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1
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Masaki S, Bayaraa B, Imafuku S. Prevalence of inflammatory bowel disease in Japanese psoriatic patients. J Dermatol 2019; 46:590-594. [PMID: 31087586 DOI: 10.1111/1346-8138.14900] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 04/07/2019] [Indexed: 01/20/2023]
Abstract
Psoriatic patients reportedly have a higher prevalence of inflammatory bowel disease (IBD); however, there have been few research studies of Japanese psoriatic patients. To elucidate the prevalence of IBD in Japanese psoriatic patients, a cross-sectional study was performed. Information was collected regarding psoriatic patients with current or prior history of Crohn's disease (CD) or ulcerative colitis (UC) who were treated at Fukuoka University Hospital from 2010 to 2018. Among 681 psoriatic patients (449 men and 232 women), eight (1.2%, six men, two women) had UC and two (0.3%, one man, one woman) had CD. Diagnosis of IBD preceded psoriasis in five patients, while diagnosis of psoriasis preceded IBD in two; the remaining patients' records did not have sufficient information. Seven of 10 UC-positive patients had mild psoriasis, two had moderate psoriasis and one had severe psoriasis. When UC-positive psoriatic patients were compared with IBD-negative psoriatic patients, there were no differences in age at onset of psoriasis, age at first visit or complications (e.g. psoriatic arthritis, hypertension, hyperlipidemia, hyperuricemia and diabetes). However, UC-positive patients had significantly higher body mass index (BMI) (26.7 vs 23.7; P = 0.021), compared with patients without IBD. The CD/UC ratio in this cohort was 0.25, while the prevalence of IBD was 1.2%; these values were both lower than those in previous reports involving Caucasian patients. Patients with psoriasis and UC may have higher BMI and milder skin symptoms than those with psoriasis alone. These observations must be further confirmed by controlled domestic studies with larger samples.
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Affiliation(s)
- Saori Masaki
- Department of Dermatology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Bolortuya Bayaraa
- Department of Dermatology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Shinichi Imafuku
- Department of Dermatology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
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2
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de Lange KM, Barrett JC. Understanding inflammatory bowel disease via immunogenetics. J Autoimmun 2015; 64:91-100. [PMID: 26257098 DOI: 10.1016/j.jaut.2015.07.013] [Citation(s) in RCA: 123] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 07/23/2015] [Indexed: 01/01/2023]
Abstract
The major inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are both debilitating disorders of the gastrointestinal tract, characterized by a dysregulated immune response to unknown environmental triggers. Both disorders have an important and overlapping genetic component, and much progress has been made in the last 20 years at elucidating some of the specific factors contributing to disease pathogenesis. Here we review our growing understanding of the immunogenetics of inflammatory bowel disease, from the twin studies that first implicated a role for the genome in disease susceptibility to the latest genome-wide association studies that have identified hundreds of associated loci. We consider the insight this offers into the biological mechanisms of the inflammatory bowel diseases, such as autophagy, barrier defence and T-cell differentiation signalling. We reflect on these findings in the context of other immune-related disorders, both common and rare. These observations include links both obvious, such as to pediatric colitis, and more surprising, such as to leprosy. As a changing picture of the underlying genetic architecture emerges, we turn to future directions for the study of complex human diseases such as these, including the use of next generation sequencing technologies for the identification of rarer risk alleles, and potential approaches for narrowing down associated loci to casual variants. We consider the implications of this work for translation into clinical practice, for example via early therapeutic hypotheses arising from our improved understanding of the biology of inflammatory bowel disease. Finally, we present potential opportunities to better understand environmental risk factors, such as the human microbiota in the context of immunogenetics.
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Affiliation(s)
- Katrina M de Lange
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1HH, United Kingdom
| | - Jeffrey C Barrett
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1HH, United Kingdom; European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1HH, United Kingdom; Centre for Therapeutic Target Validation, Wellcome Genome Campus, Hinxton, Cambridge CB10 1HH, United Kingdom.
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3
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Ahmed FE. Role of genes, the environment and their interactions in the etiology of inflammatory bowel diseases. Expert Rev Mol Diagn 2014; 6:345-63. [PMID: 16706738 DOI: 10.1586/14737159.6.3.345] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Few of the studied genes demonstrate association with inflammatory bowel disease (IBD). Three mutations in the nucleotide-binding oligomerization domain 2 gene have consistently shown to be independent risk factors for Crohn's disease, but none of the alleles exhibited high sensitivity or specificity for IBD. Linkage analysis implicated several loci on various chromosomes, and epistasis has been demonstrated. The etiopathogenesis of IBD remains unknown, and environmental contribution to their pathogenesis is evident from genetic studies that demonstrated incomplete monozygotic twins concordandance rate for both Crohn's and ulcerative colitis. Smoking has shown an opposite effect on disease phenotype, with an adverse effect on disease course for Crohn's disease, but a slight beneficial effect in ulcerative colitis. The contribution of infectious agents to susceptibility to IBD appears to be strong. However, the role of nutrition on the etiology and therapy of IBD is not clear. Inconsistencies in environmental risk factors could be due to gene-environment interactions, making it essential to study the role of genetics and environmental contribution to the etiopathology of IBD. Transgenic or knockout mice, such as interleukin-10(-/-), T-cell receptor alpha(-/-), Galphai(2) (-/-) and N-cadherin(-/-), develop colitis-like inflammation similar to humans. Therefore, animal models must be further studied to explore mechanistic interactions.
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Affiliation(s)
- Farid E Ahmed
- The Brody School of Medicine at East Carolina University, Department of Radiation Oncology, Leo W Jenkins Cancer Center, Greenville, NC 27858, USA.
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4
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Tanaka T, Sugie S. Recent advances in pathobiology and histopathological diagnosis of inflammatory bowel disease. ACTA ACUST UNITED AC 2013. [DOI: 10.7243/2052-7896-1-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Weizman AV, Silverberg MS. Have genomic discoveries in inflammatory bowel disease translated into clinical progress? Curr Gastroenterol Rep 2012; 14:139-45. [PMID: 22302508 DOI: 10.1007/s11894-012-0248-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is a heterogeneous disease that can be challenging to diagnose and manage. As a result, significant efforts have been made in attempting to identify clinical, genomic, and serologic markers of disease that can aid in patient assessment and treatment. Recent genomic discoveries have the potential to change clinical practice by identifying those susceptible to IBD, predict natural history and guide choice of therapy. Panels of genetic and genomic markers are more likely to emerge as clinical tools, as opposed to individual allelic variants. Serology and biomarkers are already being used and guiding management but await integration with genomic panels before achieving their maximal potential. This article reviews the current state of IBD genetics and evolving molecular approaches that may have potential clinical impact.
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Affiliation(s)
- Adam V Weizman
- Mount Sinai Hospital Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, University of Toronto, Ontario, Canada
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6
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Hradsky O, Dusatkova P, Lenicek M, Bronsky J, Duricova D, Nevoral J, Vitek L, Lukas M, Cinek O. Two independent genetic factors responsible for the associations of the IBD5 locus with Crohn's disease in the Czech population. Inflamm Bowel Dis 2011; 17:1523-9. [PMID: 21674708 DOI: 10.1002/ibd.21532] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2010] [Accepted: 09/21/2010] [Indexed: 12/22/2022]
Abstract
BACKGROUND The role of the IBD5 locus in development of Crohn's disease (CD) has not been clarified. In the Czech population we examined its genetic association using variants of the SLC22A4 (rs1050152), SLC22A5 (rs2631367), two single nucleotide polymorphisms (SNPs) shown to be associated with CD in genome-wide studies (rs6596075 and rs2188962), and four SNPs previously shown to tag the haplotype blocks 4, 7, 9, 10 of the IBD5 locus (IGR2063b_1, IGR2230a_1, IGR100Xa_1, IGR3236a_1). METHODS The genotype, phenotype, and allelic frequencies were compared between 469 unrelated patients with CD (177 pediatric-onset, 292 adult-onset) and 470 unrelated healthy controls, all Caucasians of Czech ancestry. RESULTS The most significant difference between patients and controls was found for the SNP rs6596075 (odds ratio [OR] = 0.70 for the G allele; 95% CI 0.52-0.94) in the dominant model and SNP IGR2063b_1 (OR = 1.38 for the G allele; 95% CI 1.14-1.67) in the log-additive model. We found a strong linkage disequilibrium across the IBD5 locus except rs6596075. The haplotype consisting of minor alleles of all tested SNPs except rs6596075 was carried by 31% patients and 23% control subjects (OR = 1.35, 95% CI 1.06-1.72). The association of variants in SLC22A4 and SLC22A5 was dependent on this risk haplotype, while the strong association of the rs6596075 was seemingly independent. In the analysis of subphenotypes we found only an association of the penetrating disease with rs6596075 (OR = 2.13; 95% CI 1.31-3.47). CONCLUSIONS Our study confirms the importance of IBD5 in determining CD susceptibility, and demonstrates that two independent genetic factors may be responsible for the association observed within this locus.
