exposure to tobacco smoke, is the cumulative effect of defects in several genes. With the aim of understanding the genetic structure that is characteristic of our patient population, we selected forty two single nucleotide polymorphisms of twenty genes based on previous studies and genotyped a total of 382 samples, which included 236 patients and 146 controls using Sequenom MassARRAY system. Allele frequencies of rs2276109 (MMP12) and rs1800925 (IL13) differed significantly between patients and controls (p = 0.013 and 0.044 respectively). Genotype analysis showed association of rs2276109 (MMP12) under additive and dominant models (p = 0.017, p = 0.012 respectively), rs1800925 (IL13) under additive model (p = 0.047) and under recessive model, rs1695 (GSTP1; p = 0.034), rs729631, rs975278, rs7583463 (SERPINE2; p = 0.024, 0.024 and 0.012 respectively), rs2568494, rs10851906 (IREB2; p = 0.026 and 0.041 respectively) and rs7671167 (FAM13A; p = 0.029). The minor alleles of rs1695 (G), rs7671167 (T), rs729631 (G), rs975278 (A) and rs7583463 (A) showed significant negative association whereas those of rs2276109 (G), rs2568494 (A), rs10851906 (G) and rs1800469 (T; TGF-β) showed significant positive association with lung function under different genetic models. Haplotypes carrying A allele of rs2276109, G allele of rs1695 showed negative correlation with lung function. Haplotypes carrying major alleles of rs7671167 (C) of FAM13A and rs729631 (C), rs975278 (G), rs7583463 (C) of SERPINE2 had protective effect on lung function. Haplotypes of IREB2 carrying major alleles of rs2568494 (G), rs2656069 (A), rs10851906 (A), rs965604 (C) and minor alleles of rs1964678 (T), rs12593229 (T) showed negative correlation with lung function. In conclusion, our study replicated the results of most of the previous studies. However, the positive correlation between the minor alleles of rs2568494 (A) and rs10851906 (G) of IREB2 and lung function needs further investigation.
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Affiliation(s)
- Cholendra Arja
- Department Of Anthropology, Division Of Human Genetics, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
| | | | | | - Krishna Mohan Surapaneni
- Department Of Biochemistry, Saveetha Medical College & Hospital, Faculty Of Medicine, Saveetha University, Chennai, Tamil Nadu, India
| | - Premanand Raya
- Premananda Allergy And Chest Hospital, Tirupati, Andhra Pradesh, India
| | | | - Kodanda Reddy Kanala
- Department Of Anthropology, Division Of Human Genetics, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
- * E-mail:
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15
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Chew SC, Lim J, Singh O, Chen X, Tan EH, Lee EJD, Chowbay B. Pharmacogenetic effects of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) on docetaxel disposition in Chinese nasopharyngeal cancer patients. Eur J Clin Pharmacol 2013; 70:155-66. [PMID: 24193570 DOI: 10.1007/s00228-013-1596-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 09/30/2013] [Indexed: 11/28/2022]
Abstract
PURPOSE This exploratory study was aimed at elucidating the pharmacogenetics of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) and their implications on docetaxel pharmacokinetics and pharmacodynamics in local Chinese nasopharyngeal cancer patients. METHODS A total of 59 single nucleotide polymorphisms (SNPs), including tag-SNPs and functionally relevant SNPs of the genes encoding these regulatory nuclear receptors (PXR/NR1I2, CAR/NR1I3, RXRα/NR2B1 and HNF4α/NR2A1), were profiled in the patients enrolled in our study by direct sequencing (N = 50). The generalized linear model was employed to estimate the haplotypic effects on the pharmacokinetics and pharmacodynamics of the patients. RESULTS The pharmacokinetic profiles of docetaxel in these patients were characterized by marked interindividual variability, with approximately four- to sixfold variations observed in Cmax, AUC0-∞ and CL. Individual SNP association tests revealed that polymorphisms in NR2B1 and NR2A1 were significantly correlated with altered docetaxel pharmacokinetics. Subsequent haplotype association analysis identified the NR2B1 LD block 2 AG haplotype [*+4458G>A(rs3132291) and *+4988A>G(rs4842198)] to be significantly associated with altered pharmacokinetics, in which patients carrying two copies of the AG haplotype had approximately a 20 % decreased Cmax and AUC0-∞ and a 21 % increased CL compared to those who carried only one copy or no copies of the haplotype. A number of SNPs in NR1I2, NR1I3, NR2B1 and NR2A1 were also associated with a significant decrease in blood counts from baseline. No haplotype was found to exert any effects on the pharmacodynamics parameters. CONCLUSIONS The present exploratory study identified several SNPs in the genes encoding regulatory nuclear receptors which may account for the interpatient variability in docetaxel pharmacokinetics and pharmacodynamics. These findings highlight the important role of regulatory nuclear receptors on the disposition of docetaxel.
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Affiliation(s)
- Sin-Chi Chew
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore, Singapore, 117597
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Liu Y, Li X, Liu Z, Chen L, Ng MK. Construction and analysis of single nucleotide polymorphism-single nucleotide polymorphism interaction networks. IET Syst Biol 2013; 7:170-81. [PMID: 24067417 PMCID: PMC8687305 DOI: 10.1049/iet-syb.2012.0055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 02/17/2013] [Accepted: 03/25/2013] [Indexed: 11/19/2022] Open
Abstract
The study of gene regulatory network and protein-protein interaction network is believed to be fundamental to the understanding of molecular processes and functions in systems biology. In this study, the authors are interested in single nucleotide polymorphism (SNP) level and construct SNP-SNP interaction network to understand genetic characters and pathogenetic mechanisms of complex diseases. The authors employ existing methods to mine, model and evaluate a SNP sub-network from SNP-SNP interactions. In the study, the authors employ the two SNP datasets: Parkinson disease and coronary artery disease to demonstrate the procedure of construction and analysis of SNP-SNP interaction networks. Experimental results are reported to demonstrate the procedure of construction and analysis of such SNP-SNP interaction networks can recover some existing biological results and related disease genes.
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Affiliation(s)
- Yang Liu
- Bioinformatics ProgramBoston University24 Cummington StreetBostonMA02215USA
| | - Xutao Li
- Department of Computer ScienceShenzhen Graduate School, Harbin Institute of TechnologyPeople's Republic of China
| | - Zhiping Liu
- Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesShanghaiPeople's Republic of China
| | - Luonan Chen
- Shanghai Institutes for Biological Sciences, Chinese Academy of SciencesShanghaiPeople's Republic of China
| | - Michael K. Ng
- Department of MathematicsHong Kong Baptist UniversityKowloon TongHong Kong
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Jha AN, Sundaravadivel P, Pati SS, Patra PK, Thangaraj K. Variations in ncRNA gene LOC284889 and MIF-794CATT repeats are associated with malaria susceptibility in Indian populations. Malar J 2013; 12:345. [PMID: 24066864 PMCID: PMC3849407 DOI: 10.1186/1475-2875-12-345] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 09/15/2013] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND There are increasing evidences on the role of non-coding RNA (ncRNA) as key regulator of cellular homeostasis. LOC284889 is an uncharacterized ncRNA gene on reverse strand to MIF mapped to 22q11.23. MIF, a lymphokine, regulates innate immune response by up-regulating the expression of TLR4, suppressing the p53 activity and has been shown to be involved in malaria pathogenesis. METHODS In this study, the possible effect of MIF variations on malaria susceptibility was investigated by re-sequencing the complete MIF gene along with 1 kb each of 5' and 3' region in 425 individuals from malaria endemic regions of the Orissa and Chhattisgarh states of India. The subjects comprised of 160 cases of severe malaria, 101 of mild malaria and 164 ethnically matched asymptomatic controls. Data were statistically compared between cases and controls for their possible association with Plasmodium falciparum malarial outcome. RESULTS It is the first study, which shows that the allele A (rs34383331T > A) in ncRNA is significantly associated with increased risk to P. falciparum malaria [severe: OR = 2.08, p = 0.002 and mild: OR = 2.09, P = 0.005]. In addition, it has been observed that the higher MIF-794CATT repeats (>5) increases malaria risk (OR = 1.61, p = 0.01). Further, diplotype (MIF-794CATT and rs34383331T > A) 5 T confers protection to severe malaria (OR = 0.55, p = 0.002) while 6A (OR = 3.07, p = 0.001) increases malaria risk. CONCLUSIONS These findings support the involvement of ncRNA in malarial pathogenesis and further emphasize the complex genetic regulation of malaria outcome. In addition, the study shows that the higher MIF-794CATT repeats (>5) is a risk factor for severe malaria. The study would help in identifying people who are at higher risk to malaria and adapt strategies for prevention and treatment.
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Affiliation(s)
- Aditya N Jha
- CSIR - Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.
