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AlOmeir O, Almuqbil M, Alotaibi NF, Alotaibi FRN, Alnazer WR, Alenazi LK, Alotaibi FN, Otaif HA, Alsanie WF, Alamri AS, Alhomrani M, Alshammary AF, Asdaq SMB. Prevalence and impact of sociodemographic factors, comorbidities, and lifestyle on diabetes complications among patients with type 2 diabetes in Riyadh. Sci Rep 2025; 15:17299. [PMID: 40389715 PMCID: PMC12089296 DOI: 10.1038/s41598-025-02559-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 05/14/2025] [Indexed: 05/21/2025] Open
Abstract
Diabetes mellitus (DM) is a growing public health concern globally, particularly in Saudi Arabia, where increasing prevalence is associated with significant morbidity. This study aimed to assess the prevalence of diabetes-related complications among patients in Riyadh and examine the impact of sociodemographic factors, comorbidities, and lifestyle habits on these complications. A cross-sectional study was conducted with 980 diabetic patients attending health centers in Riyadh from March to April 2023. Data were collected via a validated bilingual questionnaire that captured sociodemographic information, diabetes-related variables, comorbid conditions, lifestyle habits, and complications. Statistical analyses, including descriptive statistics, chi-square tests, and binary regression, were performed via SPSS to identify significant associations. A p-value less than 0.05 was considered significant for all comparisons. Among the participants (980), 38% (378) reported diabetes-related complications, primarily neuropathy (30%), retinopathy (25%), and cardiovascular diseases (20%). Complications were significantly associated with older age (p < 0.001) and longer diabetes duration (more than 5 years; p < 0.001). Individuals with hypertension, hyperlipidemia, heart disease, kidney disease, and obesity had significantly higher complication rates than those without these conditions (p < 0.05). The most pronounced association was observed in participants with heart disease (85% vs. 15%; RR = 1.506), highlighting the need for better management of these comorbidities. Consuming fruits and vegetables, milk, and regular exercise were inversely associated with the risk of complications (p < 0.05). Conversely, sugary drinks, white bread, sheesha/vaping, and inadequate sleep were linked to increased risk (p < 0.05), highlighting the protective role of healthy dietary and lifestyle habits. This study highlights the impact of sociodemographic factors and lifestyle choices-such as age, education, family history, comorbidities, and poor diet-on diabetes complications. While early detection and lifestyle interventions are vital, a cautious approach is needed when applying these findings to other regions, given differences in socioeconomic circumstances.
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Affiliation(s)
- Othman AlOmeir
- Department of Clinical Pharmacy, College of Pharmacy, Shaqra University, 11961, Shaqra, Saudi Arabia
| | - Mansour Almuqbil
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Nawaf Fahad Alotaibi
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Dariyah, 13713, Riyadh, Saudi Arabia
| | - Faisal Rashed Nawar Alotaibi
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Dariyah, 13713, Riyadh, Saudi Arabia
| | - Wael Rashad Alnazer
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Dariyah, 13713, Riyadh, Saudi Arabia
| | - Luay Khaled Alenazi
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Dariyah, 13713, Riyadh, Saudi Arabia
| | - Fahad Nasser Alotaibi
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Dariyah, 13713, Riyadh, Saudi Arabia
| | - Hussein Abdullah Otaif
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Dariyah, 13713, Riyadh, Saudi Arabia
| | - Walaa F Alsanie
- Department of Clinical Laboratory Sciences, The Faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
- Research Center for Health Sciences, Deanship of Graduate Studies and Scientific Research, Taif University, 26432, Taif, Saudi Arabia
| | - Abdulhakeem S Alamri
- Department of Clinical Laboratory Sciences, The Faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
- Research Center for Health Sciences, Deanship of Graduate Studies and Scientific Research, Taif University, 26432, Taif, Saudi Arabia
| | - Majid Alhomrani
- Department of Clinical Laboratory Sciences, The Faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
- Research Center for Health Sciences, Deanship of Graduate Studies and Scientific Research, Taif University, 26432, Taif, Saudi Arabia
| | - Amal F Alshammary
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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Triolo TM, Parikh HM, Tosur M, Ferrat LA, You L, Gottlieb PA, Oram RA, Onengut-Gumuscu S, Krischer JP, Rich SS, Steck AK, Redondo MJ. Genetic Associations With C-peptide Levels Before Type 1 Diabetes Diagnosis in At-risk Relatives. J Clin Endocrinol Metab 2025; 110:e1046-e1050. [PMID: 38767115 PMCID: PMC11913082 DOI: 10.1210/clinem/dgae349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 05/22/2024]
Abstract
OBJECTIVE We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms are associated with C-peptide preservation before type 1 diabetes diagnosis. METHODS We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known single nucleotide polymorphisms and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis. RESULTS Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before diagnosis in univariate (β = -.06, P < .0001) and multivariate (β = -.03, P = .005) analyses. Participants with the JAZF1 rs864745 T allele had lower C-peptide AUC in both univariate (β = -.11, P = .002) and multivariate (β = -.06, P = .018) analyses. CONCLUSION The type 2 diabetes-associated JAZF1 rs864745 T allele and higher T1D-GRS2 are associated with lower C-peptide AUC before diagnosis of type 1 diabetes, with implications for the design of prevention trials.
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Affiliation(s)
- Taylor M Triolo
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Hemang M Parikh
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Mustafa Tosur
- Department of Pediatrics, Division of Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA
- USDA/ARS Children's Nutrition Research Center, Houston, TX 77030, USA
| | - Lauric A Ferrat
- Institute of Biomedical and Clinical Science, Faculty of Health and Life Sciences, Exeter 5DW, UK
| | - Lu You
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Peter A Gottlieb
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, Faculty of Health and Life Sciences, Exeter 5DW, UK
| | | | - Jeffrey P Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Stephen S Rich
- University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - Andrea K Steck
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Maria J Redondo
- Department of Pediatrics, Division of Diabetes and Endocrinology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA
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Singh S, Gummadi SN. Two-stage seeding strategy and its multi-response optimization for enhanced xylitol production by Debaryomyces nepalensis NCYC 3413. BIORESOURCE TECHNOLOGY 2024; 413:131469. [PMID: 39260726 DOI: 10.1016/j.biortech.2024.131469] [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: 06/10/2024] [Revised: 08/27/2024] [Accepted: 09/07/2024] [Indexed: 09/13/2024]
Abstract
The aim was to develop a two-stage seeding strategy and its optimization to enhance the conversion of xylose to xylitol by Debaryomyces nepalensis NCYC 3413. To develop efficient seed, multi-response optimization was employed to obtain optimal inoculum age and volume where xylitol concentration, yield and productivity were maximized. The optimal conditions of inoculation age and volume were 5.86 h and 11.66 % (v/v), respectively. Maximized results were observed at 48 h as compared to 72 h pre-optimization. Xylitol concentration slightly improved from 56 g/L to 59.71 g/L (p-value = 0.043). Yield improved from 0.56 g/g to 0.66 g/g (p-value = 0.044), whereas, productivity showed a significant increase from 0.76 g/L.h to 1.24 g/L.h (p-value = 0.008). Xylose Reductase activity improved by 1.67-folds and Xylitol Dehydrogenase activity decreased by 1.3 folds. This work suggests a simple inoculum strategy that could expedite the enzyme system required for xylitol production, enabling a 1.7-fold increase in productivity.
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Affiliation(s)
- Saivi Singh
- Applied and Industrial Microbiology Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras Chennai 600 036, India
| | - Sathyanarayana N Gummadi
- Applied and Industrial Microbiology Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras Chennai 600 036, India.
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Asdaq SMB, Mannasaheb BA, Orfali R, Shaikh IA, Alshehri A, Alghamdi A, Alrashdi MM, Almadani ME, Abdalla FMA. Antidiabetic and antioxidant potential of Crocin in high-fat diet plus streptozotocin-induced type-2 diabetic rats. Int J Immunopathol Pharmacol 2024; 38:3946320231220178. [PMID: 38233742 PMCID: PMC10798082 DOI: 10.1177/03946320231220178] [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: 04/29/2023] [Accepted: 11/23/2023] [Indexed: 01/19/2024] Open
Abstract
OBJECTIVES Crocin, the principal water-soluble active constituent of saffron, possesses numerous pharmacological activities. The present investigation examined the potential antidiabetic and antioxidant characteristics of Crocin in rats with type-2 diabetes by administering it orally and intraperitoneally (i.p.). METHODS After 2 weeks of a high-fat diet, streptozotocin (STZ) (i.p., 40 mg/kg) was administered to male adult rats to induce type-2 diabetes mellitus. Body weight and fasting blood glucose (FBG) were measured on days zero, weeks 1, and 2. At the end of 2 weeks of drug administration in their respective groups, fasting insulin and glucose levels were estimated, and insulin resistance (HOMA-IR) was determined. Intraperitoneal glucose (IPGTT) and insulin tolerance tests (ITT) were carried out. Histopathological investigation and biochemical parameters were estimated in pancreatic tissues. RESULTS The Crocin (100 mg/kg) treatment has significantly improved body weight, abatement of FBG, fasting insulin, and HOMA-IR. Likewise, Crocin treatment significantly improved the glucose and insulin challenges. We observed a significantly marked elevation in endogenous antioxidant enzymes in Crocin-treated groups. Similarly, Crocin treatment reversed the histopathological changes and restored the normal integrity and function of the pancreas. CONCLUSION The overall finding indicates that intraperitoneal administration of Crocin demonstrated better control of glycemic level and body weight. Further, it has improved insulin levels in the serum and potentiated antioxidant properties.