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Affiliation(s)
- Ondrej Hradsky
- Department of Pediatrics, University Hospital Motol and Second Faculty of Medicine, Charles University in Prague, Czech Republic.
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Wang J, Wang X, Yang H, Wu D, Wang L, Qian J. Contribution of the IBD5 locus to inflammatory bowel disease: a meta-analysis. Hum Genet 2011; 129:597-609. [PMID: 21279723 DOI: 10.1007/s00439-011-0952-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Accepted: 01/17/2011] [Indexed: 12/13/2022]
Abstract
To evaluate the association of the IBD5 locus to the predisposition of inflammatory bowel diseases (IBDs), a series of meta-analyses between five IBD5 variants (OCTN1 C1672T, OCTN2 G-207C, OCTN1/2 TC haplotype, IGR2096a_1, IGR2198a_1 and IGR2230a_1) and Crohn's disease (CD) and ulcerative colitis (UC) were performed, which included a total of 26 studies. Overall, five IBD5 variants in a per-allele model of inheritance were significantly associated with elevated CD risk (for OCTN1: OR = 1.23, 95% CI = 1.16-1.30, P < 0.001; for OCTN2: OR = 1.20, 95% CI = 1.11-1.30, P < 0.001; for IGR2096a_1: OR = 1.36, 95% CI = 1.24-1.46, P < 0.001; for IGR2198a_1: OR = 1.34, 95% CI = 1.24-1.46, P < 0.001; for IGR2230a_1: OR = 1.35, 95% CI = 1.23-1.48, P < 0.001) and OCTN1/2 TC haplotype (OR = 1.32, 95% CI = 1.22-1.43, P < 0.001). In the subgroup analysis, the statistically significant associations were also observed in adult- and pediatric-onset CD and in Caucasians for five IBD5 variants and the OCTN1/2 TC haplotype. A statistically significant increase in the risk of UC was detected in a recessive model of inheritances for OCTN1 (OR = 1.23, 95% CI = 1.08-1.40, P < 0.001), OCTN2 (OR = 1.18, 95% CI = 1.05-1.33, P = 0.006), IGR2096a_1 (OR = 1.37, 95% CI = 1.15-1.62, P < 0.001) and IGR2198a_1 (OR = 1.35, 95% CI = 1.10-1.66, P = 0.004); the increased risks of UC were maintained in the adult and Caucasian subgroups, but not the pediatric subgroup. In summary, our results suggested that the IBD5 locus contributes to the susceptibility of CD in a per-allele manner in adults, children and Caucasians, and the locus contributes to the susceptibility of UC in a recessive manner in adult and Caucasian populations.
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Affiliation(s)
- Jian Wang
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, People's Republic of China
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Lees CW, Satsangi J. Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. Expert Rev Gastroenterol Hepatol 2009; 3:513-34. [PMID: 19817673 DOI: 10.1586/egh.09.45] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Epidemiological data, detailed molecular studies and recent genome-wide association studies strongly suggest that ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic diseases that share some susceptibility loci, but differ at others. To date, there are more than 50 confirmed inflammatory bowel disease genes/loci, a number that is widely anticipated to at least double in the next 2 years. Germline variation in IL23R, IL12B, JAK2 and STAT3 is associated with inflammatory bowel disease susceptibility, consistent with the newly described role for IL23 signaling and Th17 cells in disease pathogenesis. Several genes involved in different aspects of bacterial handling are defective only in CD, including NOD2 and the autophagy genes ATG16L1 and IRGM. IL10 and ECM1 are associated with UC, while inherited variation at the HLA region is related to an inflammatory colonic phenotype. The application of genome-wide association studies to inflammatory bowel disease has been successful in defining the genetic architecture of CD and UC and in delivering genuinely novel and important insights into disease pathogenesis. This has unearthed a plethora of attractive targets for the development of future therapeutics. Insights into the natural history of these complex diseases will follow and may enable appropriate patient selection for early aggressive therapy with the view to modifying the disease course.
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Affiliation(s)
- Charlie W Lees
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
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9
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Polymorphisms in the IBD5 locus are associated with Crohn disease in pediatric Ashkenazi Jewish patients. J Pediatr Gastroenterol Nutr 2009; 48:531-7. [PMID: 19412005 DOI: 10.1097/mpg.0b013e318183138a] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVES To analyze the IBD5 locus in a homogenous cohort of Ashkenazi Jewish (AJ) children with Crohn disease (CD). PATIENTS AND METHODS A total of 83 AJ children with CD and 73 AJ healthy controls were studied. Genotyping for single nucleotide polymorphisms (SNPs) including OCTN1 (SLC22A4; 1672C-->T), OCTN2 (SLC22A5; 207G-->C), IGR2096, IGR2198, and IGR2230 genes was performed using the TaqMan system. NOD2/CARD15 variants also were typed using established methods. RESULTS All IBD5 SNPs tested were in linkage disequilibrium (D'>0.8), and showed significant association with CD in our cohort of AJ children. The IGR2096 SNP, which is not located within the same linkage disequilibrium block as the OCTN1 and 2 SNPs, showed an even stronger association with CD (P = 0.017; odds ratio = 1.7). Patients with CD who had the OCTN1 susceptibility allele were more likely to carry 1 of the 3 NOD2/CARD15 SNPs tested (P = 0.01; odds ratio = 4.8). CONCLUSIONS We have demonstrated a significant association between the IBD5 locus and CD in a homogenous cohort of pediatric AJ patients. Due to the tight linkage disequilibrium in the region, it is not possible to identify the causative IBD5 variant. Future functional studies will ultimately reveal the causative gene variant at this locus.
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10
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Lakner L, Csöngei V, Sarlós P, Járomi L, Sáfrány E, Varga M, Orosz P, Magyari L, Bene J, Miheller P, Tulassay Z, Melegh B. IGR2096a_1 T and IGR2198a_1 C alleles on IBD5 locus of chromosome 5q31 region confer risk for Crohn's disease in Hungarian patients. Int J Colorectal Dis 2009; 24:503-507. [PMID: 19214536 DOI: 10.1007/s00384-009-0670-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/21/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS We investigated the possible association of IBD with C1672T of SLC22A4 and G-207C of SLC22A5 alleles, and with the novel IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility loci, all located on IBD5 locus of chromosome 5q31. MATERIALS AND METHODS DNA of 217 Crohn's disease, 252 ulcerative colitis, and 290 control patients were analyzed by polymerase chain reaction/restriction fragment length polymorphism methods. RESULTS Neither the C1672T and G-207C alleles, nor the TC haplotype were found to be risk factors. By contrast, the minor allele frequencies of IGR2096a_1 T (47.2%) and IGR2198a_1 C (45.9%) were increased in Crohn's disease compared with the controls (38.2% and 37.7%, respectively; p < 0.05); multivariate regression analysis revealed a risk nature for Crohn's disease (OR = 1.748, 95% CI 1.186-2.574; p = 0.007 for T allele, OR = 1.646, 95% CI 1.119-2.423, p = 0.011 for C allele of IGRs). CONCLUSION The data suggest a special haplotype arrangement of susceptibility genes at the IBD5 locus in Hungarians, which nation differs historically from the surrounding Caucasian ethnicities in its origin.