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18
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Namjou B, Kim-Howard X, Sun C, Adler A, Chung SA, Kaufman KM, Kelly JA, Glenn SB, Guthridge JM, Scofield RH, Kimberly RP, Brown EE, Alarcón GS, Edberg JC, Kim JH, Choi J, Ramsey-Goldman R, Petri MA, Reveille JD, Vilá LM, Boackle SA, Freedman BI, Tsao BP, Langefeld CD, Vyse TJ, Jacob CO, Pons-Estel B, on behalf of the Argentine Collaborative Group, Niewold TB, Moser Sivils KL, Merrill JT, Anaya JM, Gilkeson GS, Gaffney PM, Bae SC, Alarcón-Riquelme ME, on behalf of the BIOLUPUS and GENLES networks, Harley JB, Criswell LA, James JA, Nath SK. PTPN22 association in systemic lupus erythematosus (SLE) with respect to individual ancestry and clinical sub-phenotypes. PLoS One 2013; 8:e69404. [PMID: 23950893 PMCID: PMC3737240 DOI: 10.1371/journal.pone.0069404] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Accepted: 06/09/2013] [Indexed: 12/20/2022] Open
Abstract
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7 × 10(-9), OR = 1.40 (95% CI = 1.25-1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67-0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7 × 10(-5), OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.
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Affiliation(s)
- Bahram Namjou
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
| | - Xana Kim-Howard
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Celi Sun
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Adam Adler
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Sharon A. Chung
- Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
| | - Kenneth M. Kaufman
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
- US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, United States of America
| | - Jennifer A. Kelly
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Stuart B. Glenn
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Joel M. Guthridge
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Robert H. Scofield
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Robert P. Kimberly
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Elizabeth E. Brown
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Graciela S. Alarcón
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jeffrey C. Edberg
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jae-Hoon Kim
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Jiyoung Choi
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Rosalind Ramsey-Goldman
- Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Michelle A. Petri
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - John D. Reveille
- Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
| | - Luis M. Vilá
- Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Susan A. Boackle
- Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Barry I. Freedman
- Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest University Health Sciences, Wake Forest, North Carolina, United States of America
| | - Betty P. Tsao
- Division of Rheumatology, University of California Los Angeles, Los Angeles, California, United States of America
| | - Carl D. Langefeld
- Department of Biostatistical Sciences, Wake Forest University Health Sciences, Wake Forest, North Carolina, United States of America
| | - Timothy J. Vyse
- Divisions of Genetics and Molecular Medicine and Immunology, King's College London, London, United Kingdom
| | - Chaim O. Jacob
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | | | | | - Timothy B. Niewold
- Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Kathy L. Moser Sivils
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Joan T. Merrill
- Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Juan-Manuel Anaya
- Center for Autoimmune Diseases Research, Universidad del Rosario, Bogota, Colombia
| | - Gary S. Gilkeson
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Patrick M. Gaffney
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Sang-Cheol Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Marta E. Alarcón-Riquelme
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
- Centro de Genómica e Investigación Oncológica (GENYO) Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain
| | | | - John B. Harley
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
- US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, United States of America
| | - Lindsey A. Criswell
- Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
| | - Judith A. James
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Swapan K. Nath
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
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Wu X, Kondragunta V, Kornman KS, Wang HY, Duff GW, Renner JB, Jordan JM. IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort. Osteoarthritis Cartilage 2013; 21:930-8. [PMID: 23602982 PMCID: PMC3725144 DOI: 10.1016/j.joca.2013.04.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 03/25/2013] [Accepted: 04/06/2013] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Within the interleukin-1 (IL-1) cytokine family, IL-1 receptor antagonist (IL1RN) gene variants have been associated with radiological severity of knee osteoarthritis (OA) in cross-sectional studies. The present study tested the relation between IL1RN gene variants and progression of knee OA assessed radiographically by change in Kellgren-Lawrence (KL) score over time. DESIGN 1153 Caucasian adults (age range: 44-89) from the Johnson County Osteoarthritis Project were evaluated for unequivocal radiographic evidence of knee OA at baseline, defined as KL score ≥2, and were re-examined after 4-11 years for radiographic changes typical of OA progression. IL1RN gene variants were tested for association with OA progression and for potential interaction with body mass index (BMI). Other IL-1 gene variations were tested for association with OA progression as a secondary objective. RESULTS Of 154 subjects with OA at baseline, 88 showed progression at follow-up. Seven IL1RN single nucleotide polymorphisms (SNPs) and one IL-1 receptor SNP were associated with progression. Four IL1RN haplotypes, each occurring in >5% of this population, showed different relationships with progression, including one (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/rs579543/rs315952/rs9005/rs315943/rs1374281; ACAGATACTGCC) associated with increased progression [odds ratio (OR) 1.91 (95%CI 1.16-3.15); P = 0.012]. Haplotypes associated with progression by KL score were also associated with categorical change in joint space narrowing. BMI was associated with OA progression in subjects carrying a specific IL1RN haplotype, but not in subjects without that haplotype. CONCLUSION A significantly greater likelihood of radiological progression of knee OA was associated with a commonly occurring IL1RN haplotype that could be tagged by three IL1RN SNPs (rs419598, rs9005, rs315943). Interactions were also observed between IL1RN gene variants and BMI relative to OA progression. This suggests that IL1RN gene markers may be useful in stratifying patients for medical management and drug development.
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Affiliation(s)
- X Wu
- Interleukin Genetics, Waltham, MA 02452, USA.
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20
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Diaz-Gallo LM, Simeon CP, Broen JC, Ortego-Centeno N, Beretta L, Vonk MC, Carreira PE, Vargas S, Román-Ivorra JA, González-Gay MA, Tolosa C, López-Longo FJ, Espinosa G, Vicente EF, Hesselstrand R, Riemekasten G, Witte T, Distler JHW, Voskuyl AE, Schuerwegh AJ, Shiels PG, Nordin A, Padyukov L, Hoffmann-Vold AM, Scorza R, Lunardi C, Airo P, van Laar JM, Hunzelmann N, Gathof BS, Kreuter A, Herrick A, Worthington J, Denton CP, Zhou X, Arnett FC, Fonseca C, Koeleman BPC, Assasi S, Radstake TRDJ, Mayes MD, Martín J. Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility. Ann Rheum Dis 2013; 72:1233-8. [PMID: 23172754 PMCID: PMC3887514 DOI: 10.1136/annrheumdis-2012-202357] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). PATIENTS AND METHODS The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. RESULTS We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively). CONCLUSIONS These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
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Affiliation(s)
- Lina-Marcela Diaz-Gallo
- Cellular Biology and Immunology Department, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain.
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Kim S, Park K, Shin C, Cho NH, Ko JJ, Koh I, Kwack K. Diplotyper: diplotype-based association analysis. BMC Med Genomics 2013; 6 Suppl 2:S5. [PMID: 23819435 PMCID: PMC3654869 DOI: 10.1186/1755-8794-6-s2-s5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background It was previously reported that an association analysis based on haplotype clusters increased power over single-locus tests, and that another association test based on diplotype trend regression analysis outperformed other, more common association approaches. We suggest a novel algorithm to combine haplotype cluster- and diplotype-based analyses. Methods Diplotyper combines a novel algorithm designed to cluster haplotypes of interest from a given set of haplotypes with two existing tools: Haploview, for analyses of linkage disequilibrium blocks and haplotypes, and PLINK, to generate all possible diplotypes from given genotypes of samples and calculate linear or logistic regression. In addition, procedures for generating all possible diplotypes from the haplotype clusters and transforming these diplotypes into PLINK formats were implemented. Results Diplotyper is a fully automated tool for performing association analysis based on diplotypes in a population. Diplotyper was tested through association analysis of hepatic lipase (LIPC) gene polymorphisms or diplotypes and levels of high-density lipoprotein (HDL) cholesterol. Conclusions Diplotyper is useful for identifying more precise and distinct signals over single-locus tests.