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Affiliation(s)
| | | | - Raha Orfali
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ibrahim Ahmed Shaikh
- Department of Pharmacology, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Ahmed Alshehri
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Adel Alghamdi
- Department of Pharmaceutical Chemistry, Faculty of Clinical Pharmacy, Al-Baha University, Al-Baha, Saudi Arabia
| | - Meshal Mohammed Alrashdi
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
| | - Moneer E Almadani
- Department of Clinical Medicine, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia
| | - Faisal Mohammad Ali Abdalla
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
- Memorial University of Newfoundland, St. John’s, NL, Canada
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Sanyaolu A, Marinkovic A, Prakash S, Williams M, Dixon Y, Okorie C, Orish VN, Izurieta R. Diabetes mellitus: An overview of the types, prevalence, comorbidity, complication, genetics, economic implication, and treatment. World J Meta-Anal 2023; 11:134-143. [DOI: 10.13105/wjma.v11.i5.134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/04/2023] [Accepted: 02/02/2023] [Indexed: 06/16/2023] Open
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Zhang Y, Lu Y, Gao Y, Liang X, Zhang R, Wang X, Zou X, Yang W. Effects of Aire on perforin expression in BMDCs via TLR7/8 and its therapeutic effect on type 1 diabetes. Int Immunopharmacol 2023; 117:109890. [PMID: 36805202 DOI: 10.1016/j.intimp.2023.109890] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/30/2023] [Accepted: 02/11/2023] [Indexed: 02/19/2023]
Abstract
AIMS Type 1 diabetes, as a kind of autoimmune diseases, usually results from the broken-down of self-tolerance. Autoimmune regulator (Aire), as a transcription factor, induces peripheral tolerance by regulating Toll-like receptor (TLR) expression in dendritic cells (DCs). Several studies have recently identified a small population of perforin-expressing DCs, which is an important population of tolerogenic DCs (tolDCs) that restricts autoreactive T cells in vivo through a perforin-mediated mechanism. Thus, the present study explored the specific relationship among Aire, perforin-expressing DCs and immune tolerance, as well as their roles in type 1 diabetes. METHODS We conducted studies based on the Aire-overexpressing bone marrow-derived dendritic cell (BMDC) model. And through in vitro and in vivo experiments to observe that Aire-overexpressing BMDCs which express perforin induce immune tolerance and treat type 1 diabetes via TLR7/8. RESULTS Aire enhances the expression of perforin in BMDCs after treatment with the TLR7/8 ligand as well as promotes the expression of TLR7/8 and myeloid differentiation primary response gene 88 (MyD88)-dependent pathway molecules. Aire-overexpressing BMDCs mediate apoptosis of allogeneic CD8+ T cells via perforin in vitro. Moreover, Aire-overexpressing BMDCs enhance the therapeutic effect of type 1 diabetes in non-obese diabetic (NOD) mice via perforin and induce apoptosis of autoreactive CD8+ T cells in vivo. CONCLUSIONS These results provide an experimental basis for comprehensively elucidating the role and significance of Aire expression in peripheral DCs, thereby providing new ideas for the treatment of autoimmune diseases by using Aire as a target to induce the production of perforin-expressing DCs.
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Affiliation(s)
- Yi Zhang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yaoping Lu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yan Gao
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xiaojing Liang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Rongchao Zhang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xiaoya Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xueyang Zou
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China.
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Hochmeister S, Aeinehband S, Dorris C, Berglund R, Haindl MT, Velikic V, Gustafsson SA, Olsson T, Piehl F, Jagodic M, Zeitelhofer M, Adzemovic MZ. Effect of Vitamin D on Experimental Autoimmune Neuroinflammation Is Dependent on Haplotypes Comprising Naturally Occurring Allelic Variants of CIITA ( Mhc2ta). Front Neurol 2020; 11:600401. [PMID: 33304315 PMCID: PMC7693436 DOI: 10.3389/fneur.2020.600401] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 10/15/2020] [Indexed: 01/23/2023] Open
Abstract
An increasing body of evidence associates low vitamin D levels with increased risk of multiple sclerosis (MS), suggesting the possibility of a gene-environment interaction for this environmental factor in MS pathogenesis. Moreover, it has been shown that vitamin D downregulates major histocompatibility complex (MHC) class II expression in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We here report about the impact of a dietary vitamin D supplementation on EAE in the rat strains having functionally relevant allelic variations in the CIITA (Mhc2ta) gene, a master regulator of MHC class II expression. Full length myelin oligodendrocyte glycoprotein (MOG)-EAE was induced in DA.PVGav1-Vra4 congenic rats harboring the Vra4 locus from PVG strain in the EAE- susceptible DA background, and compared to the parental strains. The congenic rats fed with either vitamin D supplemented, deprived or regular diet developed an intermediate clinical EAE phenotype, in contrast to DA and PVG strains. Immunopathological studies revealed vitamin D dose-dependent effect on demyelination and inflammatory infiltration of the central nervous system (CNS), expression of MHC class II and CIITA, as well as downregulation of a range of pro-inflammatory genes. Taken together, our findings demonstrate an impact of vitamin D on the target tissue pathology and peripheral immune response during EAE in DA.PVGav1-Vra4 congenic strain. Thereby, our data provide evidence of a modulatory effect of vitamin D in context of genetic variances in the Vra4 locus/Mhc2ta gene in MS-like neuroinflammation, with potential relevance for the human demyelinating disease.
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Affiliation(s)
- Sonja Hochmeister
- Department of General Neurology, Medical University of Graz, Graz, Austria
| | - Shahin Aeinehband
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Charles Dorris
- School of Biosciences and Medicine, University of Surrey, Guildford, United Kingdom
| | - Rasmus Berglund
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michaela T Haindl
- Department of General Neurology, Medical University of Graz, Graz, Austria
| | - Vid Velikic
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Clinical Division of Social Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
| | - Sven A Gustafsson
- Department of Molecular Medicine and Surgery, Clinical Chemistry and Blood Coagulation Research, Karolinska Institutet, Stockholm, Sweden
| | - Tomas Olsson
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Fredrik Piehl
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Maja Jagodic
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Manuel Zeitelhofer
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Vascular Biology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Milena Z Adzemovic
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Blunk I, Thomsen H, Reinsch N, Mayer M, Försti A, Sundquist J, Sundquist K, Hemminki K. Genomic imprinting analyses identify maternal effects as a cause of phenotypic variability in type 1 diabetes and rheumatoid arthritis. Sci Rep 2020; 10:11562. [PMID: 32665606 PMCID: PMC7360775 DOI: 10.1038/s41598-020-68212-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/18/2020] [Indexed: 02/08/2023] Open
Abstract
Imprinted genes, giving rise to parent-of-origin effects (POEs), have been hypothesised to affect type 1 diabetes (T1D) and rheumatoid arthritis (RA). However, maternal effects may also play a role. By using a mixed model that is able to simultaneously consider all kinds of POEs, the importance of POEs for the development of T1D and RA was investigated in a variance components analysis. The analysis was based on Swedish population-scale pedigree data. With P = 0.18 (T1D) and P = 0.26 (RA) imprinting variances were not significant. Explaining up to 19.00% (± 2.00%) and 15.00% (± 6.00%) of the phenotypic variance, the maternal environmental variance was significant for T1D (P = 1.60 × 10-24) and for RA (P = 0.02). For the first time, the existence of maternal genetic effects on RA was indicated, contributing up to 16.00% (± 3.00%) of the total variance. Environmental factors such as the social economic index, the number of offspring, birth year as well as their interactions with sex showed large effects.
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Affiliation(s)
- Inga Blunk
- Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany.
| | - Hauke Thomsen
- Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- GeneWerk GmbH, Heidelberg, Germany
| | - Norbert Reinsch
- Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Manfred Mayer
- Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Asta Försti
- Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
- Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Jan Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
- Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA
- Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Izumo, Japan
| | - Kristina Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
- Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA
- Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Izumo, Japan
| | - Kari Hemminki
- Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic
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Singh G, Singh U, Singh S, Singh S. Immunogenetic Study of Diabetes Mellitus in Relation to HLA DQ and DR. Indian J Endocrinol Metab 2020; 24:325-332. [PMID: 33088755 PMCID: PMC7540833 DOI: 10.4103/ijem.ijem_564_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/05/2019] [Accepted: 06/25/2020] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Type-1 diabetes mellitus (T1DM) which is also known as insulin-dependent diabetes is diagnosed mainly during childhood and accounts for approximately 5%-10% of all cases of DM. In India, early onset diabetes (<15 years age) constitutes about 1%-4% of the total diabetic population. The insulitis as well as to a humoral (B cell) response with production of antibodies to IAA, GAD, and the protein tyrosine phosphatase IA2 (IA-2AA) is the main pathogenesis of T1DM. Human leukocyte antigen (HLA)-DR and DQ contributes approximately 40%-50% of the inherited susceptibility for T1DM and most frequently involved haplotypes are DRB1*0301-DQB1*0201, DRB1*0301-DQA1*0501-DQB1*0201, and DRB1*0401-DQB1*0302. METHOD AND MATERIAL Total 70 cases of DM in age group of 10 years to 65 years and 25 healthy controls of same age group 30 cases of complicated diabetic mellitus were included in the study. 2 mL blood was taken in an EDTA vial for HLA typing and 5 mL blood was taken in a plain vial for anti-GAD antibody. HLA DQB1 and DRB1 were done by sequence specific priming polymerase chain reaction method. Indirect immunofluorescent test was used for anti-GAD antibody. Statistical analysis was performed using SPSS version-16. RESULTS Total 40.9% cases of type-I DM were found seropositive for anti-GAD antibody. None of the cases of type-II DM was anti-GAD antibody positive. HLA DRB1*03010 were significantly more in diabetic patient (P < 0.011) as compared to control. DRB1*O403/6 shows that a relative risk of 1.08 was slightly more frequent in DM cases as compared to the control. DQB1*0201 was significantly high (P < 0.004) in DM patient as compared to control with a relative risk of 1.68. Correlation of DR, DQ antigen with types of DM showed that in type-I DM, DRB1*03010 was significantly high (P = 0.009) with a relative risk of 2.78 as compared type-II DM. In DQ typing, DQB1*0201 was significantly high in type-I DM in comparison to type-II DM (65% vs. 30%, P = 0.026, RR = 2.05). Comparison of DQB1 in type-I DM with healthy control showed that DQB1*0201 was significantly high in type-I DM as compared to healthy control (P = 0.0003, RR = 3.09). In type-I DM patient's homozygosity at DRB1*03010, DRB1*03010 was significantly high as compared to the control (P < 0.047, RR = 2.33). Correlation of anti-GAD antibody with DRB1 and DQB1 showed that 77.7% anti-GAD antibody positive cases were DRB1*03010 positive. Similarly, in DQB1 typing, 66.6% anti-GAD positive cases have DQB1*0201. CONCLUSION Prevalence of anti-GAD antibody in Indian population was found up to 45%. HLA DRB1*3010 and HLA DQB1*0201 were the most susceptible haplotypes for type-I DM. HLA DRB1*14 and HLA DRB1*15 were the protective haplotypes for type-I DM. Susceptibility to type-I DM increases when the homozygosity for DRB1*03010 was present. Diagnosis of type-I DM by anti-GAD antibody was possible in only 40.9% cases but if DRB1 and DQB1 typing is added in the diagnosis then diagnostic efficacy increases up to 83%.