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Affiliation(s)
- Lilla Lakner
- Department of Medicine and Gastroenterology, Markusovszky Hospital, Szombathely, Hungary
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Abstract
Crohn's disease and ulcerative colitis are chronic inflammatory disorders caused by a disruptive interaction between the immune system and gut luminal factors. Although the exact aetiology of IBD remains unclear, accumulating data, including genome-wide association studies (GWAS), have advanced our understanding of the immunopathogenesis. This review highlights the role in gut homeostasis and IBD pathogenesis. It focuses on past and recent advances in our understanding of IBD, including genetics and immunobiology. Recently published GWAS have confirmed earlier findings related to the NOD2 gene and the IBD5 locus. In addition, over 30 novel loci have been identified. Several promising associations between Crohn's disease and gene variants have been identified and replicated, the two most widely replicated being variants in the IL23R and ATG16L1 genes. These findings highlight and further support the importance of the immune system and its interactions with the intestinal flora in the pathogenesis of inflammatory bowel disease.
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Affiliation(s)
- Casper G Noomen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, C4-12 Leiden, the Netherlands.
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12
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Okazaki T, Wang MH, Rawsthorne P, Sargent M, Datta LW, Shugart YY, Bernstein CN, Brant SR. Contributions of IBD5, IL23R, ATG16L1, and NOD2 to Crohn's disease risk in a population-based case-control study: evidence of gene-gene interactions. Inflamm Bowel Dis 2008; 14:1528-41. [PMID: 18521914 PMCID: PMC3336049 DOI: 10.1002/ibd.20512] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND IBD5, IL23R, and ATG16L1 genetic variations are established Crohn's disease (CD) risks alleles. We evaluated these in a population-based case-control study within a cohort to determine their penetrance, population attributable risk, independence, and relationship to other established CD risk factors, including NOD2. METHODS DNA from 213 CD, 118 [corrected] ulcerative colitis, and 315 [corrected] healthy control subjects from the population based University of Manitoba IBD Research Registry were genotyped for IBD5 and IL23R single-nucleotide polymorphisms (SNPs),and for the Thr 300Ala ATG16L1 SNP. Univariate and multivariate analyses were performed for these and nongenetic risk factors.We introduce multidimensionality reduction (MDR) to explore gene– gene interactions. RESULTS ATG16L1, IBD5, and IL23R SNPs were significantly associated with CD. Multivariate analysis showed independent CD association for carriers of ATG16L1 (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.09-3.24), IBD5-IGR2230 (OR = 2.16, 95% CI 1.30-3.59), and IL23R-rs10889677 (OR = 2.13, 95% CI 1.39-3.28) while retaining association for NOD2 mutation carriers (OR = 4.45, 95% CI 2.68-7.38), IBD family history (OR = 2.75, 95% CI 1.42-5.31), tobacco (OR = 2.06, 95% CI 1.35-3.14), and Jewish ethnicity (OR = 20.1, 95% CI 2.16-186.8). IL23R minor variants for Arg381Gln and Intron 6 rs7517848 showed independent, CD protection and 3' untranslated variant rs108896778 showed risk. MDR analysis suggested an interaction between IBD5, ATG16L1, and IL23R risk alleles. Penetrance values for ATG16L1 and IBD5 were 0.27% for heterozygotes, and 0.35% and 0.44%, respectively, for homozygotes. IL23R rs108896778 penetrance was 0.37%. CONCLUSIONS A population-based analysis of CD risk factors is useful for characterizing the epidemiology of multiple CD genetic and nongenetic risk factors. Gene-gene interactions are likely, but require further evaluation in large population-based cohorts.
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Affiliation(s)
- Toshihiko Okazaki
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ming-Hsi Wang
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland,Department of Epidemiology and the Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Patricia Rawsthorne
- Section of Gastroenterology, University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada
| | - Michael Sargent
- Section of Gastroenterology, University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada
| | - Lisa Wu Datta
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yin Yao Shugart
- Department of Epidemiology and the Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Charles N. Bernstein
- Section of Gastroenterology, University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada
| | - Steven R. Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland,Department of Epidemiology and the Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
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Okumura S, Yuki K, Kobayashi R, Okamura S, Ohmori K, Saito H, Ra C, Okayama Y. Hyperexpression of NOD2 in intestinal mast cells of Crohn's disease patients: preferential expression of inflammatory cell-recruiting molecules via NOD2 in mast cells. Clin Immunol 2008; 130:175-85. [PMID: 18938111 DOI: 10.1016/j.clim.2008.08.027] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Accepted: 08/26/2008] [Indexed: 01/07/2023]
Abstract
NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP) has been implicated as a key player in intestinal immune health and disease. Mast cells (MCs) have been reported to be increased in the gut of patients with inflammatory bowel disease. However, NOD2 expression and its role in human primary MCs are unknown. The number of NOD2(+) intestinal MCs was significantly increased in the Crohn's disease (CD) specimens compared to Ulcerative colitis (UC) specimens and controls. IFN-gamma upregulated NOD2 expression in MCs. CXCL10 and urokinase-type plasminogen activator (uPA) upregulation was specific to MCs activated by MDP compared to MCs activated by LPS and IgE/anti-IgE. MDP-induced upregulation of ICAM-1, VCAM-1, and uPA was specific to MCs compared to mononuclear cells. The number of CXCL10(+)NOD2(+) intestinal MCs was significantly increased in the CD patients. Our results suggest that NOD2(+) MCs have specific pathogenic roles that involve the recruitment of inflammatory cells in CD.
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Affiliation(s)
- Shigeru Okumura
- Research Unit for Allergy Transcriptome, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan
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Mahasirimongkol S, Yanai H, Nishida N, Ridruechai C, Matsushita I, Ohashi J, Summanapan S, Yamada N, Moolphate S, Chuchotaworn C, Chaiprasert A, Manosuthi W, Kantipong P, Kanitwittaya S, Sura T, Khusmith S, Tokunaga K, Sawanpanyalert P, Keicho N. Genome-wide SNP-based linkage analysis of tuberculosis in Thais. Genes Immun 2008; 10:77-83. [PMID: 18843276 DOI: 10.1038/gene.2008.81] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Tuberculosis, a potentially fatal infectious disease, affects millions of individuals annually worldwide. Human protective immunity that contains tuberculosis after infection has not been clearly defined. To gain insight into host genetic factors, nonparametric linkage analysis was performed using high-throughput microarray-based single nucleotide polymorphism (SNP) genotyping platform, a GeneChip array comprised 59 860 bi-allelic markers, in 93 Thai families with multiple siblings, 195 individuals affected with tuberculosis. Genotyping revealed a region on chromosome 5q showing suggestive evidence of linkage with tuberculosis (Z(lr) statistics=3.01, logarithm of odds (LOD) score=2.29, empirical P-value=0.0005), and two candidate regions on chromosomes 17p and 20p by an ordered subset analysis using minimum age at onset of tuberculosis as the covariate (maximum LOD score=2.57 and 3.33, permutation P-value=0.0187 and 0.0183, respectively). These results imply a new evidence of genetic risk factors for tuberculosis in the Asian population. The significance of these ordered subset results supports a clinicopathological concept that immunological impairment in the disease differs between young and old tuberculosis patients. The linkage information from a specific ethnicity may provide unique candidate regions for the identification of the susceptibility genes and further help elucidate the immunopathogenesis of tuberculosis.
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Affiliation(s)
- S Mahasirimongkol
- Medical Genetic Section, National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand
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Ardesjö B, Portela-Gomes GM, Rorsman F, Gerdin E, Lööf L, Grimelius L, Kämpe O, Ekwall O. Immunoreactivity against Goblet cells in patients with inflammatory bowel disease. Inflamm Bowel Dis 2008; 14:652-61. [PMID: 18213698 DOI: 10.1002/ibd.20370] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND A number of autoantibodies have been reported in inflammatory bowel disease (IBD). The aim of this study was to investigate to what extent sera from patients with IBD contain autoantibodies directed against normal human gastrointestinal mucosa. METHODS Samples of sera from 50 patients with IBD and 50 healthy subjects were used for immunostaining of normal and affected human gastrointestinal tissues. RESULTS Eighty-four percent of the sera from IBD patients showed immunoreactivity against goblet cells in the appendix compared with 8% of the sera from healthy subjects. Goblet cell reactivity of IBD patient sera varied between regions in the gastrointestinal tract. Sera from healthy subjects only reacted with goblet cells in the appendix. In the colon and the appendix, goblet cell reactivity of IBD sera was generally weak at the base of the crypts and gradually increased toward the lumen. Three IBD sera samples reacted with gastrin cells in the antrum. In colon biopsies from patients with ulcerative colitis, immunoreactivity against the remaining goblet cells showed an inverse correlation with inflammatory activity. CONCLUSIONS These findings suggest that immunoreactivity against goblet cells may be of central importance in the pathogenesis of IBD. Identification of goblet cell antigens could lead to a better understanding of IBD and provide a new diagnostic tool.