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Affiliation(s)
- Sunshin Kim
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea
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22
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Molineros JE, Maiti AK, Sun C, Looger LL, Han S, Kim-Howard X, Glenn S, Adler A, Kelly JA, Niewold TB, Gilkeson GS, Brown EE, Alarcón GS, Edberg JC, Petri M, Ramsey-Goldman R, Reveille JD, Vilá LM, Freedman BI, Tsao BP, Criswell LA, Jacob CO, Moore JH, Vyse TJ, Langefeld CL, Guthridge JM, Gaffney PM, Moser KL, Scofield RH, Alarcón-Riquelme ME, on behalf of the BIOLUPUS Network, Williams SM, Merrill JT, James JA, Kaufman KM, Kimberly RP, Harley JB, Nath SK. Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. PLoS Genet 2013; 9:e1003222. [PMID: 23441136 PMCID: PMC3575474 DOI: 10.1371/journal.pgen.1003222] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 11/20/2012] [Indexed: 01/22/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
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Affiliation(s)
- Julio E. Molineros
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Amit K. Maiti
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Celi Sun
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Loren L. Looger
- Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, United States of America
| | - Shizhong Han
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
- Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Xana Kim-Howard
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Stuart Glenn
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Adam Adler
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Jennifer A. Kelly
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Timothy B. Niewold
- Mayo Clinic, Division of Rheumatology and Department of Immunology, Rochester, Minnesota, United States of America
| | - Gary S. Gilkeson
- Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Elizabeth E. Brown
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Graciela S. Alarcón
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jeffrey C. Edberg
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Michelle Petri
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Rosalind Ramsey-Goldman
- Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - John D. Reveille
- Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
| | - Luis M. Vilá
- Department of Medicine, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Barry I. Freedman
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Betty P. Tsao
- Division of Rheumatology, Department of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Lindsey A. Criswell
- Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, California, United States of America
| | - Chaim O. Jacob
- Department of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Jason H. Moore
- Department of Genetics, Dartmouth Medical School, Lebanon, New Hampshire, United States of America
| | - Timothy J. Vyse
- Division of Genetics and Molecular Medicine, King's College London, London, United Kingdom
- Division of Immunology, Infection and Inflammatory Diseases, Kings College London, London, United Kingdom
| | - Carl L. Langefeld
- Department of Biostatistical Sciences, Wake Forest University Health Sciences, Wake Forest, North Carolina, United States of America
| | - Joel M. Guthridge
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Patrick M. Gaffney
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Kathy L. Moser
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
- College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - R. Hal Scofield
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Marta E. Alarcón-Riquelme
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
- Centro de Genómica e Investigación Oncológica (GENyO)–Pfizer/Universidad de Granada/Junta de Andalucía, Granada, Spain
| | | | - Scott M. Williams
- Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, United States of America
| | - Joan T. Merrill
- Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Judith A. James
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
- College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Kenneth M. Kaufman
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
| | - Robert P. Kimberly
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - John B. Harley
- Cincinnati Children's Hospital Medical Center and the U.S. Department of Veterans Affairs Medical Center, Cincinnati, Ohio, United States of America
| | - Swapan K. Nath
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
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Liu K, Chen LJ, Tam POS, Shi Y, Lai TYY, Liu DTL, Chiang SWY, Yang M, Yang Z, Pang CP. Associations of the C2-CFB-RDBP-SKIV2L locus with age-related macular degeneration and polypoidal choroidal vasculopathy. Ophthalmology 2012; 120:837-43. [PMID: 23260260 DOI: 10.1016/j.ophtha.2012.10.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Revised: 10/01/2012] [Accepted: 10/01/2012] [Indexed: 10/27/2022] Open
Abstract
PURPOSE To investigate the associations of the C2-CFB-RDBP-SKIV2L region with neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). DESIGN Cross-sectional, case-control association study. PARTICIPANTS A Chinese case-control group of 200 neovascular AMD patients, 233 PCV patients, and 275 control subjects. METHODS An association analysis was performed of the C2-CFB-RDBP-SKIV2L locus with both neovascular AMD and PCV in a Chinese population using 19 haplotype-tagging single nucleotide polymorphisms (SNPs) and 6 previously reported SNPs across the C2-CFB-RDBP-SKIV2L region. All SNPs were genotyped using the TaqMan genotyping technology (TaqMan; Applied Biosystems [ABI], Foster City, CA). MAIN OUTCOME MEASURES Allele and haplotype frequencies of the SNPs in the C2-CFB-RDBP-SKIV2L region. RESULTS The SKIV2L SNPs rs429608 and rs453821 were significantly associated with neovascular AMD (P = 7.39 × 10(-5); odds ratio [OR], 0.22; 95% confidence interval [CI], 0.10-0.50; and P = 0.001; OR, 0.38; 95% CI, 0.21-0.70, respectively), whereas borderline associations were detected for C2 rs547154 (P = 0.002) and RDBP rs760070 (P = 0.003). Conditional haplotype analysis revealed that SKIV2L rs429608 could account fully for the global haplotype association identified in this region. The association of SKIV2L rs429608 with neovascular AMD remained significant after adjusting for CFH rs800292 and HTRA1 rs11200638. No individual SNP or haplotype was associated significantly with PCV. CONCLUSIONS In this concurrent investigation of the associations of the entire C2-CFB-RDBP-SKIV2L region with neovascular AMD and PCV, the results suggested that SKIV2L is a likely causal gene for neovascular AMD, conferring a significant protective effect independent of CFH and HTRA1. These data do not support a significant role of this region in PCV, suggesting different molecular mechanisms between neovascular AMD and PCV.
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Affiliation(s)
- Ke Liu
- Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong, China
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Singh O, Chan JY, Lin K, Heng CCT, Chowbay B. SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia. PLoS One 2012; 7:e51771. [PMID: 23272163 PMCID: PMC3525665 DOI: 10.1371/journal.pone.0051771] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 11/07/2012] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5 3 genetic polymorphisms on imatinib mesylate (IM) pharmacokinetics in Asian patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each) and CML patients (n = 38) were enrolled in a prospective pharmacogenetics study. Imatinib trough (C(0h)) and clearance (CL) were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM) to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test. RESULTS Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T), to be significantly associated with IM clearance (p = 0.013). Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (10(-2) L/hr/mg): CAC vs AGT: 4.03 vs 3.16, p = 0.017; CAC vs CGC: 4.03 vs 3.15, p = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C(0h) than patients carrying 0 or 1 copy [CL (10(-2) L/hr/mg): 2.19 vs 3.29, p = 0.026; C(0h) (10(-6) 1/ml): 4.76 vs 3.17, p = 0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C(0h) (p = 0.002 and 0.009, respectively). CONCLUSION This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- Adolescent
- Adult
- Aged
- Antineoplastic Agents/administration & dosage
- Antineoplastic Agents/pharmacokinetics
- Antineoplastic Agents/therapeutic use
- Asian People/genetics
- Benzamides/administration & dosage
- Benzamides/pharmacokinetics
- Benzamides/therapeutic use
- Female
- Haplotypes
- Humans
- Imatinib Mesylate
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Linkage Disequilibrium
- Malaysia/ethnology
- Male
- Middle Aged
- Organic Cation Transporter 1/genetics
- Pharmacogenetics
- Piperazines/administration & dosage
- Piperazines/pharmacokinetics
- Piperazines/therapeutic use
- Polymorphism, Single Nucleotide
- Protein Kinase Inhibitors/administration & dosage
- Protein Kinase Inhibitors/pharmacokinetics
- Protein Kinase Inhibitors/therapeutic use
- Pyrimidines/administration & dosage
- Pyrimidines/pharmacokinetics
- Pyrimidines/therapeutic use
- Treatment Outcome
- Young Adult
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Affiliation(s)
- Onkar Singh
- Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Jason Yongsheng Chan
- Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Keegan Lin
- Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Balram Chowbay
- Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore
- * E-mail:
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Sehgal M, Singh TR. Identification and analysis of biomarkers for mismatch repair proteins: A bioinformatic approach. J Nat Sci Biol Med 2012; 3:139-46. [PMID: 23225975 PMCID: PMC3510907 DOI: 10.4103/0976-9668.101887] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION Mismatch repair is a highly conserved process from prokaryotes to eukaryotes. Defects in mismatch repair can lead to mutations in human homologues of the Mut proteins and affect genomic stability which can result in microsatellite instability (MI). MI is implicated in most human cancers and majority of hereditary nonpolyposis colorectal cancers (HNPCCs) are attributed to defects in MLH1. MATERIALS AND METHODS In our study we analyzed MLH1 protein and the associated nucleotide and other protein sequences. The protein sequences involved in mismatch repair in different organisms have been found to be evolutionary related. Several other related proteins to MLH1 have also been identified through protein-protein interactions. All associated proteins are either mismatch repair proteins or associated with MLH1 in various pathways. Pathways information was also confirmed through MMR and other pathways in KEGG. QSite Finder showed that the active site of MLH1 protein involves residues from the conserved pattern and is involved in ligand-protein interactions and could be a useful site. To analyze linkage disequilibrium (LD) and common haplotype patterns in disease association, we performed statistical haplotype analysis on HapMap genotype data of SNPs genotyped in population CEU on chromosome 3 for MLH1. RESULTS Various markers have been found and LD plot was also generated. Two distinct blocks have been identified in LD plot which can be independent region of action, and there is involvement of 7 and 17 markers in first and second blocks, respectively. CONCLUSION Overall correlation of 0.95 has been found among all interactions of genotyped SNPs which is significant.
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Affiliation(s)
- Manika Sehgal
- Department of Biotechnology and Bioinformatics, Jaypee University of Information and Technology, Waknaghat, Solan, H.P., India
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Wang G, Watanabe M, Imai Y, Hara K, Manabe I, Maemura K, Horikoshi M, Ozeki A, Itoh C, Sugiyama T, Kadowaki T, Yamazaki T, Nagai R. Associations of variations in the MRF2/ARID5B gene with susceptibility to type 2 diabetes in the Japanese population. J Hum Genet 2012; 57:727-33. [DOI: 10.1038/jhg.2012.101] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Li MX, Kwan J, Sham P. HYST: a hybrid set-based test for genome-wide association studies, with application to protein-protein interaction-based association analysis. Am J Hum Genet 2012; 91:478-88. [PMID: 22958900 DOI: 10.1016/j.ajhg.2012.08.004] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 04/30/2012] [Accepted: 08/07/2012] [Indexed: 11/25/2022] Open
Abstract
The extended Simes' test (known as GATES) and scaled chi-square test were proposed to combine a set of dependent genome-wide association signals at multiple single-nucleotide polymorphisms (SNPs) for assessing the overall significance of association at the gene or pathway levels. The two tests use different strategies to combine association p values and can outperform each other when the number of and linkage disequilibrium between SNPs vary. In this paper, we introduce a hybrid set-based test (HYST) combining the two tests for genome-wide association studies (GWASs). We describe how HYST can be used to evaluate statistical significance for association at the protein-protein interaction (PPI) level in order to increase power for detecting disease-susceptibility genes of moderate effect size. Computer simulations demonstrated that HYST had a reasonable type 1 error rate and was generally more powerful than its parents and other alternative tests to detect a PPI pair where both genes are associated with the disease of interest. We applied the method to three complex disease GWAS data sets in the public domain; the method detected a number of highly connected significant PPI pairs involving multiple confirmed disease-susceptibility genes not found in the SNP- and gene-based association analyses. These results indicate that HYST can be effectively used to examine a collection of predefined SNP sets based on prior biological knowledge for revealing additional disease-predisposing genes of modest effects in GWASs.