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Affiliation(s)
- Gyanendra Singh
- Department of Pathology, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
| | - Usha Singh
- Department of Pathology, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
| | - S.K Singh
- Department of Endocrinology and, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
| | - Shailja Singh
- Former PHD Scholar, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
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Diedisheim M, Carcarino E, Vandiedonck C, Roussel R, Gautier JF, Venteclef N. Regulation of inflammation in diabetes: From genetics to epigenomics evidence. Mol Metab 2020; 41:101041. [PMID: 32603690 PMCID: PMC7394913 DOI: 10.1016/j.molmet.2020.101041] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/09/2020] [Accepted: 06/11/2020] [Indexed: 12/13/2022] Open
Abstract
Background Diabetes is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of preventive and therapeutic approaches. Genetic and environmental factors are the culprits involved in diabetes risk. Evidence from the last decade has highlighted that deregulation in the immune and inflammatory responses increase susceptibility to type 1 and type 2 diabetes. Spatiotemporal patterns of gene expression involved in immune cell polarisation depend on genomic enhancer elements in response to inflammatory and metabolic cues. Several studies have reported that most regulatory genetic variants are located in the non-protein coding regions of the genome and particularly in enhancer regions. The progress of high-throughput technologies has permitted the characterisation of enhancer chromatin properties. These advances support the concept that genetic alteration of enhancers may influence the immune and inflammatory responses in relation to diabetes. Scope of review Results from genome-wide association studies (GWAS) combined with functional and integrative analyses have elucidated the impacts of some diabetes risk-associated variants that are involved in the regulation of the immune system. Additionally, genetic variant mapping to enhancer regions may alter enhancer status, which in turn leads to aberrant expression of inflammatory genes associated with diabetes susceptibility. The focus of this review was to provide an overview of the current indications that inflammatory processes are regulated at the genetic and epigenomic levels in diabetes, along with perspectives on future research avenues that may improve understanding of the disease. Major conclusions In this review, we provide genetic evidence in support of a deregulated immune response as a risk factor in diabetes. We also argue about the importance of enhancer regions in the regulation of immune cell polarisation and how the recent advances using genome-wide methods for enhancer identification have enabled the determination of the impact of enhancer genetic variation on diabetes onset and phenotype. This could eventually lead to better management plans and improved treatment responses in human diabetes.
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Affiliation(s)
- Marc Diedisheim
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France
| | - Elena Carcarino
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France
| | - Claire Vandiedonck
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France
| | - Ronan Roussel
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France; Bichat-Claude Bernard, Hospital, AP-HP, Diabetology Department, Université de Paris, Paris, France
| | - Jean-François Gautier
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France; Lariboisière Hospital, AP-HP, Diabetology Department, Université de Paris, Paris, France
| | - Nicolas Venteclef
- Centre de Recherche des Cordeliers, INSERM, Université de Paris, IMMEDIAB Laboratory, F-75006, Paris, France.
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Morgan SA, Ali MM, Channon AA, Al-Sabahi S, Al Suwaidi H, Osman N, Al Salameen M, Khoja T. Prevalence and correlates of diabetes and its comorbidities in four Gulf Cooperation Council countries: evidence from the World Health Survey Plus. J Epidemiol Community Health 2019; 73:630-636. [PMID: 30894421 DOI: 10.1136/jech-2018-211187] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 01/31/2019] [Accepted: 02/19/2019] [Indexed: 02/02/2023]
Abstract
BACKGROUND The Gulf Cooperation Council countries are witnessing unprecedented changes due to fast economic development and population growth. The aims of this study were twofold: first, to estimate the prevalence of diabetes and its comorbidities; second, to examine the association of sociodemographic risk factors and healthcare service utilisation with diabetes. METHODS Data from the World Health Survey Plus (WHS+) from Kuwait, Oman, Saudi Arabia and the United Arab Emirates were used. The WHS+ is a nationally representative household survey of the adult population, conducted between 2008 and 2009. Both logistic regression and zero-inflated Poisson models were applied to examine the associations of risk factors, comorbidity and treatment with self-reported diabetes. RESULTS The highest level of diabetes was observed in Kuwait, with 40.8% among the oldest age group. High body mass index, older age and low education were all associated with diabetes in all settings. High levels of comorbidity existed within the diabetic population. Over 50% of diabetics in all countries reported having at least one chronic condition. In Kuwait and Saudi Arabia, one in five diabetics reported having two or more comorbidities. Treatment prevalence was above 80% across all sociodemographic categories. CONCLUSION The burden of diabetes, although high, is not uniform across populations in the four Gulf countries. Differential exposure to risk, such as unhealthy lifestyles, may be creating a disadvantage for certain populations and influencing the co-occurrence of chronic conditions. In response, a multifaceted and patient-centred approach is needed at all levels of healthcare to control and prevent non-communicable diseases.
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Affiliation(s)
- Sara Afshar Morgan
- Primary Care and Population Health, University of Southampton, Southampton, UK
| | - Mohamed Mahmoud Ali
- Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
| | - Andrew Amos Channon
- Department of Social Statistics and Demography, University of Southampton, Southampton, UK
| | | | - Huda Al Suwaidi
- Vulnerable Group Department, Community Development Authority, Dubai, United Arab Emirates
| | - Nabil Osman
- General Director for Health Statistics and Information, Ministry of Health, Riyadh, Saudi Arabia
| | - Mostafa Al Salameen
- Department of Health Registration, National Center of Health Information, Ministry of Health, Kuwait City, State of Kuwait, Kuwait
| | - Tawfik Khoja
- Department of Primary Care & Public Health, School of Public Health, Imperial College, London, UK
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Alper CA, Larsen CE, Trautwein MR, Alford DR. A stochastic epigenetic Mendelian oligogenic disease model for type 1 diabetes. J Autoimmun 2018; 96:123-133. [PMID: 30309752 DOI: 10.1016/j.jaut.2018.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 09/12/2018] [Indexed: 01/14/2023]
Abstract
The incidence of type 1 diabetes (T1D) and some other complex diseases is increasing. The cause has been attributed to an undefined changing environment. We examine the role of the environment (or any changing non-genetic mechanism) in causing the rising incidence, and find much evidence against it: 1) Dizygotic twin T1D concordance is the same as siblings of patients in general; 2) If the environment is responsible for both the discordance among identical twins of patients with T1D and its rising incidence, the twin concordance rate should be rising, but it is not; 3) Migrants from high-to low-incidence countries continue to have high-incidence children; 4) TID incidence among the offspring of two T1D parents is identical to the monozygotic twin rate. On the other hand, genetic association studies of T1D have revealed strong susceptibility in the major histocompatibility complex and many optional additive genes of small effect throughout the human genome increasing T1D risk. We have, from an analysis of previously published family studies, developed a stochastic epigenetic Mendelian oligogenic (SEMO) model consistent with published observations. The model posits a few required recessive causal genes with incomplete penetrance explaining virtually all of the puzzling features of T1D, including its rising incidence and the specific low T1D incidence rates among first-degree relatives of patients. Since historic selection against any causal gene could prevent T1D, we postulate that the rising incidence is because of increasing population mixing of parents from some previously isolated populations that had selected against different causal genes.
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Affiliation(s)
- Chester A Alper
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA; Department of Pediatrics, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA.
| | - Charles E Larsen
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA; Department of Pediatrics, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA
| | - Michael R Trautwein
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Dennis R Alford
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
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Yang J, Sun L, Fan X, Yin B, Kang Y, Tang L, An S. Effect of exercise on bone in poorly controlled type 1 diabetes mediated by the ActRIIB/Smad signaling pathway. Exp Ther Med 2018; 16:3686-3693. [PMID: 30233727 DOI: 10.3892/etm.2018.6601] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 08/01/2018] [Indexed: 02/07/2023] Open
Abstract
Myostatin (MSTN) is not only a key negative regulator of skeletal muscle secretion, however is also an endocrine factor that is transmitted to bone. To investigate the effect and possible mechanism of weight-bearing treadmill running on bone with poorly controlled Type 1 diabetes, rats were randomly divided into three groups: Normal control (NC), diabetic mellitus (DM) and diabetic exercise training groups (DM-WTR). The DM-WTR rats were trained with weight-bearing running. The results demonstrated that the levels of serum insulin, body weight, bone mass, muscle mass, grip strength, and serum calcium in the DM-WTR rats were significantly increased, whereas the levels of blood glucose, alkaline phosphatase, and tartrate-resistant acid phosphatase were markedly reduced in the DM-WTR rats compared with the DM rats. Weight-bearing running inhibited streptozocin (STZ)-induced MSTN mRNA and protein expression in the diabetic rats. The mRNA and protein expression levels of activin type IIB receptor and mothers against decapentaplegic homolog 2/3 and its phosphorylation in femur DM-WTR rats were reduced compared with DM rats. In addition, weight-bearing running enhanced the STZ-induced Wnt and β-catenin expression levels and reduced the STZ-induced glycogen synthase kinase (GSK)-3β expression in diabetic rats' femora. In conclusion, the results suggested that weight-bearing running could partially ameliorate STZ-induced femur atrophy via MSTN downregulation, and this may be associated with the inactivation of Activin A Receptor Type 2B/Smad2/3 signaling pathways and the activation of the Wnt/GSK3β/β-catenin signaling pathway. Further studies are needed to verify these conclusions.