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Affiliation(s)
- Brita Ardesjö
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Evidence for a gene-gene interaction in predicting children's behavior problems: association of serotonin transporter short and dopamine receptor D4 long genotypes with internalizing and externalizing behaviors in typically developing 7-year-olds. Dev Psychopathol 2008; 19:1105-16. [PMID: 17931437 DOI: 10.1017/s0954579407000569] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Recent work on the molecular genetics of complex traits in typical and atypical human development has focused primarily on associations of single genes with behavior. Disparate literature suggests that the presence of one or two copies of the short allele of the serotonin transporter (5-HTT) gene and the long allele (7-repeat allele) version of the dopamine receptor D4 (DRD4) gene predicts internalizing- and externalizing-related behaviors, respectively. Apparently for the first time in the extant literature, we report a gene-gene statistical interaction on behavior problems in a group of typically developing children at age 7. DNA was extracted from buccal cells collected from 108 children and genotyped for short and long alleles of the 5-HTT gene and the short (2-5 repeats) versus long (6-8 repeats) allele of the DRD4 gene. Mothers completed the Child Behavior Checklist. As predicted, children with one or two copies of the short allele of the 5-HTT gene and the long allele version of the DRD4 gene exhibited significantly more internalizing and externalizing behaviors at age 7 than children with other combinations of the 5-HTT and DRD4 short and long genotypes. As well, children with the 5-HTT long and DRD4 long genotypes had the lowest reported scores on internalizing and externalizing behaviors at age 7, suggesting that the presence of the 5-HTT long genotype may serve as a protective factor against these behaviors in children with the long DRD4 genotype. Implications of these findings for understanding cumulative biological risk and protective factors in childhood behavior problems and psychopathology are discussed.
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17
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Yan J, Tamboli CP. Testing concordance of clinical characteristics in familial studies with application to inflammatory bowel diseases. Biom J 2008; 49:840-53. [PMID: 17979220 DOI: 10.1002/bimj.200710383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The etiology of chronic Inflammatory Bowel Diseases (IBD) remains unknown, with both genetic and environmental risk factors having been implicated. A recent collaborative study of IBD provides clinical data from families with three or more affected first-degree relatives. The scientific question is whether specific clinical characteristics aggregate among affected individuals within families. Gastroenterological researchers have examined the number of concordant familial pairs in familial aggregation studies, but methods and results have been discrepant. This article investigates concepts of concordance and gives a comprehensive statistical treatment for testing concordance of various clinical traits in familial studies. For dichotomous traits, the distribution of this statistic under the null hypothesis of no familial aggregation is obtained by three methods: asymptotic, probability generating function, and permutation. The permutation method is extended to analyze aggregation for non-dichotomous traits and co-aggregations between two traits. We apply the permutation method to analyze the aforementioned multiply-affected IBD family data. Evidence is found for familial clustering of various traits, some of which are not revealed in existing studies. Such analyses provide a basis for investigating the dependence of trait aggregation upon genetic or environmental risk factors.
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Affiliation(s)
- Jun Yan
- Department of Statistics and Actuarial Science, The University of Iowa, 241 Schaeffer Hall, Iowa City, IA 52242, USA.
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18
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Abstract
Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn’s disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.
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Diverse effects of the CARD15 and IBD5 loci on clinical phenotype in 630 patients with Crohn's disease. Eur J Gastroenterol Hepatol 2008; 20:37-45. [PMID: 18090989 DOI: 10.1097/meg.0b013e3282f1622b] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Genetic variants at the CARD15 and IBD5 loci are strongly associated with Crohn's disease (CD), but evidence of the effect of these variants on the clinical expression of CD is conflicting and has often been hampered by small sample sizes. We studied 630 well-characterized patients to clarify the genotype/phenotype relationship in CD. METHODS Patients and healthy controls were genotyped for three common mutations in CARD15 and a marker of the IBD5 risk haplotype. Allele frequencies were compared between phenotypic subgroups using chi2 or Fisher's exact tests. Genotype/phenotype analysis was carried out using multinomial logistic regression modelling allowing for adjustment for correlated or confounding factors. RESULTS The mean age at diagnosis was significantly lower in carriers of the CARD15 or IBD5 risk alleles. After correction for age and smoking, CARD15 mutations were strongly associated with both ileal disease (P=8.8 x 10(-6)) and stenotic disease (P=0.003), but the association with stenotic disease appeared to be due to a confounding effect with ileal disease. CARD15 mutations were also associated with the presence of granulomas (P=5.7 x 10(-5)), which remained significant after adjustment for age at diagnosis and disease location (P=0.0047). The IBD5 risk haplotype frequency was significantly elevated in cases with perianal disease (P=0.028) and axial spondyloarthropathy (P=0.012). CONCLUSION Genetic variants at the CARD15 and IBD5 loci have diverse effects on clinical expression in CD. CARD15 mutations are significantly correlated with the presence of granulomas.
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20
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Abstract
Great progress in the understanding of the molecular genetics of inflammatory bowel disease (IBD) has been made over the last 10 years. Strong epidemiological evidence, based initially on concordance data in twin/family studies, led to the application of genome-wide linkage analysis involving multiply affected families and the identification of a number of susceptibility loci. Further characterization of the IBD1 locus on chromosome 16 led to the discovery of the NOD2/CARD15 gene as the first susceptibility gene in Crohn's disease for 2001. This landmark finding has led to a redirection of basic research in IBD with interest focused principally on regulation of the innate immune response and mucosal barrier function. Within the last year, the use of genome-wide association studies has provided new insights into primary pathogenetic mechanisms; several new genes such as the Interleukin-23 receptor (IL23R) and ATG16L1 (autophagy-related 16-like 1) genes are strongly implicated. Overall, these studies promise to change our fundamental understanding of IBD pathophysiology and to have implications for clinical practice.
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Affiliation(s)
- Johan Van Limbergen
- Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom
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21
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Biank V, Broeckel U, Kugathasan S. Pediatric inflammatory bowel disease: clinical and molecular genetics. Inflamm Bowel Dis 2007; 13:1430-8. [PMID: 17600381 DOI: 10.1002/ibd.20213] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pediatric-onset inflammatory bowel disease (IBD) is characterized by distinct phenotypic differences compared to adult-onset IBD. This raises the question whether early (pediatric) onset IBD represents the same disease process occurring in adults but merely at an earlier age or does IBD in children have a very different etiology and pathogenesis but with the same clinical presentation as adults. The use of techniques such as whole genome association studies to perform broad, unbiased screening for the contributions of common genetic variations to complex disease has rapidly assisted in the identification of several novel susceptibility loci associated with pediatric-onset Crohn's disease such as IL23R and ATG16L1. These genes join the already confirmed IBD susceptibility genes such as NOD2/CARD15, IBD5, and DLG5. Therefore, there is hope that advances in the field of clinical and molecular genetics will assist in answering the fundamental question of whether pediatric IBD has a different etiology and pathogenesis compared to adult IBD. This review examines the current status of clinical and molecular genetics of pediatric IBD, and highlights the differences between pediatric and adult IBD in disease phenotypes and genotypes. Finally, the future directions of genetic investigations in pediatric IBD are discussed.
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Affiliation(s)
- Vincent Biank
- Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a clinically and, likely, genetically heterogeneous group of disorders. A recent report suggests that genetic variations in the TNFSF15 gene contribute to the susceptibility of IBD in both Japanese and Caucasian populations. The aim was to confirm the association between TNFSF15 high- and low-risk haplotypes and IBD in a Caucasian population. METHODS Five single-nucleotide polymorphisms (SNPs) that comprise the 2 common haplotypes were genotyped in 599 Caucasian patients with Crohn's disease (CD), 382 Caucasian patients with ulcerative colitis (UC), and 230 ethnically matched healthy controls, including both Jews and non-Jews. RESULTS The previously reported 'risk' haplotype was not associated with CD or UC (88.2% in CD cases versus 88.3% in controls, P = 0.96; 88.1% in UC cases versus 88.3% in controls, P = 0.78). We did, however, observe an increased frequency of the "protective" haplotype in non-Jewish controls for both CD and UC (38.8% CD cases versus 50% controls, P = 0.01; 37.3% UC cases versus 50% controls, P = 0.01) with no such effect observed in the Jewish samples. There was an interactive effect between ethnicity and the protective haplotype in CD (P = 0.04). CONCLUSIONS We observed a protective haplotype, consisting of the minor alleles for all 5 markers, to have a higher frequency in the non-Jewish controls than in CD and UC. Of further interest, the haplotype frequency was in the opposite direction in our Jewish case-control panels (both CD and UC), leading us to conclude 1) that TNFSF15 is indeed an IBD susceptibility gene, and 2) the disease susceptibility is ethnic-specific.