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Chew SC, Sandanaraj E, Singh O, Chen X, Tan EH, Lim WT, Lee EJD, Chowbay B. Influence of SLCO1B3 haplotype-tag SNPs on docetaxel disposition in Chinese nasopharyngeal cancer patients. Br J Clin Pharmacol 2012; 73:606-18. [PMID: 21995462 DOI: 10.1111/j.1365-2125.2011.04123.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT SLCO1B3 is an influx transporter located at the hepatocyte basolateral membrane and it is involved in the uptake of a broad range of drug substrates including docetaxel. The pharmacogenetics of SLCO1B3 is not well characterized and previous in vivo and in vitro studies reported conflicting results with regards to the functional effects of the limited number of SLCO1B3 polymorphisms that were studied. Docetaxel displays a wide interindividual variability in its pharmacokinetics and pharmacodynamics and an understanding of SLCO1B3 pharmacogenetics might provide clinical benefits in guiding docetaxel dosing. WHAT THIS STUDY ADDS The SLCO1B3 gene was comprehensively screened in the local healthy Asian populations (n= 168). A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15 haplotype-tag SNPs (htSNPs) were identified. These htSNPs were profiled in a cohort of Chinese nasopharyngeal cancer (NPC) patients (n= 50). Genotypic-phenotypic analysis showed that a haplotypic construct comprising of four variants [IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA] was the critical determinant of docetaxel disposition. This study suggests that the comprehensive screening and haplotypic linkage analysis of SLCO1B3 can better elucidate its pharmacogenetic effects on interpatient variability of docetaxel and other putative drug substrates. Further studies are warranted in cancer patients belonging to other ethnic groups. AIMS To completely screen the SLCO1B3 gene in three distinct healthy Asian populations (Chinese, Malay and Indian, n= 168) and investigate the influence of haplotype-tag SNPs (htSNPs) on docetaxel disposition in 50 nasopharyngeal carcinoma patients. METHODS Genomic DNA of individuals was screened for SLCO1B3 polymorphisms by direct sequencing. htSNPs were derived based on the sequence clustering algorithm and profiled in the patients. Population based genetic association analysis was performed using Haplostats package implemented in R and PLINK. RESULTS A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15-htSNPs were identified. The SLCO1B3 haplotypic region comprising seven htSNPs was found to be significantly associated with docetaxel clearance (P= 0.003). Conditional haplotype analyses revealed that the haplotypic constructs comprising the IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA polymorphisms were critical determinants of variability in docetaxel disposition [clearance and area under the plasma concentration-time curve (AUC(0,∞)): r(2) = 29% and 22%, respectively]. Patients harbouring the GAG*347insA haplotype were significantly associated with a 30% decrease in clearance and a 40% increase in AUC(0,∞) of docetaxel compared with patients harbouring the reference haplotype, GGA*347wt (P= 0.025 and 0.018, respectively). In contrast, a 50% higher clearance was observed in patients carrying the GAG*347wt haplotype compared with those with the reference haplotype (P= 0.002). The functional SLCO1B3 haplotypic constructs included the widely studied Met233Ile variant and *347_*348insA located in the putative miR-890 binding site in the 3'-untranslated region which may influence the transport characteristics of SLCO1B3. CONCLUSIONS This study highlights the importance of SLCO1B3 polymorphic variations in influencing docetaxel disposition in nasopharyngeal carcinoma patients.
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Affiliation(s)
- Sin Chi Chew
- Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore
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Karinen S, Saarinen S, Lehtonen R, Rastas P, Vahteristo P, Aaltonen LA, Hautaniemi S. Rule-based induction method for haplotype comparison and identification of candidate disease loci. Genome Med 2012; 4:21. [PMID: 22429919 PMCID: PMC3446271 DOI: 10.1186/gm320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Accepted: 03/19/2012] [Indexed: 11/21/2022] Open
Abstract
There is a need for methods that are able to identify rare variants that cause low or moderate penetrance disease susceptibility. To answer this need, we introduce a rule-based haplotype comparison method, Haplous, which identifies haplotypes within multiple samples from phased genotype data and compares them within and between sample groups. We demonstrate that Haplous is able to accurately identify haplotypes that are identical by descent, exclude common haplotypes in the studied population and select rare haplotypes from the data. Our analysis of three families with multiple individuals affected by lymphoma identified several interesting haplotypes shared by distantly related patients.
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Affiliation(s)
- Sirkku Karinen
- Research Programs Unit, Genome-Scale Biology, and Institute of Biomedicine, Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, Helsinki, FIN-00014, Finland.
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Namjou B, Choi CB, Harley ITW, Alarcón-Riquelme ME, Kelly JA, Glenn SB, Ojwang JO, Adler A, Kim K, Gallant CJ, Boackle SA, Criswell LA, Kimberly RP, Brown EE, Edberg J, Alarcón GS, Stevens AM, Jacob CO, Gilkeson GS, Kamen DL, Tsao BP, Anaya JM, Kim EM, Park SY, Sung YK, Guthridge JM, Merrill JT, Petri M, Ramsey-Goldman R, Vilá LM, Niewold TB, Martin J, Pons-Estel BA, Vyse TJ, Freedman BI, Moser KL, Gaffney PM, Williams AH, Comeau ME, Reveille JD, Kang C, James JA, Scofield RH, Langefeld CD, Kaufman KM, Harley JB, Bae SC. Evaluation of TRAF6 in a large multiancestral lupus cohort. ACTA ACUST UNITED AC 2012; 64:1960-9. [PMID: 22231568 DOI: 10.1002/art.34361] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. METHODS Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. RESULTS Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10(-5) and P = 4.73 × 10(-5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r(2) = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10(-6) , OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. CONCLUSION Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
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Affiliation(s)
- Bahram Namjou
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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Clarke TK, Dempster E, Docherty SJ, Desrivieres S, Lourdsamy A, Wodarz N, Ridinger M, Maier W, Rietschel M, Schumann G. Multiple polymorphisms in genes of the adrenergic stress system confer vulnerability to alcohol abuse. Addict Biol 2012; 17:202-8. [PMID: 21070505 DOI: 10.1111/j.1369-1600.2010.00263.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Environmental factors such as stress influence both the predisposition to and development of alcoholism, as well as have significant implications for alcoholism relapse. One predominant biological response to acute stress is the release of norepinephrine, which activates the peripheral stress response and also the hypothalamic-pituitary-adrenal axis. We aimed to examine the role of two genes of the adrenergic system (SLC6A2 and ADRA2A) in alcoholism by genotyping 21 SNPs in 785 adult alcohol-dependent patients and 1237 controls. Two single nucleotide polymorphisms (SNP) (rs36020 and rs36029) in SLC6A2 were significantly associated with alcoholism [false discovery rate corrected P-value (FDR) P = 0.007]. Two SNPs in ADRA2A (rs521674 and rs602618) were associated with a positive family history of alcoholism (FDR P ≤ 0.05). A combined SNP-set analysis was also carried out to determine the risk of harbouring multiple alcohol risk alleles across SLC6A2 and ADRA2A. Logistic regression analysis revealed that an increase in the number of alcohol risk alleles increased the risk for alcoholism (P = 0.000567, odds ratio = 1.75, 95% confidence interval 1.26-2.44). A three-SNP haplotype consisting of rs187715, rs36020 and rs40147 alleles, AGC, was also found, which was significantly over-represented in cases compared with controls (61% versus 56%). We therefore demonstrate an association of SLC6A2 and ADRA2A with adult alcoholism. These data confirm the relevance of the adrenergic stress system when considering genetic predisposition to alcohol dependence and suggest that SLC6A2 and ADRA2A should be studied in additional alcohol-dependent cohorts.
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Affiliation(s)
- Toni-Kim Clarke
- MRC-SGDP Centre, Institute of Psychiatry, King's College, UK.
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IL-1 receptor-associated kinase 3 gene (IRAK3) variants associate with asthma in a replication study in the Spanish population. J Allergy Clin Immunol 2011; 129:573-5, 575.e1-10. [PMID: 22070913 DOI: 10.1016/j.jaci.2011.10.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Revised: 09/22/2011] [Accepted: 10/04/2011] [Indexed: 11/21/2022]
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Lu KC, Yang HY, Lin YF, Kao SY, Lai CH, Chu CM, Wu CC, Su SL. The T-1237C polymorphism of the Toll-like receptor-9 gene is associated with chronic kidney disease in a Han Chinese population. TOHOKU J EXP MED 2011; 225:109-116. [PMID: 21908957 DOI: 10.1620/tjem.225.109] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. As inflammatory processes and genetic factors are involved in the pathogenesis of CKD, we have investigated the potential genetic contribution of Toll-like receptor (TLR) gene polymorphisms in CKD. In a case-control association study, 149 CKD patients and 429 healthy controls were genotyped by real-time polymerase chain reaction. CKD patients were defined as kidney damage (albuminuria, proteinuria or hematuria) or glomerular filtration rate < 60 ml/min/1.73 m(2) for 3 months or more. Single nucleotide polymorphisms (SNPs) at TLR-2 G2408A, TLR-4 A12874G and C13174T, and TLR-9 T-1237C, T-1486C, and G1635A were assessed, and linkage disequilibrium calculations and haplotype association analysis were undertaken. The functions of TLR-9 have been documented to recognize the viral and bacterial CpG DNA sequences, whereas detects microbe-derived peptidoglycan and lipopeptides and TLR-4 binds lipopolysaccharides. SNPs within the TLR genes may influence promoter activity, mRNA conformation and subcellular localization, and/or protein structure and function. Our results show that only the TLR-9 T-1237C and G1635A gene polymorphisms demonstrate an association with CKD (p = 0.002 and p = 0.04, respectively). The TLR-9 TCA haplotype at T-1237C, T-1486C, and G1635A was associated with a lower risk of CKD, whereas the TTA haplotype was associated with a higher risk of CKD. In the Han Chinese population, those who carry the C and A alleles at SNPs T-1237C and G1635A in the TLR-9 gene appear to be more susceptible to the development of CKD.