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Affiliation(s)
- Jin Yang
- Department of Physical Education, Xi'an University of Posts and Telecommunications, Xi'an, Shaanxi 710121, P.R. China.,College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062, P.R. China
| | - Lijun Sun
- Institute of Sports Biology, Shaanxi Normal University, Xi'an, Shaanxi 710119, P.R. China
| | - Xiushan Fan
- Institute of Sports Biology, Shaanxi Normal University, Xi'an, Shaanxi 710119, P.R. China
| | - Bo Yin
- Institute of Sports Biology, Shaanxi Normal University, Xi'an, Shaanxi 710119, P.R. China
| | - Yiting Kang
- Institute of Sports Biology, Shaanxi Normal University, Xi'an, Shaanxi 710119, P.R. China
| | - Liang Tang
- Institute of Sports Biology, Shaanxi Normal University, Xi'an, Shaanxi 710119, P.R. China
| | - Shucheng An
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710062, P.R. China
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Redondo MJ, Steck AK, Pugliese A. Genetics of type 1 diabetes. Pediatr Diabetes 2018; 19:346-353. [PMID: 29094512 PMCID: PMC5918237 DOI: 10.1111/pedi.12597] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 09/18/2017] [Accepted: 09/20/2017] [Indexed: 12/23/2022] Open
Abstract
Type 1 diabetes (T1D) results from immune-mediated loss of pancreatic beta cells leading to insulin deficiency. It is the most common form of diabetes in children, and its incidence is on the rise. This article reviews the current knowledge on the genetics of T1D. In particular, we discuss the influence of HLA and non-HLA genes on T1D risk and disease progression through the preclinical stages of the disease, and the development of genetic scores that can be applied to disease prediction. Racial/ethnic differences, challenges and future directions in the genetics of T1D are also discussed.
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Affiliation(s)
- Maria J. Redondo
- Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030
| | - Andrea K. Steck
- University of Colorado School of Medicine, Barbara Davis Center for Childhood Diabetes, Aurora, CO, 80045
| | - Alberto Pugliese
- Diabetes Research Institute, Department of Medicine, Division of Endocrinology and Metabolism, Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136
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15
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16
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Fierabracci A. Type 1 Diabetes in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED): A "Rare" Manifestation in a "Rare" Disease. Int J Mol Sci 2016; 17:1106. [PMID: 27420045 PMCID: PMC4964482 DOI: 10.3390/ijms17071106] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 07/01/2016] [Indexed: 02/06/2023] Open
Abstract
Type 1 autoimmune polyglandular syndrome (APS1) is a rare autosomal recessive disease, caused by mutations in the autoimmune regulator gene (AIRE); the encoded Aire protein plays an important role in the establishment of the immunological tolerance acting as a transcriptional regulator of the expression of organ-specific antigens within the thymus in perinatal age. While a high prevalence for this rare syndrome is reported in Finland and Scandinavia (Norway), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) cohorts of patients are also detected in continental Italy and Sardinia, among Iranian Jews, as well as in other countries. The syndrome is diagnosed when patients present at least two out of the three fundamental disorders including chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Among the associated conditions insulin-dependent diabetes mellitus (Type 1 diabetes) has been rarely reported in different series of patients and occurring more frequently in Finnish APECED patients. In this review, we analyze the incidence of Type 1 diabetes as a clinical manifestation of APECED in different populations highlighting the peculiar genetic and immunological features of the disease when occurring in the context of this syndrome.
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Affiliation(s)
- Alessandra Fierabracci
- Infectivology and Clinical Trials Area, Children's Hospital Bambino Gesù, Rome 00146, Italy.
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Čukić I, Mõttus R, Luciano M, Starr JM, Weiss A, Deary IJ. Do personality traits moderate the manifestation of type 2 diabetes genetic risk? J Psychosom Res 2015; 79:303-8. [PMID: 26213352 PMCID: PMC4579920 DOI: 10.1016/j.jpsychores.2015.07.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/04/2015] [Accepted: 07/07/2015] [Indexed: 12/29/2022]
Abstract
OBJECTIVE To test whether personality traits moderate type 2 diabetes (T2D) genetic risk. METHODS Using a large community-dwelling sample (n=837, Mage=69.59±0.85years, 49% males) we fitted a series of linear regression models predicting glycated haemoglobin (HbA1c) from T2D polygenic risk - aggregation of small individual effects of a large number of single nucleotide polymorphisms (SNPs) - and five personality traits. We tested the main effects of personality traits and their interactions with T2D polygenic risk score, controlling for age and sex. The models in the final set were adjusted for cognitive ability, highest educational qualification, and occupational class. RESULTS Lower levels of openness were associated with heightened levels of HbA1c (β=-0.014, p=.032). There was a significant interaction between T2D polygenic risk score and agreeableness: lower agreeableness was related to a stronger association between T2D polygenic risk and HbA1c (β=-0.08, p=.021). In the model adjusted for cognitive ability, the main effect of openness was not significant (β=-0.08, p=.057). The interaction between agreeableness and T2D polygenic risk was still present after controlling for cognitive ability and socioeconomic status indicators, and the interaction between conscientiousness and polygenic risk score was also significant: lower conscientiousness was associated with a stronger association between T2D polygenic risk and HbA1c levels (β=0.09, p=.04). CONCLUSIONS Personality may be associated with markers of diabetes, and may moderate the expression of its genetic risk.
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Affiliation(s)
- Iva Čukić
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, UK; Department of Psychology, University of Edinburgh, UK.
| | - René Mõttus
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, UK; Department of Psychology, University of Edinburgh, UK; Department of Psychology, University of Tartu, Estonia.
| | - Michelle Luciano
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, UK; Department of Psychology, University of Edinburgh, UK.
| | - John M Starr
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, UK; Geriatric Medicine Unit, Western General Hospital, Edinburgh, UK.
| | | | - Ian J Deary
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, UK; Department of Psychology, University of Edinburgh, UK.
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Anwar WA, Khyatti M, Hemminki K. Consanguinity and genetic diseases in North Africa and immigrants to Europe. Eur J Public Health 2015; 24 Suppl 1:57-63. [PMID: 25107999 DOI: 10.1093/eurpub/cku104] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Endemic diseases are caused by environmental and genetic factors. While in this special issue several chapters deal with environmental factors, including infections, the present focus is on genetic causes of disease clustering due to inbreeding and recessive disease mechanisms. Consanguinity is implying sharing of genetic heritage because of marriage between close relatives originating from a common ancestor. With limited natural selection, recessive genes may become more frequent in an inbred compared with an outbred population. Consanguinity is common in North Africa (NA), and the estimates range from 40 to 49% of all marriages in Tunisia and 29-33% in Morocco. As a consequence, recessive disorders are common in the NA region, and we give some examples. Thalassaemia and sickle cell disease/anaemia constitute the most common inherited recessive disorders globally and they are common in NA, but with immigration they have spread to Europe and to other parts of the world. Another example is familial Mediterranean fever, which is common in the Eastern Mediterranean area. With immigrantion from that area to Sweden, it has become the most common hereditary autoinflammatory disease in that country, and there is no evidence that any native Swede would have been diagnosed with this disease. The examples discussed in this chapter show that the historic movement of populations and current immigration are influencing the concept of 'endemic' disease.
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Affiliation(s)
- Wagida A Anwar
- 1 Community Medicine Department, Ain Shams University, Cairo, Egypt
| | | | - Kari Hemminki
- 3 Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany4 Center for Primary Health Care Research, Lund University, 205 02, Malmö, Sweden
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19
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Molecular modeling and identification of novel glucokinase activators through stepwise virtual screening. J Mol Graph Model 2015; 57:122-30. [DOI: 10.1016/j.jmgm.2015.01.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 01/28/2015] [Accepted: 01/29/2015] [Indexed: 11/17/2022]
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Lee CN, Lew AM, Wu L. The potential role of dendritic cells in the therapy of Type 1 diabetes. Immunotherapy 2014; 5:591-606. [PMID: 23725283 DOI: 10.2217/imt.13.48] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Type 1 diabetes (T1D) is the result of T-cell mediated autoimmune destruction of pancreatic islet β-cells. The two current treatments for T1D are based on insulin or islet-cell replacement rather than the pathogenesis of T1D and remain problematic. Islet/pancreas transplantation does not cater for the majority of sufferers due to the lack of supply of organs and the need for continuous immunosuppression regimens. The mainstay treatment is insulin replacement, but this is disruptive to lifestyle and does not protect against severe long-term complications. An early vaccination and long-term restoration of immune tolerance to self-antigens in T1D patients (reversing the immunopathogenesis of the disease) would be preferable. Dendritic cells (DCs) are potent APCs and play an important role in inducing and maintaining immune tolerance. Targeting DCs through different DC surface molecules shows effective modulation of immune responses. Their feasibility for immunotherapy to prolong transplant survival and cancer immunotherapy has been demonstrated. Therefore, DCs could potentially be used in the treatment of autoimmune diseases. This review summarizes new insights into DCs as a potential therapeutic target for the treatment of T1D.
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Affiliation(s)
- Chin-Nien Lee
- Molecular Immunology Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
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Fekih Mrissa N, Mrad M, Ouertani H, Baatour M, Sayeh A, Nsiri B, Lamine K, Zidi B, Gritli N. Association of HLA-DR-DQ polymorphisms with diabetes in Tunisian patients. Transfus Apher Sci 2013; 49:200-4. [DOI: 10.1016/j.transci.2013.01.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2012] [Revised: 10/01/2012] [Accepted: 01/10/2013] [Indexed: 12/18/2022]
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Wu YL, Ding YP, Gao J, Tanaka Y, Zhang W. Risk factors and primary prevention trials for type 1 diabetes. Int J Biol Sci 2013; 9:666-79. [PMID: 23904791 PMCID: PMC3729009 DOI: 10.7150/ijbs.6610] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2013] [Accepted: 07/09/2013] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease resulting in the designated immune destruction of insulin producing β-cells, usually diagnosed in youth, and associated with important psychological, familial, and social disorders. Once diagnosed, patients need lifelong insulin treatment and will experience multiple disease-associated complications. There is no cure for T1DM currently. The last decade has witnessed great progress in elucidating the causes and treatment of the disease based on numerous researches both in rodent models of spontaneous diabetes and in humans. This article summarises our current understanding of the pathogenesis of T1DM, the roles of the immune system, genes, environment and other factors in the continuing and rapid increase in T1DM incidence at younger ages in humans. In addition, we discuss the strategies for primary and secondary prevention trials of T1DM. The purpose of this review is to provide an overview of this disorder's pathogenesis, risk factors that cause the disease, as well as to bring forward an ideal approach to prevent and cure the disorder.