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Affiliation(s)
- Yoana Picornell
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Ling Mei
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Kent Taylor
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Huiying Yang
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Stephan R. Targan
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center Los Angeles, CA 90048
| | - Jerome I. Rotter
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
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Abstract
Exciting new results from a genetic study in humans and functional studies in mice have pinpointed interleukin 23 (IL23) and its receptor as a key pathway in the pathogenesis of inflammatory bowel disease (IBD). These findings reveal a hitherto unappreciated role for the IL23 axis in intestinal inflammation and may open new avenues for development of therapeutic strategies in IBD.
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Affiliation(s)
- Dermot McGovern
- Imperial College, London, Hammersmith Hospital Campus Du Cane Road, London W12 0HS, UK.
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24
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Cho JH, Weaver CT. The genetics of inflammatory bowel disease. Gastroenterology 2007; 133:1327-39. [PMID: 17919503 DOI: 10.1053/j.gastro.2007.08.032] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2007] [Accepted: 08/01/2007] [Indexed: 12/21/2022]
Affiliation(s)
- Judy H Cho
- Inflammatory Bowel Disease Center, Section of Digestive Diseases, Yale University, New Haven, Connecticut 06520-8019, USA.
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25
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Browning BL, Huebner C, Petermann I, Demmers P, McCulloch A, Gearry RB, Barclay ML, Shelling AN, Ferguson LR. Association of DLG5 variants with inflammatory bowel disease in the New Zealand Caucasian population and meta-analysis of the DLG5 R30Q variant. Inflamm Bowel Dis 2007; 13:1069-76. [PMID: 17455201 DOI: 10.1002/ibd.20157] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Variants in the DLG5 gene have been associated with inflammatory bowel disease (IBD) in samples from some, but not all populations. In particular, 2 nonsynonymous single-nucleotide polymorphisms (SNPs), R30Q (rs1248696) and P1371Q (rs2289310), have been associated with an increased risk of IBD, and a common haplotype (called haplotype "A") has been associated with reduced risk. METHODS We genotyped R30Q, P1371Q, and a haplotype A tagging SNP (rs2289311) in a New Zealand Caucasian cohort of 389 Crohn's disease (CD) patients, 406 ulcerative colitis (UC) patients, and 416 population controls. Each SNP was tested for association with disease susceptibility and clinical phenotypes. We also performed a meta-analysis of R30Q data from published association studies. RESULTS The haplotype A tagging SNP was associated with reduced risk of IBD at the 0.05 significance level (P=0.036) with an allelic odds ratio of 0.83 (95% confidence interval [CI]: 0.69-0.99). Association with haplotype A was strongest (odds ratio approximately 0.57) in UC patients with familial IBD or extraintestinal manifestations. The R30Q and P1371Q polymorphisms were not significantly associated with UC, CD, or IBD. Analysis of male and female data did not find any gender-specific associations. Meta-analysis gave no evidence of association of R30Q with IBD. CONCLUSIONS Meta-analysis demonstrates that the minor allele of R30Q is not a risk factor for IBD across populations. This study provides some evidence that DLG5 haplotype A is associated with reduced risk of IBD in the New Zealand Caucasian population, but this association will need to be replicated in an independent sample.
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Affiliation(s)
- Brian L Browning
- Discipline of Nutrition, Department of Statistics, University of Auckland, New Zealand, and Department of Gastroenterology, Box Hill Hospital, Monash, Australia.
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26
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Abstract
A modern approach to inflammatory bowel disease (IBD) research has been under way for little over one-half century, but only during the last two decades has progress accelerated and finally generated tangible results that have been translated into practical and better therapeutic strategies. The areas where progress has been more evident are those currently believed to be the key components of IBD pathogenesis, and include the environment, genetics, enteric microbiology, and immune reactivity. Progress in these different areas has been somewhat uneven, yielding a better understanding of the mechanisms behind gut inflammation and tissue injury rather than of specific etiological agents or predisposing factors. However, with the rapidly increasing utilization of novel methodological approaches like genetics, genomics, proteomics, and pharmacogenomics, it is reasonable to anticipate that the etiopathogenesis of IBD will be unveiled in the next couple of decades and more definitive, perhaps disease-modifying, approaches will be uncovered and implemented.
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Affiliation(s)
- Subra Kugathasan
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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27
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Tuvlin JA, Raza SS, Bracamonte S, Julian C, Hanauer SB, Nicolae DL, King AC, Cho JH. Smoking and inflammatory bowel disease: trends in familial and sporadic cohorts. Inflamm Bowel Dis 2007; 13:573-9. [PMID: 17345609 DOI: 10.1002/ibd.20043] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) and Crohn's disease (CD) result from genetic and environmental factors. Never smoking and formerly smoking increase the risk of UC, whereas smoking exacerbates the course of CD. We sought to define the age-dependent effects of smoking on the development of UC and CD in familial and sporadic cohorts. METHODS University of Chicago patients diagnosed with UC or CD between 1990 and 2002 were surveyed about their tobacco use relative to their diagnosis. Smoking trends were used to estimate age-dependent odds ratios and the attributable risks of smoking in the IBD cohort compared to in the general population. RESULTS One thousands and thirteen patients were included in the study: 245 with sporadic UC; 216 with sporadic CD; 249 with familial UC; and 303 with familial CD. Being an ex-smoker conferred an increased risk for UC in the 25-44 age group in both the sporadic and familial cohorts, but not in the 45-64 age group in the familial UC cohort. Furthermore, there was no difference in tobacco use between patients with sporadic CD and the general population, although there was a significant increase in smoking in younger patients with familial CD. CONCLUSIONS Ex-smokers make up an increasing percentage of older patients diagnosed with UC, accounting for more than 35% of the attributable risk of late onset (>45 years) UC and a large component of the second peak in diagnosis. Current smokers account for a large percentage of patients diagnosed at a younger age with familial CD but not with sporadic CD. Families with IBD should be counseled that early tobacco use significantly increases the risk of developing CD or, if an ex-smoker, UC at a young age.
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Van Limbergen J, Russell RK, Nimmo ER, Ho GT, Arnott ID, Wilson DC, Satsangi J. Genetics of the innate immune response in inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:338-55. [PMID: 17206667 DOI: 10.1002/ibd.20096] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The discovery of nucleotide-binding oligomerization domain 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15) as the first susceptibility gene in Crohn's disease (CD) has shifted the focus of research into the pathogenesis of inflammatory bowel disease (IBD) firmly to the innate immune response and the integrity of the epithelial barrier. The subsequent implication in IBD of variant alleles of OCTN, DLG5, MDR1, and TLRs has provided further support for a new, more complex model of innate immunity function in the gastrointestinal tract. In this review, we examine the recent advances in our understanding of the influence of genetics of the innate immune response on IBD. We will focus on germline variation of genes encoding pathogen-recognition receptors, proteins involved in epithelial homeostasis and secreted antimicrobial proteins.
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Affiliation(s)
- Johan Van Limbergen
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.
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29
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Cucchiara S, Latiano A, Palmieri O, Staiano AM, D'Incà R, Guariso G, Vieni G, Rutigliano V, Borrelli O, Valvano MR, Annese V. Role of CARD15, DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases. World J Gastroenterol 2007; 13:1221-1229. [PMID: 17451203 PMCID: PMC4146997 DOI: 10.3748/wjg.v13.i8.1221] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2006] [Revised: 12/01/2006] [Accepted: 01/12/2007] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predisposition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS Two hundred patients with Crohn's disease (CD), 186 ulcerative colitis (UC) patients, 434 parents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more common in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an increased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was more frequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric onset of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.