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Affiliation(s)
- Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, Taipei, Taiwan, ROC
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Li C, Li Y, Xu J, Lv J, Ma Y, Shao T, Gong B, Tan R, Xiao Y, Li X. Disease-driven detection of differential inherited SNP modules from SNP network. Gene 2011; 489:119-29. [PMID: 21920414 DOI: 10.1016/j.gene.2011.08.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 08/02/2011] [Accepted: 08/27/2011] [Indexed: 01/15/2023]
Abstract
Detection of the synergetic effects between variants, such as single-nucleotide polymorphisms (SNPs), is crucial for understanding the genetic characters of complex diseases. Here, we proposed a two-step approach to detect differentially inherited SNP modules (synergetic SNP units) from a SNP network. First, SNP-SNP interactions are identified based on prior biological knowledge, such as their adjacency on the chromosome or degree of relatedness between the functional relationships of their genes. These interactions form SNP networks. Second, disease-risk SNP modules (or sub-networks) are prioritised by their differentially inherited properties in IBD (Identity by Descent) profiles of affected and unaffected sibpairs. The search process is driven by the disease information and follows the structure of a SNP network. Simulation studies have indicated that this approach achieves high accuracy and a low false-positive rate in the identification of known disease-susceptible SNPs. Applying this method to an alcoholism dataset, we found that flexible patterns of susceptible SNP combinations do play a role in complex diseases, and some known genes were detected through these risk SNP modules. One example is GRM7, a known alcoholism gene successfully detected by a SNP module comprised of two SNPs, but neither of the two SNPs was significantly associated with the disease in single-locus analysis. These identified genes are also enriched in some pathways associated with alcoholism, including the calcium signalling pathway, axon guidance and neuroactive ligand-receptor interaction. The integration of network biology and genetic analysis provides putative functional bridges between genetic variants and candidate genes or pathways, thereby providing new insight into the aetiology of complex diseases.
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Affiliation(s)
- Chuanxing Li
- College of Bioinformatics Science and Technology, Harbin Medical University, PR China
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Tan W, Sunahori K, Zhao J, Deng Y, Kaufman KM, Kelly JA, Langefeld CD, Williams AH, Comeau ME, Ziegler JT, Marion MC, Bae SC, Lee JH, Lee JS, Chang DM, Song YW, Yu CY, Kimberly RP, Edberg JC, Brown EE, Petri MA, Ramsey-Goldman R, Vilá LM, Reveille JD, Alarcón-Riquelme ME, Harley JB, Boackle SA, Stevens AM, Scofield RH, Merrill JT, Freedman BI, Anaya JM, Criswell LA, Jacob CO, Vyse TJ, Niewold TB, Gaffney PM, Moser KL, Gilkeson GS, Kamen DL, James JA, Grossman JM, Hahn BH, Tsokos GC, Tsao BP. Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups. ARTHRITIS AND RHEUMATISM 2011; 63:2755-63. [PMID: 21590681 PMCID: PMC3163110 DOI: 10.1002/art.30452] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Collaborators] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac. METHODS We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction. RESULTS A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P=3.8×10(-7)). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ∼2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P=0.007). CONCLUSION Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians.
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Affiliation(s)
- Wenfeng Tan
- University of California, Los Angeles, California, USA
| | - Katsue Sunahori
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Jian Zhao
- University of California, Los Angeles, California, USA
| | - Yun Deng
- University of California, Los Angeles, California, USA
| | - Kenneth M. Kaufman
- Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
- US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
| | | | - Carl D. Langefeld
- Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
| | | | - Mary E. Comeau
- Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
| | - Julie T. Ziegler
- Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
| | - Miranda C. Marion
- Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
| | - Sang-Cheol Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Joo Hyun Lee
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Ji-Seon Lee
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | | | | | | | | | | | | | - Michelle A. Petri
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Luis M. Vilá
- University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - John D. Reveille
- University of Texas Health Science Center at Houston, Houston, USA
| | - Marta E. Alarcón-Riquelme
- Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
- Center for Genomics and Oncological Research Pfizer-University of Granada-Junta de Andalucía, Granada, Spain
| | - John B. Harley
- Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
| | - Susan A. Boackle
- University of Colorado Denver School of Medicine, Aurora, Colorado, USA
| | - Anne M. Stevens
- University of Washington, Seattle Children's Hospital, Seattle, Washington, USA
| | - R. Hal Scofield
- Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Joan T. Merrill
- Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Barry I. Freedman
- Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
| | - Juan-Manuel Anaya
- Center for Autoimmune Diseases Research, Universidad del Rosario, Bogota, Colombia
| | - Lindsey A. Criswell
- Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, California, USA
| | - Chaim O. Jacob
- University of Southern California, Los Angeles, California, USA
| | | | | | | | - Kathy L. Moser
- Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Gary S. Gilkeson
- Medical University of South Carolina, Charleston, South Carolina, USA
| | - Diane L. Kamen
- Medical University of South Carolina, Charleston, South Carolina, USA
| | - Judith A. James
- Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
- University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | | | - Bevra H. Hahn
- University of California, Los Angeles, California, USA
| | - George C. Tsokos
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Betty P. Tsao
- University of California, Los Angeles, California, USA
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Collaborators
Sandra D'Alfonso, Bernard R Lauwerys, Emoke Endreffy, László Kovács, Carlos Vasconcelos, Berta Martins da Silva, Iñigo Rúa Figueroa, Hugo R Scherbarth, Pilar C Marino, Estela L Motta, Susana Gamron, Cristina Drenkard, Emilia Menso, Alberto Allievi, Guillermo A Tate, Jose L Presas, Simon A Palatnik, Marcelo Abdala, Mariela Bearzotti, Alejandro Alvarellos, Francisco Caeiro, Ana Bertoli, Sergio Paira, Susana Roverano, Cesar E Graf, Estela Bertero, Cesar Caprarulo, Griselda Buchanan, Carolina Guillerón, Sebastian Grimaudo, Jorge Manni, Luis J Catoggio, Enrique R Soriano, Carlos D Santos, Cristina Prigione, Fernando A Ramos, Sandra M Navarro, Guillermo a Berbotto, Marisa Jorfen, Elisa J Romero, Mercedes A Garcia, Juan C Marcos, Ana I Marcos, Carlos E Perandones, Alicia Eimon, Cristina G Battagliotti, Eduardo Acevedo, Mariano Cucho, Ignacio García de la Torre, Mario Cardiel Ríos, José Francisco Moctezuma, Marco Maradiaga Ceceña,
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36
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Muise AM, Walters T, Xu W, Shen-Tu G, Guo CH, Fattouh R, Lam GY, Wolters VM, Bennitz J, van Limbergen J, Renbaum P, Kasirer Y, Ngan BY, Turner D, Denson LA, Sherman PM, Duerr RH, Cho J, Lees CW, Satsangi J, Wilson DC, Paterson AD, Griffiths AM, Glogauer M, Silverberg MS, Brumell JH. Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis. Gastroenterology 2011; 141:633-41. [PMID: 21684284 PMCID: PMC3152589 DOI: 10.1053/j.gastro.2011.04.057] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Revised: 04/16/2011] [Accepted: 04/26/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS RAC1 is a guanosine triphosphatase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases are associated with dysregulation of immune defenses. We studied the role of RAC1 in inflammatory bowel diseases using human genetic and functional studies and animal models of colitis. METHODS We used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 messenger RNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulfate sodium. RESULTS We observed a genetic association between RAC1 with ulcerative colitis in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the single nucleotide polymorphisms rs10951982 (P(combined UC) = 3.3 × 10(-8), odds ratio = 1.43 [95% confidence interval: 1.26-1.63]) and rs4720672 (P(combined UC) = 4.7 × 10(-6), odds ratio = 1.36 [95% confidence interval: 1.19-1.58]). Patients with inflammatory bowel disease who had the rs10951982 risk allele had increased expression of RAC1 compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected against dextran sulfate sodium-induced colitis. CONCLUSIONS Human studies and knockout mice demonstrated a role for the guanosine triphosphatase RAC1 in the development of ulcerative colitis; increased expression of RAC1 was associated with susceptibility to colitis.