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Affiliation(s)
- Yan-Ling Wu
- Virus Inspection Department, Zhejiang Provincial Center for Disease Control and Prevention, 630 Xincheng Road, Hangzhou, 310051, PR China.
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Andersson C, Vaziri-Sani F, Delli A, Lindblad B, Carlsson A, Forsander G, Ludvigsson J, Marcus C, Samuelsson U, Ivarsson S, Lernmark A, Larsson HE. Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes. Pediatr Diabetes 2013; 14:97-105. [PMID: 22957668 DOI: 10.1111/j.1399-5448.2012.00916.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 06/08/2012] [Accepted: 07/06/2012] [Indexed: 01/26/2023] Open
Abstract
OBJECTIVE To establish the diagnostic sensitivity of and the relationships between autoantibodies to all three Zinc transporter 8 (Zinc transporter 8 autoantibody to either one, two, or all three amino acid variants at position 325, ZnT8A) variants to human leukocyte antigen (HLA)-DQ and to autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A), and insulin (IAA). METHODS We analyzed 3165 patients with type 1 diabetes (T1D) in the Better Diabetes Diagnosis study for HLA-DQ genotypes and all six autoantibodies (ZnT8RA, arginine 325 Zinc transporter 8 autoantibody; ZnT8WA, tryptophan 325 Zinc transporter 8 autoantibody; ZnT8QA, glutamine 325 Zinc transporter 8 autoantibody; GADA, IA-2A, and IAA). RESULTS ZnT8A was found in 65% of the patients and as many as 108 of 3165 (3.4%) had 1-3 ZnT8A alone. None had ZnT8QA alone. Together with GADA (56%), IA-2A (73%), and IAA (33%), 93% of the T1D patients were autoantibody positive. All three ZnT8A were less frequent in children below 2 yr of age (p < 0.0001). All three ZnT8A were associated with DQA1-B1*X-0604 (DQ6.4) and DQA1-B1*03-0302 (DQ8). ZnT8WA and ZnT8QA were negatively associated with DQA1-B1*05-02 (DQ2). CONCLUSIONS Analysis of ZnT8A increased the diagnostic sensitivity of islet autoantibodies for T1D as only 7% remained islet autoantibody negative. The association between DQ6.4 and all three ZnT8A may be related to ZnT8 antigen presentation by the DQ6.4 heterodimer.
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Affiliation(s)
- C Andersson
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
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Antibodies recognizing specific Mycobacterium avium subsp. paratuberculosis's MAP3738c protein in type 1 diabetes mellitus children are associated with serum Th1 (CXCL10) chemokine. Cytokine 2012; 61:337-9. [PMID: 23265968 DOI: 10.1016/j.cyto.2012.11.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 09/26/2012] [Accepted: 11/16/2012] [Indexed: 11/24/2022]
Abstract
Recently Mycobacterium avium subsp. paratuberculosis (Map) was associated to type 1 diabetes mellitus (T1DM). In this study we investigated for Map presence in children affected by T1DM compared to healthy children. A pool of 212 sera from T1DM children at onset was compared to sera from 57 healthy children for humoral immune response towards the Map specific protein MAP3738c by ELISA. Serum concentrations of CXCL10 (pro-Th1) and CCL2 (pro-Th2) chemokines were also measured in both sera pool. Results showed that T1DM children had a stronger seropositivity towards MAP3738c protein compared to healthy children. Data highlighted also the correlation between serum activity of T1DM patients towards the specific protein of Map and the increase of CXCL10 concentration if compared to non-diabetic subjects. In conclusion, an immune response to Map in T1DM patients at onset was observed and this may indicate a role of the bacterium in triggering or precipitating the disease.
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Cardwell CR, Stene LC, Ludvigsson J, Rosenbauer J, Cinek O, Svensson J, Perez-Bravo F, Memon A, Gimeno SG, Wadsworth EJK, Strotmeyer ES, Goldacre MJ, Radon K, Chuang LM, Parslow RC, Chetwynd A, Karavanaki K, Brigis G, Pozzilli P, Urbonaite B, Schober E, Devoti G, Sipetic S, Joner G, Ionescu-Tirgoviste C, de Beaufort CE, Harrild K, Benson V, Savilahti E, Ponsonby AL, Salem M, Rabiei S, Patterson CC. Breast-feeding and childhood-onset type 1 diabetes: a pooled analysis of individual participant data from 43 observational studies. Diabetes Care 2012; 35:2215-25. [PMID: 22837371 PMCID: PMC3476923 DOI: 10.2337/dc12-0438] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders. RESEARCH DESIGN AND METHODS Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies. RESULTS Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64-0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75-1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81-1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78-1.00). These associations were all subject to marked heterogeneity (I(2) = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75-0.99), and heterogeneity was reduced (I(2) = 0%). Adjustments for potential confounders altered these estimates very little. CONCLUSIONS The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies.
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Affiliation(s)
- Chris R Cardwell
- School of Medicine and Dentistry, Queen’s University Belfast, Belfast, UK.
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Tang S, Peng W, Wang C, Tang H, Zhang Q. Association of the PTPN22 gene (+1858C/T, -1123G/C) polymorphisms with type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract 2012; 97:446-52. [PMID: 22572103 DOI: 10.1016/j.diabres.2012.04.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 02/28/2012] [Accepted: 04/16/2012] [Indexed: 10/28/2022]
Abstract
OBJECTIVE A meta-analysis was conducted to evaluate the association of PTPN22 gene (+1858C/T -1123G/C) polymorphism with T1DM susceptibility. METHODS Electronic databases were used to identify published studies before September 2011. We adopted the most appropriate genetic model. The combined odds ratio (OR) with 95% confidence interval (95% CI) was calculated to estimate the strength of the association in a fixed or random effect model. Heterogeneity and publication bias were also assessed. RESULTS Totally, 25 case-control studies including 8613 T1DM cases and 10,133 healthy controls (24 studies containing 8129 cases and 9641 controls for PTPN22 +1858C/T, 5 studies including 1460 cases and 1609 controls for PTPN22 -1123G/C) were identified as eligible and analyzed. The most appropriate co-dominant model was adopted. A significant association of PTPN22 +1858C/T gene polymorphism was found in overall population. When stratified by race, significance was observed in Europe and America, but not in Asia. We did not detect any association for PTPN22 -1123G/C polymorphism. CONCLUSIONS Our study indicated that T1DM is associated with PTPN22 +1858C/T gene polymorphism, and targeting this promoter polymorphism should be dependent on ethnicity. Whether -1123G/C polymorphism is a susceptibility locus for T1DM, further studies with well-designed among different ethnicity populations are required.
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Affiliation(s)
- Songtao Tang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Hemminki K. Familial risks in understanding type 1 diabetes genetics. Nat Rev Genet 2012; 13:146; author reply 146. [DOI: 10.1038/nrg3069-c1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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El-Ella SSA, Shaltout A, Tawfik MA, Deeb M, EL-Lahony DM, Khatab ES, Barseem NF. Non HLA genetic markers association with type-1 diabetes mellitus. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2011. [DOI: 10.1016/j.ejmhg.2011.02.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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D’Angeli MA, Merzon E, Valbuena LF, Tirschwell D, Paris CA, Mueller BA. Environmental factors associated with childhood-onset type 1 diabetes mellitus: an exploration of the hygiene and overload hypotheses. ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE 2010; 164:732-8. [PMID: 20679164 PMCID: PMC3064074 DOI: 10.1001/archpediatrics.2010.115] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To assess the relationship between selected maternal and infant characteristics and risk of type 1 diabetes mellitus, specifically characteristics identified from birth records that may pertain to the hygiene or overload hypotheses. DESIGN Population-based case-control study. SETTING Washington State from 1987 to 2005. PARTICIPANTS All children younger than 19 years hospitalized for type 1 diabetes (International Classification of Diseases, Ninth Revision codes 250.x1 and 250.x3) identified (n=1852) from hospital discharge data and linked with their birth certificates. Controls (n=7408) were randomly selected from birth records, frequency matched on year of birth. MAIN EXPOSURES Maternal factors included age, race, educational attainment, marital status, use of Medicaid insurance, body mass index, prepregnancy weight, prior births, timing and adequacy of prenatal care, and cesarean delivery. Infant factors included birth weight, size for gestational age, and gestational age. MAIN OUTCOME MEASURE The main outcome was first hospitalization for type 1 diabetes mellitus; adjusted odds ratios were estimated for the association of selected maternal and infant characteristics with type 1 diabetes. RESULTS Consistent with the hygiene hypothesis, type 1 diabetes was negatively associated with having older siblings (for >or=3 siblings, odds ratio [OR], 0.56; 95% confidence interval [CI], 0.45-0.70) and with indicators of lower economic status or care access, such as an unmarried mother (OR, 0.79; 95% CI, 0.69-0.91), inadequate prenatal care (OR, 0.53; 95% CI, 0.40-0.71), or Medicaid insurance (OR, 0.67; 95% CI, 0.58-0.77). Related to the overload hypothesis, maternal body mass index of 30 or higher (OR, 1.29; 95% CI, 1.01-1.64) was associated with increased risk of diabetes. CONCLUSION Environmental factors related to decreased antigenic stimulation in early life and maternal obesity may be associated with type 1 diabetes.