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Affiliation(s)
- S Cucchiara
- Clinica Pediatrica, Università L Sapienza, Roma, Italy
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30
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Walters TD, Silverberg MS. Genetics of inflammatory bowel disease: current status and future directions. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2007; 20:633-9. [PMID: 17066152 PMCID: PMC2660789 DOI: 10.1155/2006/326025] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Thomas D Walters
- Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario
| | - Mark S Silverberg
- Department of Medicine, Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario
- Correspondence: Dr Mark S Silverberg, Mount Sinai Hospital Inflammatory Bowel Disease Centre, Room 441, 600 University Avenue, Toronto, Ontario M5G 1X5. Telephone 416-586-8236, fax 416-586-4878, e-mail
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Silverberg MS, Duerr RH, Brant SR, Bromfield G, Datta LW, Jani N, Kane SV, Rotter JI, Philip Schumm L, Hillary Steinhart A, Taylor KD, Yang H, Cho JH, Rioux JD, Daly MJ. Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn's disease. Eur J Hum Genet 2007; 15:328-35. [PMID: 17213842 DOI: 10.1038/sj.ejhg.5201756] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Although the general association of the inflammatory bowel disease (IBD) 5 region on chromosome 5q31 to Crohn's disease (CD) has been replicated repeatedly, the identity of the precise causal variant within the region remains unknown. A recent report proposed polymorphisms in solute carrier family 22, member 4 (SLC22A4) organic cation transporter 1(OCTN1) and solute carrier family 22, member 5 (SLC22A5) (OCTN2) as responsible for the IBD5 association, but definitive, large-sample comparison of those polymorphisms with others known to be in strong linkage disequilibrium was not performed. We evaluated 1879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for six IBD5 tag single nucleotide polymorphisms (SNPs) to evaluate association localization and ethnic and subphenotypic specificity. We confirm association to the IBD5 region (best SNP IGR2096a_1/rs12521868, P<0.0005) and show this association to be exclusive to the non-Jewish (NJ) population (P=0.00005) (risk allele undertransmitted in Ashkenazi Jews). Using Phase II HapMap data, we demonstrate that there are a set of polymorphisms, spanning genes from prolyl 4-hydroxylase (P4HA2) through interferon regulatory factor 1 (IRF1) with equivalent statistical evidence of association to the reported SLC22A4 variant and that each, by itself, could entirely explain the IBD5 association to CD. Additionally, the previously reported SLC22A5 SNP is rejected as the potential causal variant. No specificity of association was seen with respect to disease type and location, and a modest association to ulcerative colitis is also observed. We confirm the importance of IBD5 to CD susceptibility, demonstrate that the locus may play a role in NJ individuals only, and establish that IRF1, PDLIM, and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.
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Affiliation(s)
- Mark S Silverberg
- Department of Medicine, Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada
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Briones T, Salvadalena G. An Introduction to Genetics and Application to Crohnʼs Disease. J Wound Ostomy Continence Nurs 2007; 34:80-7. [PMID: 17228211 DOI: 10.1097/00152192-200701000-00012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gene-based diagnostics and therapeutics are being explored for application in many areas of healthcare. An understanding of the principles of genomics has become fundamental to patient care within all specialties of nursing and is expected to be included in certification exams in the near future. This introductory article is designed to provide practicing Wound, Ostomy, and Continence nurses with basic information to enhance their abilities to comprehend genetics information, apply it to practice, and translate it to colleagues and patients. Specifics about the genetic basis of Crohn's disease are used to illustrate the application of the concepts described in the article.
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Affiliation(s)
- Tess Briones
- Department of Medical-Surgical Nursing, College of Nursing, University of Illinois at Chicago, IL, USA
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33
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Goyette P, Labbé C, Trinh TT, Xavier RJ, Rioux JD. Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Ann Med 2007; 39:177-99. [PMID: 17457716 DOI: 10.1080/07853890701197615] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.
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Affiliation(s)
- Philippe Goyette
- Université de Montréal, Department of Medicine, Montréal, Québec, Canada
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McGovern DPB, Butler H, Ahmad T, Paolucci M, van Heel DA, Negoro K, Hysi P, Ragoussis J, Travis SPL, Cardon LR, Jewell DP. TUCAN (CARD8) genetic variants and inflammatory bowel disease. Gastroenterology 2006; 131:1190-6. [PMID: 17030188 DOI: 10.1053/j.gastro.2006.08.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2005] [Accepted: 07/05/2006] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS The identification of the association between Crohn's disease (CD) and NOD2 (CARD15) confirmed both the heritability of CD and highlighted the role of the nuclear factor kappaB (NFkappaB) pathway in disease pathogenesis. Other susceptibility loci exist. TUCAN (CARD8) is located beneath a CD peak of linkage on chromosome 19q. TUCAN is expressed in the gut and is a negative regulator of NFkappaB, making it an excellent candidate gene for gastrointestinal inflammation. METHODS Ten single nucleotide polymorphisms (SNP) across TUCAN were genotyped in 365 controls, 372 patients with CD, and 373 patients with ulcerative colitis. A diagnostic panel for CD was constructed using smoking status and TUCAN, NOD2, IBD5, NOD1, and TNFSF15 data. RESULTS We demonstrate significant association between a TUCAN SNP and CD (OR 1.35, P = .0083). The association was more pronounced with disease affecting sites other than the colon (odds ratio, 1.52) and NOD2-negative CD (odds ratio, 1.50). Combination of these data with smoking and NOD2, IBD5, NOD1, and TNFSF15 status demonstrated very strong associations with CD and high sensitivities (96.3%), specificities (99.4%), and likelihood ratios (12.8) for CD, although further work will be needed before this model can be translated into direct clinical utility. CONCLUSIONS We have shown an association between a likely functional polymorphism in TUCAN and CD. The combination of these data in a genetic panel suggests that clinicians may soon be able to translate genetic advances into direct benefits for patients.
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Affiliation(s)
- Dermot P B McGovern
- Wellcome Trust Centre for Human Genetics, University of Oxford, Drive, Headington, Oxford OX3 7BN, England, UK.
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35
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Abstract
Inflammatory bowel diseases (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory autoimmune conditions of the gastrointestinal tract. Other organs, such as the eyes, skin and articulations, are often affected and IBD may be accompanied by other diseases of autoimmune origin. There is no single etiological factor responsible for the onset of IBD. Recent advances in genetics and in the molecular mechanisms of the proteins coded by these genes have given rise to a new vision in understanding these complex diseases. Activation of specific genes that affect antigen presentation and the handling of cells by innate immunity may lead to autoimmunity with the consequent activation of the major histocompatibility complex (MHC) and multiple cytokines involved in the regulation of acquired immunity. In this review IBD is described as a constellation of diseases that can best be classified as barrier diseases. This vision, developed by Kiel in Germany, includes the idea that changes in our environment due to the westernization of civilization have not been met with adaptation of the innate immune system, and this has given rise to autoimmune diseases. These diseases affect 1-5 of 1000 individuals and represent a major burden on the national health systems of many countries on different continents. On a world scale, a major challenge is to generate interventions to prevent the development of these diseases in Asia, Latin America and Africa.
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Affiliation(s)
- A S Peña
- VU University Medical Centre, Head, Department of Gastroenterology, 1007 MB Amsterdam, The Netherlands.
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Russell RK, Drummond HE, Nimmo ER, Anderson NH, Noble CL, Wilson DC, Gillett PM, McGrogan P, Hassan K, Weaver LT, Bisset WM, Mahdi G, Satsangi J. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease. Gut 2006; 55:1114-23. [PMID: 16469794 PMCID: PMC1856267 DOI: 10.1136/gut.2005.082107] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Revised: 01/15/2006] [Accepted: 02/01/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The OCTN1 (SLC22A4 1672C-->T) and OCTN2 (SLC22A5 -207G-->C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn's disease (CD), but their contribution in children has not been examined. METHODS These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a_1, IGR2198a_1, and IGR2230a_1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls. RESULTS All SNPs were in strong linkage disequilibrium (D' >0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (p<0.04). The homozygous mutant OCTN1/2 haplotype was increased in IBD (24.3% v 16.1%, p = 0.02) and UC (28.2% v 16.1%, p = 0.02) compared with controls. The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility. Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight, height, and BMI centile (<9(th) centile) at diagnosis (weight: 87.9% v 67.3% (p = 0.002), odds ratio (OR) = 3.52 (95% confidence interval, 1.51 to 8.22); height: 84.1% v 68.4% (p<0.05), OR = 2.44 (1.00 to 5.99); BMI: 79.6% v 61.1% (p = 0.02), OR = 2.49 (1.14 to 5.44)), and lower weight centile at follow up (87.5% v 64.6% (p = 0.03), OR = 3.83 (1.03 to 14.24)). Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis (p = 0.02, OR = 3.41 (1.20 to 9.66)). CONCLUSIONS These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis.