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Affiliation(s)
- Aleixo M Muise
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
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Huang YH, Lee MH, Chen WJ, Hsiao CK. Using an uncertainty-coding matrix in Bayesian regression models for haplotype-specific risk detection in family association studies. PLoS One 2011; 6:e21890. [PMID: 21789192 PMCID: PMC3137600 DOI: 10.1371/journal.pone.0021890] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Accepted: 06/08/2011] [Indexed: 11/22/2022] Open
Abstract
Haplotype association studies based on family genotype data can provide more biological information than single marker association studies. Difficulties arise, however, in the inference of haplotype phase determination and in haplotype transmission/non-transmission status. Incorporation of the uncertainty associated with haplotype inference into regression models requires special care. This task can get even more complicated when the genetic region contains a large number of haplotypes. To avoid the curse of dimensionality, we employ a clustering algorithm based on the evolutionary relationship among haplotypes and retain for regression analysis only the ancestral core haplotypes identified by it. To integrate the three sources of variation, phase ambiguity, transmission status and ancestral uncertainty, we propose an uncertainty-coding matrix which combines these three types of variability simultaneously. Next we evaluate haplotype risk with the use of such a matrix in a Bayesian conditional logistic regression model. Simulation studies and one application, a schizophrenia multiplex family study, are presented and the results are compared with those from other family based analysis tools such as FBAT. Our proposed method (Bayesian regression using uncertainty-coding matrix, BRUCM) is shown to perform better and the implementation in R is freely available.
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Affiliation(s)
- Yung-Hsiang Huang
- Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hsien Lee
- Department of Mathematics and Computer Science Education, Taipei Municipal University of Education, Taipei, Taiwan
| | - Wei J. Chen
- Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
- Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan
- Research Center for Genes, Environment, and Human Health, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chuhsing Kate Hsiao
- Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
- Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan
- Research Center for Genes, Environment, and Human Health, College of Public Health, National Taiwan University, Taipei, Taiwan
- Bioinformatics and Biostatistics Core, NTU Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan
- * E-mail:
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Chung CC, Ciampa J, Yeager M, Jacobs KB, Berndt SI, Hayes RB, Gonzalez-Bosquet J, Kraft P, Wacholder S, Orr N, Yu K, Hutchinson A, Boland J, Chen Q, Feigelson HS, Thun MJ, Diver WR, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Cancel-Tassin G, Cussenot O, Valeri A, Andriole GL, Crawford ED, Haiman CA, Henderson BE, Kolonel L, Le Marchand L, Siddiq A, Riboli E, Key TJ, Kaaks R, Isaacs WB, Isaacs SD, Grönberg H, Wiklund F, Xu J, Vatten LJ, Hveem K, Njolstad I, Gerhard DS, Tucker M, Hoover RN, Fraumeni JF, Hunter DJ, Thomas G, Chatterjee N, Chanock SJ. Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer. Hum Mol Genet 2011; 20:2869-78. [PMID: 21531787 PMCID: PMC3118760 DOI: 10.1093/hmg/ddr189] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Revised: 04/12/2011] [Accepted: 04/26/2011] [Indexed: 11/14/2022] Open
Abstract
Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10(-8)) with rs10896449 the most significant (P= 7.94 × 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10(-5), adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2)= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10(-3), adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2)= 0.17; rs10896449-rs10896438, r(2)= 0.10; rs12793759-rs10896438, r(2)= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.
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Affiliation(s)
- Charles C. Chung
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Julia Ciampa
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Meredith Yeager
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
- Core Genotyping Facility, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA
| | - Kevin B Jacobs
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
- Core Genotyping Facility, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Richard B. Hayes
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
- Department of Environmental Medicine, NYU School of Medicine, New York, NY, USA
| | - Jesus Gonzalez-Bosquet
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Peter Kraft
- Program in Molecular and Genetic Epidemiology, Department of Epidemiology and
| | - Sholom Wacholder
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Nick Orr
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Kai Yu
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Amy Hutchinson
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
- Core Genotyping Facility, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA
| | - Joseph Boland
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
- Core Genotyping Facility, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA
| | - Quan Chen
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
- Core Genotyping Facility, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA
| | | | - Michael J. Thun
- Department of Epidemiology, American Cancer Society, Atlanta, GA, USA
| | - W. Ryan Diver
- Department of Epidemiology, American Cancer Society, Atlanta, GA, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Jarmo Virtamo
- Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
| | - Stephanie Weinstein
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Fredrick R. Schumacher
- Program in Molecular and Genetic Epidemiology, Department of Epidemiology and
- Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
- Department of Preventive Medicine, Keck School of Medicine, Los Angeles, CA, USA
| | - Geraldine Cancel-Tassin
- Centre de Recherche pour les Pathologies Prostatiques, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75970 Paris, France
| | - Olivier Cussenot
- Centre de Recherche pour les Pathologies Prostatiques, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75970 Paris, France
| | - Antoine Valeri
- Centre de Recherche pour les Pathologies Prostatiques, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75970 Paris, France
| | - Gerald L. Andriole
- Division of Urologic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - E. David Crawford
- Department of Surgery, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA
| | | | - Brian E. Henderson
- Department of Preventive Medicine, Keck School of Medicine, Los Angeles, CA, USA
| | - Laurence Kolonel
- Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, USA
| | - Loic Le Marchand
- Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, USA
| | - Afshan Siddiq
- Division of Epidemiology, Public Health and Primary Care, Imperial College London, London, UK
| | - Elio Riboli
- Division of Epidemiology, Public Health and Primary Care, Imperial College London, London, UK
| | - Tim J. Key
- Cancer Epidemiology Unit, University of Oxford, Oxford, UK
| | - Rudolf Kaaks
- Division of Clinical Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - William B. Isaacs
- Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Sarah D. Isaacs
- Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Henrik Grönberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm SE-17177, Sweden
| | - Fredrik Wiklund
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm SE-17177, Sweden
| | - Jianfeng Xu
- Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Lars J. Vatten
- Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway
| | - Kristian Hveem
- Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway
| | - Inger Njolstad
- Institute of Community Medicine, University of Tromso, Tromso, Norway
| | - Daniela S. Gerhard
- Office of Cancer Genomics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Margaret Tucker
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Robert N. Hoover
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Joseph F. Fraumeni
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - David J. Hunter
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
- Program in Molecular and Genetic Epidemiology, Department of Epidemiology and
- Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
- Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA and
| | - Gilles Thomas
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
- Synergie-Lyon-Cancer, Universite Lyon 1, Lyon, France
| | - Nilanjan Chatterjee
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
| | - Stephen J. Chanock
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services and
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Lins TC, Vieira RG, Grattapaglia D, Pereira RW. Population analysis of vitamin D receptor polymorphisms and the role of genetic ancestry in an admixed population. Genet Mol Biol 2011; 34:377-85. [PMID: 21931507 PMCID: PMC3168175 DOI: 10.1590/s1415-47572011000300003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2011] [Accepted: 04/27/2011] [Indexed: 12/04/2022] Open
Abstract
The vitamin D receptor (VDR) is an essential protein related to bone metabolism. Some VDR alleles are differentially distributed among ethnic populations and display variable patterns of linkage disequilibrium (LD). In this study, 200 unrelated Brazilians were genotyped using 21 VDR single nucleotide polymorphisms (SNPs) and 28 ancestry informative markers. The patterns of LD and haplotype distribution were compared among Brazilian and the HapMap populations of African (YRI), European (CEU) and Asian (JPT+CHB) origins. Conditional regression and haplotype-specific analysis were performed using estimates of individual genetic ancestry in Brazilians as a quantitative trait. Similar patterns of LD were observed in the 5′ and 3′ gene regions. However, the frequency distribution of haplotype blocks varied among populations. Conditional regression analysis identified haplotypes associated with European and Amerindian ancestry, but not with the proportion of African ancestry. Individual ancestry estimates were associated with VDR haplotypes. These findings reinforce the need to correct for population stratification when performing genetic association studies in admixed populations.
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Affiliation(s)
- Tulio C Lins
- Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil
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40
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Shab-Bidar S, Neyestani TR, Djazayery A. Efficacy of vitamin D3-fortified-yogurt drink on anthropometric, metabolic, inflammatory and oxidative stress biomarkers according to vitamin D receptor gene polymorphisms in type 2 diabetic patients: a study protocol for a randomized controlled clinical trial. BMC Endocr Disord 2011; 11:12. [PMID: 21696575 PMCID: PMC3146888 DOI: 10.1186/1472-6823-11-12] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Accepted: 06/22/2011] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Development of type 2 diabetes mellitus (T2DM) is determined by the interactions of genetic and environmental factors. This study was designed to evaluate the possible role of VDR single nucleotide polymorphisms (SNPs) on different aspects of diabetic host response (anthropometric, metabolic, oxidative stress and inflammatory) to daily intake of vitamin D through fortified yogurt drink for 12 weeks. METHODS/DESIGN This study comprises two parts: (i) a case-control study; and (ii) an intervention trial. In the first part, VDR polymorphisms (Taq1, FokI, Apa1, Bsm1, and Cdx2) are determined in 350 T2DM patients and 350 non-diabetic subjects. In the second part, the possible effects of daily intake of two servings of vitamin D3-fortified yogurt drink (FYD; 500 IU vitamin D/250 mL) on some selected metabolic (including insulin resistance), inflammatory and oxidative stress biomarkers in 135 T2DM patients are assessed. To relate the resulted changes in the biomarkers to vitamin D replenishment, another group of diabetic patients (n = 45) are also included in the study who receive 2 servings of plain yogurt drink (PYD) a day. The primary outcome is serum level of 25(OH) D, which it is expected to be elevated only in FYD group. Secondary outcomes include improvements in glycemic, metabolic, inflammatory and oxidative stress biomarkers in FYD group compared to PYD group. Three VDR FokI polymorphisms are determined only in FYD group followed by comparison of changes in the biomarkers among these genotypic variants. DISCUSSION The present study, at least in part, elucidates the discrepancies in the results of different vitamin D-diabetes studies pertaining to the genetic variations of the population. If VDR polymorphisms are found to influence the response to our intervention, then knowing distribution of VDR polymorphisms in both diabetic and non-diabetic populations can give a picture of the proportion of the community in whom up to 1000 IU/d vitamin D may not be effective enough to improve insulin resistance and related morbidities. Therefore, they should ideally receive further nutritional support according to their genotype. TRIAL REGISTRATION ClinicalTrials.gov: NCT01236846.