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Affiliation(s)
- Marisa A. D’Angeli
- Washington State Department of Health, Communicable Disease Epidemiology, 1610 NE 150 St., Shoreline, WA 98155
| | - Eugene Merzon
- Department of Family Medicine Tel Aviv University, Ramat Aviv, Israel and Department of Family Medicine, Leumit Health Fund, Israel
| | - Luisa F. Valbuena
- Department of Epidemiology, University of Washington, Box 357236, Seattle, WA 98195-7236
| | - David Tirschwell
- UW Medicine/Harborview Stroke Center, Department of Neurology, University of Washington, 325 Ninth Avenue, Box 359775, Seattle, WA 98104
| | - Carolyn A. Paris
- Department of Pediatrics, Division of Emergency Medicine, Seattle Children’s Hospital, 4800 Sand Point Way, Box 359300, Seattle, WA 98105
| | - Beth A. Mueller
- Department of Epidemiology, University of Washington, Box 357236, Seattle, WA 98195-7236
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Pociot F, Akolkar B, Concannon P, Erlich HA, Julier C, Morahan G, Nierras CR, Todd JA, Rich SS, Nerup J. Genetics of type 1 diabetes: what's next? Diabetes 2010; 59:1561-71. [PMID: 20587799 PMCID: PMC2889752 DOI: 10.2337/db10-0076] [Citation(s) in RCA: 229] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2010] [Accepted: 04/05/2010] [Indexed: 12/21/2022]
Affiliation(s)
- Flemming Pociot
- Department of Genome Biology, Hagedorn Research Institute, Gentofte, Denmark.
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Rosinger S, Nutland S, Mickelson E, Varney MD, Boehm BO, Olsem GJ, Hansen JA, Nicholson I, Hilner JE, Perdue LH, Pierce JJ, Akolkar B, Nierras C, Steffes MW. Collection and processing of whole blood for transformation of peripheral blood mononuclear cells and extraction of DNA: the Type 1 Diabetes Genetics Consortium. Clin Trials 2010; 7:S65-74. [PMID: 20595244 PMCID: PMC2917848 DOI: 10.1177/1740774510373493] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND and PURPOSE To yield large amounts of DNA for many genotype analyses and to provide a renewable source of DNA, the Type 1 Diabetes Genetics Consortium (T1DGC) harvested DNA and peripheral blood mononuclear cells (PBMCs) from individuals with type 1 diabetes and their family members in several regions of the world. METHODS DNA repositories were established in Asia-Pacific, Europe, North America, and the United Kingdom. To address region-specific needs, different methods and sample processing techniques were used among the laboratories to extract and to quantify DNA and to establish Epstein-Barr virus transformed cell lines. RESULTS More than 98% of the samples of PBMCs were successfully transformed. Approximately 20-25 microg of DNA were extracted per mL of whole blood. Extraction of DNA from the cell pack ranged from 92 to 165 microg per cell pack. In addition, the extracted DNA from whole blood or transformed cells was successfully utilized in each regional human leukocyte antigen genotyping laboratory and by several additional laboratories performing consortium-wide genotyping projects. LIMITATIONS Although the isolation of PBMCs was consistent among sites, the measurement of DNA was difficult to harmonize. CONCLUSIONS DNA repositories can be established in different regions of the world and produce similar amounts of high-quality DNA for a variety of high-throughput genotyping techniques. Furthermore, even with the distances and time necessary for transportation, highly efficient transformation of PBMCs is possible. For future studies/trials involving several laboratories in different locations, the T1DGC experience includes examples of protocols that may be applicable. In summary, T1DGC has developed protocols that would be of interest to any scientific organization attempting to overcome the logistical problems associated with studies/trials spanning multiple research facilities, located in different regions of the world.
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Affiliation(s)
- Silke Rosinger
- Division of Endocrinology and Diabetes, Department of Internal Medicine, Ulm University, Ulm, Germany
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Chiocchetti A, Orilieri E, Cappellano G, Barizzone N, D'Alfonso S, D'Annunzio G, Lorini R, Ravazzolo R, Cadario F, Martinetti M, Calcaterra V, Cerutti F, Bruno G, Larizza D, Dianzani U. The Osteopontin Gene +1239A/C Single Nucleotide Polymorphism is Associated with Type 1 Diabetes Mellitus in the Italian Population. Int J Immunopathol Pharmacol 2010; 23:263-9. [DOI: 10.1177/039463201002300124] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Secreted phosphoprotein 1, also known as Osteopontin (Opn), is a proinflammatory cytokine involved in the TH1 response and is highly expressed in the islets and pancreatic lymph nodes of non-obese diabetic mice before the onset of diabetes. In humans, typing of the +1239A/C single nucleotide polymorphism (SNP) in the 3'UTR of the Opn gene (SPP1) showed that +1239C carriers displayed higher Opn serum levels than +1239A homozygotes and a higher risk of developing autoimmune/lymphoproliferative syndrome, multiple sclerosis, and systemic lupus erythematosus. The aim of this work is to evaluate whether +1239A/C is also associated with type 1 diabetes mellitus (T1DM). We typed +1239A/C in an initial cohort of 184 T1DM patients and 361 controls, and confirmed our data in a second cohort of 513 patients and 857 controls. In both cohorts, +1239C carriers displayed a significantly higher risk of T1DM than +1239A homozygotes (combined cohorts: OR=1.63, 95%CI: 1.34–1.97). Clinical analysis did not detect any differences between patients carrying or not +1239C in terms of gender distribution and age at T1DM diagnosis. These data suggest that SPP1 variants marked by +1239C are associated with T1DM development in the Italian population. The predisposing effect may depend on its effect on Opn levels.
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Affiliation(s)
| | | | | | | | | | - G. D'Annunzio
- Department of Pediatric Sciences and Laboratory of Molecular Genetics, Gaslini Institute-IRCCS, University of Genoa, Genoa
| | - R. Lorini
- Department of Pediatric Sciences and Laboratory of Molecular Genetics, Gaslini Institute-IRCCS, University of Genoa, Genoa
| | - R. Ravazzolo
- Department of Pediatric Sciences and Laboratory of Molecular Genetics, Gaslini Institute-IRCCS, University of Genoa, Genoa
| | | | - M. Martinetti
- Immunohaematology and Transfusion Center Fondazione IRCCS Policlinico San Matteo, Pavia
| | - V. Calcaterra
- Department of Pediatric Sciences University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia
| | - F. Cerutti
- Department of Pediatrics, University of Turin, Turin, Italy
| | - G. Bruno
- Department of Internal Medicine, University of Turin, Turin, Italy
| | - D. Larizza
- Department of Pediatric Sciences University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia
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Abstract
OBJECTIVE Our aim was to study the recurrence risk of type 1 diabetes in the offspring of parents with adult-onset (15-39 years) type 1 diabetes and to evaluate the transmission of diabetes within a continuum of parental age at onset of diabetes from childhood to adulthood. RESEARCH DESIGN AND METHODS Diabetes status of all offspring (n = 9,636) in two Finnish cohorts of parents with type 1 diabetes was defined until the end of year 2007. Cumulative incidences of type 1 diabetes among the offspring were estimated, and several factors contributing to the risk were assessed. RESULTS During 137,455 person-years, a total of 413 offspring were diagnosed with type 1 diabetes. The cumulative incidence by 20 years was 4.0% (95% CI 3.1-4.8) for the offspring of parents with adult-onset diabetes. The risk was equal according to the sex of the parents. The cumulative incidence decreased in parallel with the increase in age at onset of diabetes in the fathers. In the offspring of diabetic mothers, the risk was equal regardless of the age at onset of diabetes. However, the reduced risk in the maternal offspring was most pronounced in the daughters of the mothers with a diagnosis age <10 years. CONCLUSIONS Type 1 diabetes transmission ratio distortion is strongly related to the sex and age at onset of diabetes in the diabetic parents.
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Affiliation(s)
- Valma Harjutsalo
- Folkhälsan Institute of Genetics, Folkhälsan Research Centre, Biomedicum Helsinki, Helsinki, Finland.
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Hemminki K, Li X, Sundquist J, Sundquist K. Familial association between type 1 diabetes and other autoimmune and related diseases. Diabetologia 2009; 52:1820-8. [PMID: 19543881 DOI: 10.1007/s00125-009-1427-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2009] [Accepted: 05/28/2009] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS In the era of genome-wide association studies, familial risks are used to estimate disease heritability and success in gene identification. We wanted to estimate associations between type 1 diabetes mellitus and 33 autoimmune and related diseases in parents, offspring, singleton siblings and twins. METHODS The availability of a Multigeneration Register in Sweden provides reliable access to families throughout the last century. The diseases in individual family members were obtained through linkage to the Hospital Discharge Register. Standardised incidence ratios (SIRs) were calculated as relative risks of contracting type 1 diabetes in family members of affected patients compared with those lacking affected family members. RESULTS Among a total of 450,899 patients, 21,168 were diagnosed with type 1 diabetes. Familial cases amounted to 10.3% of all type 1 diabetes patients. SIR for type 1 diabetes was 8.23 in offspring of affected parents, 11.92 in singleton siblings, 39.22 in multiplex families and 21.88 in twins; the calculated risk for monozygotic twins was 32.33. Type 1 diabetes in offspring was associated with 13 diseases in parents, including Addison's disease (SIR 2.41), asthma (1.38), coeliac disease (2.73), Graves' disease/hyperthyroidism (1.86), Hashimoto disease/hypothyroidism (2.35), pernicious anaemia (3.09), primary biliary cirrhosis (3.63), rheumatoid arthritis (2.12), sarcoidosis (1.62), systemic lupus erythematosus (2.04), ulcerative colitis (1.23) and Wegener's granulomatosis (2.12). CONCLUSIONS/INTERPRETATION The concordant familial risks for type 1 diabetes were high and the calculated risk for multiplex families and monozygotic twins may be explained by epistatic gene x gene or gene x environment interactions. Familial associations with several autoimmune and related diseases suggest genetic sharing and challenge to gene identification.