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Affiliation(s)
- R K Russell
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, UK.
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Fisher SA, Hampe J, Onnie CM, Daly MJ, Curley C, Purcell S, Sanderson J, Mansfield J, Annese V, Forbes A, Lewis CM, Schreiber S, Rioux JD, Mathew CG. Direct or indirect association in a complex disease: the role of SLC22A4 and SLC22A5 functional variants in Crohn disease. Hum Mutat 2006; 27:778-785. [PMID: 16835882 DOI: 10.1002/humu.20358] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
A common haplotype spanning 250 kb on chromosome 5q31 is strongly associated with Crohn disease (CD). Recently, two functional variants within the SLC22A4 and SLC22A5 genes at this locus (IBD5), L503F (c.1507C > T) and G-207C (c.-207G > C), have been proposed to contribute directly to susceptibility to CD. However, extensive linkage disequilibrium at the IBD5 locus has complicated efforts to distinguish causal variants from association of the general risk haplotype. We genotyped the SLC22A4 and SLC22A5 variants and other polymorphisms across the risk haplotype in four populations of European origin, and applied regression-based haplotype analysis to over 1,200 fully genotyped case-control pairs, modeling case/control status on the presence of one or more SNPs to test for conditional association and to identify risk haplotypes. We found highly significant association of SNPs at the IBD5 locus with Crohn disease in all populations tested. However, the frequencies of L503F and G-207C in individuals who did not carry the general IBD5 risk haplotype were not significantly different in cases and controls, with associated disease odds ratios (ORs) of 0.90 (95% CI, 0.57-1.40) and 0.90 (95% CI, 0.65-1.23), respectively. Haplotype analysis showed that addition of the SLC22A4 and SLC22A5 variants to a null model that included the background risk haplotype did not significantly improve the model fit. In addition to the common risk haplotype, several rare haplotypes had an increased frequency in cases compared to controls. This study suggests that the molecular basis for Crohn disease susceptibility at the IBD5 locus remains to be defined, and highlights the challenge of the identification of causal variants in a complex disease in regions of extensive linkage disequilibrium.
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Affiliation(s)
- Sheila A Fisher
- Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, United Kingdom
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38
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Abstract
Inflammatory bowel disease (IBD) is a complex disease, controlled by multiple risk factors that evolve and interact together. In a genetically susceptible host, there are multiple processing steps controlled by the host and the environment, from environmental exposure to the clinical and biological expression of IBD-related phenotypes. This article discusses the recent genetic discoveries, along with the proposed environmental risk factors that have been implicated in IBD. Technical advances of the HapMap project and the promise of whole genome association scans have given hopes for clarifying gene-environmental interactions in IBD that ultimately lead to a clearer understanding of the pathogenesis.
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Affiliation(s)
- Subra Kugathasan
- Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Hunt KA, Monsuur AJ, McArdle WL, Kumar PJ, Travis SPL, Walters JRF, Jewell DP, Strachan DP, Playford RJ, Wijmenga C, van Heel DA. Lack of association of MYO9B genetic variants with coeliac disease in a British cohort. Gut 2006; 55:969-72. [PMID: 16423886 PMCID: PMC1856329 DOI: 10.1136/gut.2005.086769] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Revised: 12/19/2005] [Accepted: 12/22/2005] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Development of coeliac disease involves an interaction between environmental factors (especially dietary wheat, rye, and barley antigens) and genetic factors (there is strong inherited disease susceptibility). The known human leucocyte antigen (HLA)-DQ2 and -DQ8 association explains only a minority of disease heritability. A recent study in the Dutch population suggested that genetic variation in the 3' region of myosin IXB (MYO9B) predisposes to coeliac disease. MYO9B is a Rho family GTPase activating protein involved in epithelial cell cytoskeletal organisation. MYO9B is hypothesised to influence intestinal permeability and hence intestinal antigen presentation. METHODS Four single nucleotide polymorphisms were chosen to tag all common haplotypes of the MYO9B 3' haplotype block (exons 15-27). We genotyped 375 coeliac disease cases and 1366 controls (371 healthy and 995 population based). All individuals were of White UK Caucasian ethnicity. RESULTS UK healthy control and population control allele frequencies were similar for all MYO9B variants. Case control analysis showed no significant association of any variant or haplotype with coeliac disease. CONCLUSIONS Genetic variation in MYO9B does not have a major effect on coeliac disease susceptibility in the UK population. Differences between populations, a weaker effect size than originally described, or possibly a type I error in the Dutch study might explain these findings.
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Affiliation(s)
- K A Hunt
- Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine and Dentistry, Turner St, London E1 2AD, USA
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40
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Abstract
Crohn’s disease and ulcerative colitis are inflammatory disorders of the gastrointestinal tract with a substantial heritable component. The IBD5 region on chromosome 5q31 is one of only two loci widely confirmed to be associated with Crohn’s disease in multiple independent cohorts. Although many populations have demonstrated association with IBD5, there remains uncertainty as to the causal variant within the region. A recent report identified polymorphisms in SLC22A4 (OCTN1) and SLC22A5 (OCTN2) as being responsible for the IBD5 association, however, these findings have not been replicated. This review discusses the data evaluating the IBD5 locus and the OCTN genes and their relationship to inflammatory bowel disease. Several other genes, including IRF1 and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.
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Affiliation(s)
- Mark-S Silverberg
- Mount Sinai Hospital IBD Centre, Department of Medicine, Toronto, Ontario, Canada.
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Babusukumar U, Wang T, McGuire E, Broeckel U, Kugathasan S. Contribution of OCTN variants within the IBD5 locus to pediatric onset Crohn's disease. Am J Gastroenterol 2006; 101:1354-61. [PMID: 16771961 DOI: 10.1111/j.1572-0241.2006.00564.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS The IBD5 locus on chromosome 5q31 is a confirmed Crohn's disease (CD) susceptibility locus in adults. Recently, two polymorphisms in the organic cation transporter (OCTN) gene cluster within the IBD5 locus have been found to be associated with CD. Although the original report of significant linkage to IBD5 was in families with at least one case of early age at onset CD, there are no published reports on the role of OCTN genes in pediatric onset CD. We performed a comprehensive analysis of OCTN variants in an independent, exclusively pediatric onset CD cohort and examined the genotype/phenotype correlations. METHODS 264 Caucasian CD children (172 of them were trios) were genotyped along with 527 controls for OCTN1 (SLC22A4 C1672T), OCTN2 (SLC22A5 G-207C), and two haplotype-tagging SNPs (IGR2230 and IGR2198). RESULTS TDT confirmed the association of SLC22A4 and SLC22A5. Case-control analysis of the SLC22A4 1672T, SLC22A5-207C diplotype showed significant association (p=0.04) with CD susceptibility compared with controls. Little correlation was seen with regard to clinical phenotype and the SLC22A4/SLC22A5 diplotype. There was no significant interaction between the SLC22A4/SLC22A5 diplotype and the three CD-associated CARD15 SNPs. CONCLUSIONS We confirm the association of the OCTN variants (SLC22A4 and SLC22A5) in pediatric onset CD as seen in adult CD cohorts. However, when an extended IBD5 haplotype was examined, no independent association between OCTN variants and pediatric onset CD can be demonstrated. Compared with adults, a relatively weak association of the OCTN variants was observed in our CD cohort. No definitive genotype-phenotype correlation or gene-gene interactions with CARD15 were observed. Although the IBD5 locus is associated with pediatric onset CD, no definitive conclusions can be drawn about OCTN variants as causative genes in pediatric CD at this point.