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Affiliation(s)
- Sakineh Shab-Bidar
- Department of Nutrition and Biochemistry, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Tirang R Neyestani
- Laboratory of Nutrition Research, National Research Institute and Faculty of Nutrition and Food Technology; Shahid Beheshti University of Medical Sciences (SBUM), Tehran, Iran
| | - Abolghassem Djazayery
- Department of Nutrition and Biochemistry, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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Gusev A, Kenny EE, Lowe JK, Salit J, Saxena R, Kathiresan S, Altshuler DM, Friedman JM, Breslow JL, Pe'er I. DASH: a method for identical-by-descent haplotype mapping uncovers association with recent variation. Am J Hum Genet 2011; 88:706-717. [PMID: 21620352 DOI: 10.1016/j.ajhg.2011.04.023] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 04/13/2011] [Accepted: 04/26/2011] [Indexed: 02/01/2023] Open
Abstract
Rare variants affecting phenotype pose a unique challenge for human genetics. Although genome-wide association studies have successfully detected many common causal variants, they are underpowered in identifying disease variants that are too rare or population-specific to be imputed from a general reference panel and thus are poorly represented on commercial SNP arrays. We set out to overcome these challenges and detect association between disease and rare alleles using SNP arrays by relying on long stretches of genomic sharing that are identical by descent. We have developed an algorithm, DASH, which builds upon pairwise identical-by-descent shared segments to infer clusters of individuals likely to be sharing a single haplotype. DASH constructs a graph with nodes representing individuals and links on the basis of such segments spanning a locus and uses an iterative minimum cut algorithm to identify densely connected components. We have applied DASH to simulated data and diverse GWAS data sets by constructing haplotype clusters and testing them for association. In simulations we show this approach to be significantly more powerful than single-marker testing in an isolated population that is from Kosrae, Federated States of Micronesia and has abundant IBD, and we provide orthogonal information for rare, recent variants in the outbred Wellcome Trust Case-Control Consortium (WTCCC) data. In both cohorts, we identified a number of haplotype associations, five such loci in the WTCCC data and ten in the isolated, that were conditionally significant beyond any individual nearby markers. We have replicated one of these loci in an independent European cohort and identified putative structural changes in low-pass whole-genome sequence of the cluster carriers.
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Affiliation(s)
- Alexander Gusev
- Department of Computer Science, Columbia University, New York, NY 10027, USA
| | - Eimear E Kenny
- Department of Computer Science, Columbia University, New York, NY 10027, USA; Medical Sciences and Human Genetics, Rockefeller University, New York, NY 10065, USA
| | - Jennifer K Lowe
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Jaqueline Salit
- Medical Sciences and Human Genetics, Rockefeller University, New York, NY 10065, USA
| | - Richa Saxena
- Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Sekar Kathiresan
- Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Cardiovascular Disease Prevention Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - David M Altshuler
- Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Center for Human Genetic Research and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Jeffrey M Friedman
- Medical Sciences and Human Genetics, Rockefeller University, New York, NY 10065, USA
| | - Jan L Breslow
- Medical Sciences and Human Genetics, Rockefeller University, New York, NY 10065, USA
| | - Itsik Pe'er
- Department of Computer Science, Columbia University, New York, NY 10027, USA.
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Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO, Adler A, Alarcón-Riquelme ME, Gallant CJ, Boackle SA, Criswell LA, Kimberly RP, Brown E, Edberg J, Stevens AM, Jacob CO, Tsao BP, Gilkeson GS, Kamen DL, Merrill JT, Petri M, Goldman RR, Vila LM, Anaya JM, Niewold TB, Martin J, Pons-Estel BA, Sabio JM, Callejas JL, Vyse TJ, Bae SC, Perrino FW, Freedman BI, Scofield RH, Moser KL, Gaffney PM, James JA, Langefeld CD, Kaufman KM, Harley JB, Atkinson JP. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 2011; 12:270-9. [PMID: 21270825 PMCID: PMC3107387 DOI: 10.1038/gene.2010.73] [Citation(s) in RCA: 214] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Revised: 12/07/2010] [Accepted: 12/08/2010] [Indexed: 01/16/2023]
Abstract
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3'-5' exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi-Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case-control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25-2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E-13, OR=5.2, 95% CI=3.18-8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.
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Affiliation(s)
- B Namjou
- Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
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Han S, Yang BZ, Kranzler HR, Oslin D, Anton R, Gelernter J. Association of CHRNA4 polymorphisms with smoking behavior in two populations. Am J Med Genet B Neuropsychiatr Genet 2011; 156B:421-9. [PMID: 21445957 PMCID: PMC3742073 DOI: 10.1002/ajmg.b.31177] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2010] [Accepted: 02/17/2011] [Indexed: 12/18/2022]
Abstract
CHRNA4, the gene that encodes the nicotinic acetylcholine receptor α(4) subunit, is a potential candidate gene for nicotine dependence (ND). However, studies of the association of CHNRA4 with smoking behavior have shown inconsistent results. Our meta-analysis of linkage studies of smoking behavior identified a genome-wide significant linkage of the phenotype maximum number of cigarettes smoked in a 24-hour period to a region (20q13.12-q13.32) harboring CHRNA4. This motivated us to examine the association of CHRNA4 with smoking behavior in two independent samples. In this study, we examined five single nucleotide polymorphisms (SNPs) within CHRNA4 and three smoking-related behaviors: one quantitative trait [cigarettes smoked per day (CPD)], and two binary traits [DSM-IV diagnosis of ND and dichotomized Fagerstrom test of ND (FTND)], in 1,249 unrelated European-Americans (EAs) and 1,790 unrelated African-Americans (AAs). Using the combined sample with sex, age, and race as covariates, the synonymous SNP rs1044394 was significantly associated with ND (P = 0.001) and FTND (P = 0.01). Rs2236196, which has a low correlation with rs1044394, was also significantly associated with CPD (P = 0.003). The pattern of association for these SNPs was similar in AAs and EAs. After correction for multiple testing, the association between rs1044394 and ND in the combined sample remained significant (P = 0.033). In summary, our study supports association between CHRNA4 common variation and ND in AA and EA samples. Additional studies will be necessary to evaluate the role of rare variants at CHRNA4 for ND.
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Affiliation(s)
- Shizhong Han
- Department of Psychiatry, Division of Human Genetics, Yale
University School of Medicine, New Haven, CT 06511, USA
- VA CT Healthcare Center 116A2; 950 Campbell Avenue; West Haven, CT
06516
| | - Bao-Zhu Yang
- Department of Psychiatry, Division of Human Genetics, Yale
University School of Medicine, New Haven, CT 06511, USA
- VA CT Healthcare Center 116A2; 950 Campbell Avenue; West Haven, CT
06516
| | - Henry R. Kranzler
- Department of Psychiatry, University of Pennsylvania School of
Medicine, Philadelphia, PA 19104 and VISN 4 MIRECC, Philadelphia VAMC, Philadelphia,
PA 19104
| | - David Oslin
- Department of Psychiatry, University of Pennsylvania School of
Medicine, Philadelphia, PA, 19104 USA
| | - Raymond Anton
- Department of Psychiatry and Behavioral Sciences, Medical University
of South Carolina, Charleston, SC, 29425 USA
| | - Joel Gelernter
- Department of Psychiatry, Division of Human Genetics, Yale
University School of Medicine, New Haven, CT 06511, USA
- Department of Genetics, Yale University School of Medicine, New
Haven, CT 06511, USA
- Department of Neurobiology, Yale University School of Medicine, New
Haven, CT 06511, USA
- VA CT Healthcare Center 116A2; 950 Campbell Avenue; West Haven, CT
06516
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Paré G, Ridker PM, Rose L, Barbalic M, Dupuis J, Dehghan A, Bis JC, Benjamin EJ, Shiffman D, Parker AN, Chasman DI. Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. PLoS Genet 2011. [PMID: 21533024 DOI: 10.1371/journal.pgen.1001374］] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P = 5.8 × 10(-9)), RELA (rs1049728, P = 2.7 × 10(-16)), and SH2B3 (rs3184504, P = 2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.