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Affiliation(s)
- K Hemminki
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
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Morahan G, Mehta M, McKinnon E, James I. Effect of linkage status of affected sib-pairs on the search for novel type 1 diabetes susceptibility genes in the HLA complex. Diabetes Obes Metab 2009; 11 Suppl 1:67-73. [PMID: 19143817 PMCID: PMC2753859 DOI: 10.1111/j.1463-1326.2008.01005.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
AIM Type 1 diabetes susceptibility is influenced by a number of genes, of which those with the strongest effects map to the human leucocyte antigen (HLA) complex. Evidence for linkage of non-HLA genes in several affected sib-pair analyses was increased if the HLA or gender status of the sibs was considered independently. We investigated whether linkage status at the HLA complex differentially affected transmission of alleles to sibs depending on their HLA or gender linkage status. METHODS Genotypes of 2437 markers typed on 11 279 individuals from 2363 families, stratified according to HLA and gender, were examined using the transmission disequilibrium test. RESULTS Several significant single nucleotide polymorphisms (SNPs) loci were found near the class II genes; no significant SNPs were found by these analyses near the class I or class II genes. Other significant effects were found when the gender of the sibs or the parents was considered. There was not a significant difference in HLA-DRB genotypes between the stratified sets. CONCLUSIONS These results suggest the presence of novel recessive susceptibility gene(s) within the HLA complex.
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Affiliation(s)
- G Morahan
- Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Perth, Western Australia, Australia.
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Huber A, Menconi F, Corathers S, Jacobson EM, Tomer Y. Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms. Endocr Rev 2008; 29:697-725. [PMID: 18776148 PMCID: PMC2583387 DOI: 10.1210/er.2008-0015] [Citation(s) in RCA: 143] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Type 1 diabetes (T1D) and autoimmune thyroid diseases (AITD) frequently occur together within families and in the same individual. The co-occurrence of T1D and AITD in the same patient is one of the variants of the autoimmune polyglandular syndrome type 3 [APS3 variant (APS3v)]. Epidemiological data point to a strong genetic influence on the shared susceptibility to T1D and AITD. Recently, significant progress has been made in our understanding of the genetic association between T1D and AITD. At least three genes have been confirmed as major joint susceptibility genes for T1D and AITD: human leukocyte antigen class II, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22. Moreover, the first whole genome linkage study has been recently completed, and additional genes will soon be identified. Not unexpectedly, all the joint genes for T1D and AITD identified so far are involved in immune regulation, specifically in the presentation of antigenic peptides to T cells. One of the lessons learned from the analysis of the joint susceptibility genes for T1D and AITD is that subset analysis is a key to dissecting the etiology of complex diseases. One of the best demonstrations of the power of subset analysis is the CTLA-4 gene in T1D. Although CTLA-4 showed very weak association with T1D, when analyzed in the subset of patients with both T1D and AITD, the genetic effect of CTLA-4 was significantly stronger. Gene-gene and genetic-epigenetic interactions most likely play a role in the shared genetic susceptibility to T1D and AITD. Dissecting these mechanisms will lead to a better understanding of the etiology of T1D and AITD, as well as autoimmunity in general.
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Affiliation(s)
- Amanda Huber
- Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA
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Harnesk K, Swanberg M, Ockinger J, Diez M, Lidman O, Wallström E, Lobell A, Olsson T, Piehl F. Vra4 congenic rats with allelic differences in the class II transactivator gene display altered susceptibility to experimental autoimmune encephalomyelitis. THE JOURNAL OF IMMUNOLOGY 2008; 180:3289-96. [PMID: 18292553 DOI: 10.4049/jimmunol.180.5.3289] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Presentation of Ag bound to MHC class II (MHC II) molecules to CD4+ T cells is a key event in adaptive immune responses. Genetic differences in MHC II expression in the rat CNS were recently positioned to allelic variability in the CIITA gene (Mhc2ta), located within the Vra4 locus on rat chromosome 10. In this study, we have examined reciprocal Vra4-congenic strains on the DA and PVGav1 backgrounds, respectively. After experimental nerve injury the strain-specific MHC II expression on microglia was reversed in the congenic strains. Similar findings were obtained after intraparenchymal injection of IFN-gamma in the brain. Expression of MHC class II was also lower on B cells and dendritic cells from the DA.PVGav1-Vra4- congenic strain compared with DA rats after in vitro stimulation with IFN-gamma. We next explored whether Vra4 may affect the outcome of experimental autoimmune disease. In experimental autoimmune encephalomyelitis induced by immunization with myelin oligodendrocyte glycoprotein, DA.PVGav1-Vra4 rats displayed a lower disease incidence and milder disease course compared with DA, whereas both PVGav1 and PVGav1.DA-Vra4 rats were completely protected. These results demonstrate that naturally occurring allelic differences in Mhc2ta have profound effects on the quantity of MHC II expression in the CNS and on immune cells and that this genetic variability also modulates susceptibility to autoimmune neuroinflammation.
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Affiliation(s)
- Karin Harnesk
- Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden
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Rabin RL, Levinson AI. The nexus between atopic disease and autoimmunity: a review of the epidemiological and mechanistic literature. Clin Exp Immunol 2008; 153:19-30. [PMID: 18505431 DOI: 10.1111/j.1365-2249.2008.03679.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
There has been considerable interest in defining the relationship between the expression of allergic and autoimmune diseases in populations of patients. Are patients with autoimmune disease 'protected' from developing allergic (immunoglobulin E-mediated) diseases? Does the establishment of an atopic phenotype reduce the risk of the subsequent development of autoimmune diseases? Although there are clinical studies addressing this question, methodological problems, particularly in identification of atopic subjects, limits their usefulness. Moreover, an immune-based explanation of the observed epidemiological findings has relied on a paradigm that is currently undergoing increased scrutiny and modification to include newly defined effector cell subsets and the interaction between genetic and environmental factors, such as early endotoxin or mycobacterial exposure. To address this question, we reviewed a series of clinical reports that addressed coincidence or co-prevalence of atopy with four autoimmune diseases: psoriasis, rheumatoid arthritis, multiple sclerosis and type I diabetes mellitus. We present a model whereby active T helper type 1 (Th1) inflammation may suppress the development of atopy, and atopy may suppress the severity but not necessarily the onset of autoimmunity, and then discuss our model in the context of mechanisms of adaptive immunity with particular reference to the Th1/Th2 paradigms. Because the ultimate goal is to ameliorate or cure these diseases, our discussion may help to predict or interpret unexpected consequences of novel therapeutic agents used to target autoimmune or atopic diseases.
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Affiliation(s)
- R L Rabin
- Center for Biologics Evaluation and Research, USFDA, Bethesda, MD 20892-4555, USA.
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40
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Orilieri E, Cappellano G, Clementi R, Cometa A, Ferretti M, Cerutti E, Cadario F, Martinetti M, Larizza D, Calcaterra V, D'Annunzio G, Lorini R, Cerutti F, Bruno G, Chiocchetti A, Dianzani U. Variations of the perforin gene in patients with type 1 diabetes. Diabetes 2008; 57:1078-83. [PMID: 18198357 DOI: 10.2337/db07-0947] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1, cause familial hemophagocytic lymphohistiocytosis but have also been associated with lymphomas and the autoimmune/lymphoproliferative syndrome. The aim of this work was to investigate the role of PRF1 variations in type 1 diabetes. RESEARCH DESIGN AND METHODS We typed for the N252S and A91V variations in an initial population of 352 type 1 diabetic patients and 816 control subjects and a second population of 365 patients and 964 control subjects. Moreover, we sequenced the coding sequence and intron-exons boundaries in 200 patients and 300 control subjects. RESULTS In both cohorts, allelic frequency of N252S was significantly higher in patients than in control subjects (combined cohorts: 1.5 vs. 0.4%; odds ratio 6.68 [95% CI 1.83-7.48]). Sequencing of the entire coding region detected one novel mutation in one patient, causing a P477A amino acid change not detected in 199 patients and 300 control subjects. Typing for HLA-DQA1 and DQB1 alleles showed that type 1 diabetes-predisposing DQ alpha/DQ beta heterodimers were less frequent in patients carrying N252S or P477A than in those carrying wild-type PRF1. We previously found that natural killer (NK) activity is not decreased in most N252S heterozygotes, but we detected one whose NK activity was normal at the age of 12 but strikingly low in early childhood. Here, we discovered that NK function was low in three heterozygotes in early childhood, one homozygous adult, and in the subject carrying P477A. CONCLUSIONS These data suggest that N252S and possibly other PRF1 variations are susceptibility factors for type 1 diabetes development.
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Affiliation(s)
- Elisabetta Orilieri
- Interdisciplinary Research Center of Autoimmune Diseases and Department of Medical Sciences, A. Avogadro University of Eastern Piedmont, Novara, Italy
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Santiago JL, Martínez A, Núñez C, de la Calle H, Fernández-Arquero M, de la Concha EG, Urcelay E. Association of MYO9B haplotype with type 1 diabetes. Hum Immunol 2008; 69:112-5. [DOI: 10.1016/j.humimm.2008.01.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2007] [Revised: 12/20/2007] [Accepted: 01/10/2008] [Indexed: 12/11/2022]
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42
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Abstract
The discovery that a single-nucleotide polymorphism (SNP) in lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, is associated with type 1 diabetes (T1D) has now been verified by numerous studies and has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis (JRA), systemic lupus erythematosus, Graves' disease, generalized vitiligo and other human autoimmune diseases. In this paper, we discuss the association of PTPN22 with autoimmunity, the biochemistry of the PTPN22-encoded phosphatase, and the molecular mechanism(s) by which the disease-predisposing allele contributes to the development of human disease.
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MESH Headings
- Alleles
- Autoimmune Diseases/enzymology
- Autoimmune Diseases/genetics
- Autoimmune Diseases/immunology
- Autoimmunity
- Genetic Predisposition to Disease
- Humans
- Polymorphism, Single Nucleotide
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/chemistry
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
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Affiliation(s)
- Torkel Vang
- The Burnham Institute for Medical Research, La Jolla, CA 92037, USA
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43
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Shin JH, Janer M, McNeney B, Blay S, Deutsch K, Sanjeevi CB, Kockum I, Lernmark A, Graham J, Arnqvist H, Björck E, Eriksson J, Nyström L, Ohlson LO, Scherstén B, Ostman J, Aili M, Bååth LE, Carlsson E, Edenwall H, Forsander G, Granström BW, Gustavsson I, Hanås R, Hellenberg L, Hellgren H, Holmberg E, Hörnell H, Ivarsson SA, Johansson C, Jonsell G, Kockum K, Lindblad B, Lindh A, Ludvigsson J, Myrdal U, Neiderud J, Segnestam K, Sjöblad S, Skogsberg L, Strömberg L, Ståhle U, Thalme B, Tullus K, Tuvemo T, Wallensteen M, Westphal O, Aman J. IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5. Genes Immun 2007; 8:503-12. [PMID: 17641683 DOI: 10.1038/sj.gene.6364413] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.
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Affiliation(s)
- J-H Shin
- Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, British Columbia, Canada
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44
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Abstract
In part 1 of this 2-part article the author discusses the physiology and complications of diabetes mellitus (DM), a chronic and progressive disorder which affects all ages of the population. The number of people diagnosed with diabetes is approximately 1.8 million and an estimated further 1 million are undiagnosed (Department of Health, 2005). In the UK, 1-2% of the population have diabetes and among school children this is approximately 2 in 1000 (Watkins, 1996). There are two main types of diabetes--type 1 and type 2 (Porth, 2005). The aetiology of DM is unknown; however, genetic and environmental factors have been linked to its development. Type 1 results from the loss of insulin production in the beta cells of the pancreas, and type 2 from a lack of serum insulin or poor uptake of glucose into the cells. Diabetes causes disease in many organs in the body, which may be life-threatening if untreated. Complications such as heart disease, vascular disease, renal failure and blindness (Roberts, 2005) have all been reported. The increased prevalence may be caused by factors such as environmental aspects, diet, an ageing population and low levels of physical exercise.
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45
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Maffei A, Harris PE. Targeting vesicular monoamine transporter Type 2 for noninvasive PET-based β-cell mass measurements. Expert Rev Endocrinol Metab 2007; 2:35-46. [PMID: 30743747 DOI: 10.1586/17446651.2.1.35] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The common pathology in both Types 1 and 2 diabetes is insufficient β-cell mass to meet the metabolic needs of insulin production. The rising worldwide incidence of diabetes, combined with the lack of reliable endpoints of the body's true capacity to produce insulin, constitute a serious dilemma facing healthcare professionals and the pharmaceutical industry. Recent advances in imaging science and molecular imaging chemistry, as well as a broader understanding of basic islet biology, now allow the collection of quantitative information about β cells deep within the pancreas. The ability to noninvasively measure the mass of insulin-producing cells will most likely be of value towards characterizing new drugs and refining the diagnosis and treatment of this burdensome disease.
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Affiliation(s)
- Antonella Maffei
- a Research Scientist, IGB - CNR: Institute of Genetics and Biophysics, Adriano Buzzati-Traverso, Naples, 80131, Italy.
| | - Paul E Harris
- b Research Scientist, Columbia University Medical Center, Department of Medicine, BB 20-06, College of Physicians and Surgeons 650 West 168th Street, New York, NY, 10032, USA.
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46
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Abstract
A recent addition to the list of widely confirmed type 1 diabetes risk loci is the PTPN22 gene encoding a lymphoid-specific phosphatase (Lyp). However, evidence supporting a role for PTPN22 in type 1 diabetes derives entirely from the study of just one coding single nucleotide polymorphism, 1858C/T. In the current study, the haplotype structure of the PTPN22 region was determined, and individual haplotypes were tested for association with type 1 diabetes in family-based tests. The 1858T risk allele occurred on only a single haplotype that was strongly associated with type 1 diabetes (P = 7.9 x 10(-5)). After controlling for the effects of this allele, two other haplotypes were observed to be weakly associated with type 1 diabetes (P < 0.05). Sequencing of the coding region of PTPN22 on these haplotypes revealed a novel variant (2250G/C) predicted to result in a nonsynonymous amino acid substitution. Analysis of PTPN22 transcripts from a subject heterozygous for this variant indicated that it interfered with normal mRNA splicing, resulting in a premature termination codon after exon 17. These results support the conclusion that the 1858C/T allele is the major risk variant for type 1 diabetes in the PTPN22 locus, but they suggest that additional infrequent coding variants at PTPN22 may also contribute to type 1 diabetes risk.
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Affiliation(s)
- Suna Onengut-Gumuscu
- Molecular Genetics Program, Benaroya Research Institute, 1201 Ninth Ave., Seattle, WA 98101-2795, USA
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47
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Onengut-Gumuscu S, Concannon P. Recent advances in the immunogenetics of human type 1 diabetes. Curr Opin Immunol 2006; 18:634-8. [PMID: 16884898 DOI: 10.1016/j.coi.2006.07.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2006] [Accepted: 07/21/2006] [Indexed: 11/21/2022]
Abstract
Type 1 diabetes (T1D), a disorder of glucose homeostasis, is caused by autoimmune destruction of the essential insulin-secreting beta cells in the pancreas. Both genetic and environmental factors contribute to the risk of T1D and, for decades, this complexity has challenged investigators interested in identifying the genes that contribute to this risk. Nevertheless, in recent years, a number of well-supported T1D risk loci have been identified and replicated. Owing to development of more powerful study designs, the availability of dense marker maps, progress in high-throughput genotyping and a better basic understanding of the roles of genes in the immune system, this trend is likely to continue.
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Affiliation(s)
- Suna Onengut-Gumuscu
- Program in Molecular Genetics, Benaroya Research Institute, Seattle, WA 98101-2795, USA
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48
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Abstract
We recently discovered that a single-nucleotide polymorphism (SNP) in the lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene on chromosome 1p13, correlates strongly with the incidence of type 1 diabetes (T1D) in two independent populations. This findings has now been verified by numerous studies and it has been expanded to rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, generalized vitiligo and other autoimmune disease. Here we review the genetics of the SNP and its association with autoimmunity, discuss the function of the phosphatase in signaling, the biochemistry of the disease-predisposing allele, and the possible mechanisms by which PTPN22 contributes to the development of human disease.
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Affiliation(s)
- Nunzio Bottini
- Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, United States
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49
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Turunen JA, Wessman M, Forsblom C, Kilpikari R, Parkkonen M, Pöntynen N, Ilmarinen T, Ulmanen I, Peltonen L, Groop PH. Association analysis of the AIRE and insulin genes in Finnish type 1 diabetic patients. Immunogenetics 2006; 58:331-8. [PMID: 16552513 DOI: 10.1007/s00251-006-0088-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2005] [Accepted: 01/11/2006] [Indexed: 11/28/2022]
Abstract
Mutations in the autoimmune regulator (AIRE) gene cause a recessive Mendelian disorder autoimmune polyendocrinopathy syndrome type 1 (APS-1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). APS-1 patients develop multiorgan autoimmune diseases including type 1 diabetes (prevalence 12%). The AIRE protein controls the central tolerance induction in the thymus by regulating the expression levels of tissue-specific peripheral antigens, such as insulin. We hypothesized that the insulin gene (INS) polymorphisms together with the AIRE variations may predispose individuals to diabetes. The role of the AIRE gene was tested both independently and on the condition of the INS risk genotype in the Finnish type 1 diabetes sample. A total of 733 type 1 diabetic cases and 735 age- and sex-matched healthy controls were used in the analysis. Five common single nucleotide polymorphisms (SNPs) in the AIRE gene were selected from the public database (dbSNP). The -23HphI polymorphism was used as a surrogate marker for the INS gene promoter repeat. The five genotyped SNPs in the AIRE gene showed no evidence of association with type 1 diabetes. As expected, the INS gene polymorphism -23HphI was significantly associated with susceptibility to type 1 diabetes (P=6.8 x 10(-12), chi(2) test). When the subclass of patients carrying the homozygote genotype of the INS gene was used in the analysis, the AIRE polymorphisms showed no association with the disease. In conclusion, the AIRE gene does not seem to contribute to disease susceptibility in Finnish type 1 diabetic patients, whereas the insulin gene represents a notable risk factor for disease in this population.
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Affiliation(s)
- Joni A Turunen
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki (C318b), University of Helsinki, P.O. Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland
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50
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Tobon GJ, Arango A, Abad V, García J, Cuervo H, Velásquez A, Angel ID, Vega P, Abad A, Anaya JM. Clinical and immunological characteristics of type 1 diabetes mellitus in a northwestern Colombian population. Diabetes Res Clin Pract 2006; 72:170-5. [PMID: 16325957 DOI: 10.1016/j.diabres.2005.10.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2005] [Revised: 10/04/2005] [Accepted: 10/12/2005] [Indexed: 12/01/2022]
Abstract
We underwent a project aimed to define the clinical and immunological characteristics of type 1 diabetes (T1D) in a Colombian population. This was a multicenter and cross-sectional study. Patients were systematically interviewed and their medical records reviewed, using a questionnaire that sought information about demographic, clinical and immunological characteristics. Glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase antibodies (IA-2A) and insulin antibodies (IAA) were examined by radioimmunoassay. There were 107 patients with T1D. Male:female ratio was 1:1. Half of the patients developed diabetes ketoacidosis at onset. GADA, IA-2A, and IAA were detected in 45%, 40%, and 69% of the cases, respectively. GADA positive patients were older and had a less duration of disease than patients without these autoantibodies (p<0.01). Association between breast feeding with the presence of antibodies or clinical characteristics was not observed. The results highlight some differences of T1D expression according to geographic location and ethnicity. Differences in age at onset and clinical variables may point to an environmental factor or deficient access to health care system. Genetic studies underway will provide important information in this population. These results might help to define public health policies in our population to improve T1D diagnosis, patients' quality of life and their outcome.
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Affiliation(s)
- G J Tobon
- Cellular Biology and Immunogenetics Unit, Corporación para Investigaciones Biológicas, Cra. 72-A No 78-B-141, Medellín, Colombia
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