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Affiliation(s)
- Guillaume Paré
- Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
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45
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Clarke TK, Laucht M, Ridinger M, Wodarz N, Rietschel M, Maier W, Lathrop M, Lourdusamy A, Zimmermann US, Desrivieres S, Schumann G. KCNJ6 is associated with adult alcohol dependence and involved in gene × early life stress interactions in adolescent alcohol drinking. Neuropsychopharmacology 2011; 36:1142-8. [PMID: 21307845 PMCID: PMC3079832 DOI: 10.1038/npp.2010.247] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 11/16/2010] [Accepted: 12/08/2010] [Indexed: 11/09/2022]
Abstract
Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p=0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene-environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p=0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement.
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Affiliation(s)
- Toni-Kim Clarke
- Section of Addiction Biology, MRC-SGDP Centre, Institute of Psychiatry, King's College London, London, UK.
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46
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Paré G, Ridker PM, Rose L, Barbalic M, Dupuis J, Dehghan A, Bis JC, Benjamin EJ, Shiffman D, Parker AN, Chasman DI. Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. PLoS Genet 2011; 7:e1001374. [PMID: 21533024 PMCID: PMC3080865 DOI: 10.1371/journal.pgen.1001374] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2010] [Accepted: 03/15/2011] [Indexed: 02/06/2023] Open
Abstract
Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4×10−9), PNPLA3 (rs738409, P = 5.8×10−9), RELA (rs1049728, P = 2.7×10−16), and SH2B3 (rs3184504, P = 2.9×10−17). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function. Soluble Intercellular Adhesion Molecule 1 (sICAM-1) is an inflammatory marker that has been associated with several common diseases such as diabetes, heart disease, stroke, and malaria. While it is known that blood concentrations of sICAM-1 are at least partially genetically determined, our current knowledge of which genes mediate this effect is limited. Taking advantage of technologies allowing us to interrogate genetic variation on a whole-genome basis, we found that variation in the NFKBIK, PNPLA3, RELA, and SH2B3 genes are important determinant of sICAM-1 blood concentrations. The NFKBIB and RELA genes are involved in regulation of inflammation. These observations are significant because this is the first report of genetic association within these extensively studied inflammation genes. The PNPLA3 gene has previously been associated with liver disease, and the SH2B3 gene has been associated with a multitude of traits including cardiovascular disease. Extension of these associations to sICAM-1 adds to the intriguing diversity of effects of these genes.
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Affiliation(s)
- Guillaume Paré
- Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
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Fan Y, Tao JH, Zhang LP, Li LH, Ye DQ. The association between BANK1 and TNFAIP3 gene polymorphisms and systemic lupus erythematosus: a meta-analysis. Int J Immunogenet 2011; 38:151-9. [PMID: 21208380 DOI: 10.1111/j.1744-313x.2010.00990.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The past decade has witnessed hundreds of reports declaring or not being able to replicable genetic association with systemic lupus erythematosus (SLE) susceptibility. BANK1 is a gene that encodes a B-cell-specific scaffold protein and its activation can affect B-cell-receptor-induced calcium mobilization from intracellular calcium stores. TNFAIP3 encodes the ubiquitin-modifying enzyme, also known as A20, which is a cytoplasmic zinc finger protein that inhibits nuclear factor kappa-B (NFKB) activity and tumour necrosis factor (TNF)-mediated programmed cell death. The association of BANK1 and TNFAIP3 polymorphism with SLE has been reported in several studies. The aim of this study was to assess whether combined evidence shows the association between BANK1 and TNFAIP3 polymorphism and SLE. We report the results of a meta-analysis of genome-wide association scans and replication in independent sets for BANK1 and TNFAIP3 polymorphism and SLE that includes 12,416 subjects with SLE and 19,113 control subjects. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on random effects models. Both of BANK1 and TNFAIP3 harbour several controversial single nucleotide polymorphisms (SNPs). We selected and identified three SNPs of BANK1 associated with SLE (rs17266594, P = 1.949e-10; OR = 1.380; 95% CI: 1.250-1.525; rs10516487, P = 2.642e-13; OR = 1.317; 95% CI: 1.223-1.417; rs3733197, P = 3.452e-06; OR = 1.193; 95% CI: 1.107-1.286); one SNP of TNFAIP3 associated with SLE (rs2230926, P = 1.502e-12; OR = 1.826; 95% CI: 1.545-2.157). This meta-analysis demonstrates a significant association between BANK1 and TNFAIP3 gene polymorphism and SLE in multiple ethnic populations. These findings reinforce the value of large sample series for discovery and follow-up of genetic variants contributing to the aetiology of SLE.
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Affiliation(s)
- Y Fan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
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48
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Zlojutro M, Manz N, Rangaswamy M, Xuei X, Flury-Wetherill L, Koller D, Bierut LJ, Goate A, Hesselbrock V, Kuperman S, Nurnberger J, Rice JP, Schuckit MA, Foroud T, Edenberg HJ, Porjesz B, Almasy L. Genome-wide association study of theta band event-related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 2011; 156B:44-58. [PMID: 21184583 PMCID: PMC3139811 DOI: 10.1002/ajmg.b.31136] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2009] [Accepted: 09/16/2010] [Indexed: 01/19/2023]
Abstract
Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype-frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1 M microarray were selected from the theta ERO GWAS for replication in family-based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P = 3.68 × 10⁻⁶). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10⁻⁴), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case-controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case-control and family-based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders.
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Affiliation(s)
- Mark Zlojutro
- Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA.
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Lee SH, Nyholt DR, Macgregor S, Henders AK, Zondervan KT, Montgomery GW, Visscher PM. A simple and fast two-locus quality control test to detect false positives due to batch effects in genome-wide association studies. Genet Epidemiol 2010; 34:854-62. [PMID: 21104888 PMCID: PMC3674525 DOI: 10.1002/gepi.20541] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Revised: 07/28/2010] [Accepted: 09/09/2010] [Indexed: 12/04/2022]
Abstract
The impact of erroneous genotypes having passed standard quality control (QC) can be severe in genome-wide association studies, genotype imputation, and estimation of heritability and prediction of genetic risk based on single nucleotide polymorphisms (SNP). To detect such genotyping errors, a simple two-locus QC method, based on the difference in test statistic of association between single SNPs and pairs of SNPs, was developed and applied. The proposed approach could detect many problematic SNPs with statistical significance even when standard single SNP QC analyses fail to detect them in real data. Depending on the data set used, the number of erroneous SNPs that were not filtered out by standard single SNP QC but detected by the proposed approach varied from a few hundred to thousands. Using simulated data, it was shown that the proposed method was powerful and performed better than other tested existing methods. The power of the proposed approach to detect erroneous genotypes was ∼80% for a 3% error rate per SNP. This novel QC approach is easy to implement and computationally efficient, and can lead to a better quality of genotypes for subsequent genotype-phenotype investigations.
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Affiliation(s)
- Sang Hong Lee
- Queensland Institute of Medical Research, Herston, Queensland, Australia.
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50
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Xu X, Valtonen-André C, Sävblom C, Halldén C, Lilja H, Klein RJ. Polymorphisms at the Microseminoprotein-beta locus associated with physiologic variation in beta-microseminoprotein and prostate-specific antigen levels. Cancer Epidemiol Biomarkers Prev 2010; 19:2035-42. [PMID: 20696662 PMCID: PMC2946372 DOI: 10.1158/1055-9965.epi-10-0431] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND rs10993994, a single nucleotide polymorphism (SNP) at the genetic locus encoding beta-microseminoprotein (beta-MSP), is associated with both prostate cancer risk and levels of blood prostate-specific antigen (PSA), a biomarker used in prostate cancer screening. Therefore, we wished to determine the association between SNPs at MSMB, the gene encoding beta-MSP, and the levels of prostate-produced biomarkers beta-MSP, PSA, and human kallikrein 2 (hK2) in blood and semen. METHODS Blood and semen from 304 healthy young Swedish men (ages 18-21) were assayed for beta-MSP, PSA, and hK2. SNPs around MSMB were genotyped from matched DNA and analyzed for quantitative association with biomarker levels. Empirical P values were multiple test-corrected and the independence of each SNP's effect was determined. RESULTS rs10993994 was significantly associated with the blood and semen levels of beta-MSP (both P < 1.0 x 10(-7)) and PSA (P = 0.00014 and P = 0.0019), and semen levels of hK2 (P = 0.00027). Additional copies of the prostate cancer risk allele resulted in lower beta-MSP but higher PSA levels, and singly explained 23% and 5% of the variation seen in semen beta-MSP and PSA, respectively. Additional SNPs at MSMB are associated with beta-MSP and PSA independently of rs10993994. CONCLUSIONS SNPs at MSMB correlate with physiologic variation in beta-MSP and PSA levels in the blood and semen of healthy young Swedish men. In particular, rs10993994 has a strong effect on beta-MSP levels. IMPACT Our results suggest a mechanism by which rs10993994 might predispose to prostate cancer and raise the possibility that genetic variation might need to be considered in interpreting the levels of these biomarkers.
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Affiliation(s)
- Xing Xu
- Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Camilla Valtonen-André
- Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Skåne University Hospital, 205 02 Malmö, Sweden
| | - Charlotta Sävblom
- Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Skåne University Hospital, 205 02 Malmö, Sweden
| | - Christer Halldén
- Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Skåne University Hospital, 205 02 Malmö, Sweden
| | - Hans Lilja
- Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Skåne University Hospital, 205 02 Malmö, Sweden
- Department of Clinical Laboratories, Surgery (Urology) and Medicine (GU-Oncology), Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Robert J. Klein
- Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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