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Affiliation(s)
- Umesh Babusukumar
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
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42
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Waller S, Tremelling M, Bredin F, Godfrey L, Howson J, Parkes M. Evidence for association of OCTN genes and IBD5 with ulcerative colitis. Gut 2006; 55:809-14. [PMID: 16361305 PMCID: PMC1856215 DOI: 10.1136/gut.2005.084574] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Genetic association between Crohn's disease (CD) and OCTN1 (SLC22A4) C1672T/OCTN2 (SLC22A5) G-207C variants in IBD5 has recently been reported. These genes encode solute carriers and the association was suggested to be distinct from the background IBD5 risk haplotype. There have been conflicting reports of the association between markers in the IBD5 region and ulcerative colitis (UC) and interaction (epistasis) between this locus and CARD15. Our aim was to ascertain the contribution of OCTN variants to UC and CD in a large independent UK dataset, to seek genetic evidence that the OCTN association is distinct from the IBD5 risk haplotype and to identify interactions between the IBD5 and CARD15 loci. METHODS A total of 1104 unrelated Caucasian subjects with inflammatory bowel disease (IBD) (496 CD, 512 UC, 96 indeterminate) and 750 ethnically matched controls were genotyped for three single nucleotide polymorphisms (SNPs) in the CD associated genes (OCTN1+1672, OCTN2-207, and IGR2230), and two flanking IBD5 tagging SNPs, IGR2096 and IGR3096. Data were analysed by logistic regression methods within STATA. RESULTS OCTN variants were as strongly associated with UC and IBD overall as they were with CD (p = 0.0001; OR 1.3 (95% confidence interval 1.1-1.5)). OCTN variants were in tight linkage disequilibrium with the extended IBD5 risk haplotype D' 0.79 and 0.88, and r2 = 0.62 and 0.72 for IGR2096 and 3096, respectively. There was no deviation from a multiplicative model of interaction between CARD15 and IBD5 on the penetrance scale. CONCLUSIONS The OCTN variants were associated with susceptibility to IBD overall. The effect was equally strong in UC and CD. Although OCTN variants may account for the increased risk of IBD associated with IBD5, a role for other candidate genes within this extended haplotype was not excluded. There was no statistical evidence of interaction between CARD15 and either OCTN or IBD5 variants in susceptibility to IBD.
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Affiliation(s)
- S Waller
- IBD Researcg Group, Department of Medicine, University of Cambridge, Cambridge, UK
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43
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Onnie C, Fisher SA, King K, Mirza M, Roberts R, Forbes A, Sanderson J, Lewis CM, Mathew CG. Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31. Genes Immun 2006; 7:359-65. [PMID: 16724073 DOI: 10.1038/sj.gene.6364307] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chromosome 5q31 contains a cluster of genes involved in immune response, including a 250 kb risk haplotype associated with Crohn's disease (CD) susceptibility. Recently, two functional variants in SLC22A4 and SLC22A5 (L503F and G-207C), encoding the cation transporters OCTN1 and OCTN2, were proposed as causal variants for CD, but with conflicting genetic evidence regarding their contribution. We investigated this locus by resequencing the coding regions of 10 genes in 24 CD cases and deriving a linkage disequilibrium (LD) map of the 27 single nucleotide polymorphisms (SNPs) detected. Ten SNPs representative of the LD groups observed, were tested for CD association. L503F in SLC22A4 was the only nonsynonymous SNP significantly associated with CD (P=0.003), but was not associated with disease in the absence of other markers of the 250 kb risk haplotype. Two other SNPs, rs11242115 in IRF1 and rs17166050 in RAD50, lying outside the 250 kb risk haplotype, also showed CD association (P=0.019 and P=0.0080, respectively). The RAD50 gene contains a locus control region regulating expression of the Th2 cytokine genes at this locus. Other as yet undiscovered SNPs in this region may therefore modulate gene expression and contribute to the risk of CD, and perhaps of other inflammatory phenotypes.
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Affiliation(s)
- C Onnie
- Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK
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44
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Abstract
Recent advances in the field of inflammatory bowel disease (IBD) genetics have enabled the definition and refinement of multiple IBD susceptibility loci and the identification of gene variants within such regions showing association with Crohn's disease (CD) and/or ulcerative colitis (UC). Most notable among the newly defined genetic determinants of IBD are specific variants in the CARD15 gene, which have been shown widely to influence both susceptibility and phenotype in CD. These genetic data have inspired intensive studies of CARD15 biologic functions and the information emerging from these analyses has already substantively enhanced understanding of the signaling pathways coupling bacterial pathogens to the host immune response. Genetic data implicating various other signaling effectors in IBD susceptibility have similarly focused attention on the molecular pathways driven or regulated by these proteins and the biochemical events linking effector/pathway dysfunction to intestinal inflammation and disease. In this review, progress in defining the genetic determinants of IBD is described with an emphasis on the impact of such knowledge on understanding of IBD molecular pathophysiology.
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Affiliation(s)
- Katherine Anne Siminovitch
- Department of Medicine, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld and Toronto General Hospital Research Institutes, 600 University Avenue, Room 778D, Toronto, Ont., Canada M5G 1X5.
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45
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De Jager PL, Graham R, Farwell L, Sawcer S, Richardson A, Behrens TW, Compston A, Hafler DA, Kere J, Vyse TJ, Rioux JD. The role of inflammatory bowel disease susceptibility loci in multiple sclerosis and systemic lupus erythematosus. Genes Immun 2006; 7:327-34. [PMID: 16642031 DOI: 10.1038/sj.gene.6364303] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
To date, three loci have been validated to confer susceptibility to inflammatory bowel disease (IBD): the CARD15/NOD2 gene, the discs large homolog 5 gene (DLG5), and the IBD5 locus on 5q31 (IBD5). We have explored the possibility that these loci may also be associated with susceptibility to two other chronic inflammatory diseases, multiple sclerosis (MS) and systemic lupus erythematosus (SLE). As the CARD15 risk alleles had previously been assessed in our collection of 496 MS trios, we focused our efforts on the DLG5 risk allele and the IBD5(risk) haplotype (IBD5(risk)) for MS. While there is no evidence of association within our MS sample with either of these polymorphisms, screening of 1027 subjects with SLE suggests that IBD5(risk) may have a modest contribution to disease risk in the subset of SLE subjects without lupus nephritis. In addition, a pooled analysis of existing published and unpublished data in 1305 cases of SLE genotyped for the CARD15 risk alleles suggests that only the CARD15(908R) IBD risk allele may have a strong effect on risk of SLE. Our data, therefore, suggest that both the CARD15 gene and the IBD5 locus may have a role as general susceptibility loci for certain common, genetically complex inflammatory diseases.
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Affiliation(s)
- P L De Jager
- Center for Neurologic Diseases, Department of Neurology, Harvard Medical School and Brigham and Women's Hospital, MA, USA
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46
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Abstract
The chronic inflammatory bowel diseases Crohn's disease and ulcerative colitis are common causes of gastrointestinal disease in northern Europe, affecting as many as one in 250 people. Although mortality is low, morbidity associated with these diseases is substantial. We review the recent advances in the genetics of inflammatory bowel disease, with particular emphasis on the data that have been generated since the discovery of the CARD15 (NOD2) gene in 2001.
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Affiliation(s)
- Daniel R Gaya
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
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47
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Lakatos PL, Fischer S, Lakatos L, Gal I, Papp J. Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors: pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take "toll" ? World J Gastroenterol 2006; 12:1829-1841. [PMID: 16609988 PMCID: PMC4087507 DOI: 10.3748/wjg.v12.i12.1829] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2005] [Revised: 10/20/2005] [Accepted: 11/10/2005] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is only partially understood. Various environmental and host (e.g. genetic-, epithelial-, immune and non-immune) factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity. Some genes are associated with IBD itself, while others increase the risk of ulcerative colitis (UC) or Crohn's disease (CD) or are associated with disease location and/or behaviour. This review addresses recent advances in the genetics of IBD. The article discusses the current information on the crosstalk between microbial and genetic factors (e.g. NOD2/CARD15, SLC22A46A5 and DLG5). The genetic data acquired in recent years help in understanding the pathogenesis of IBD and can identify a number of potential targets for therapeutic intervention. In the future, genetics may help more accurately diagnose and predict disease course in IBD.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083 Budapest, Hungary.
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48
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Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A, Kuechler I, Krueger S, Schmidt HHJ, Lochs H. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut 2006; 55:342-7. [PMID: 16000642 PMCID: PMC1856071 DOI: 10.1136/gut.2005.065557] [Citation(s) in RCA: 251] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn's disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesise that a CARD15 mutation may be associated with an impaired intestinal barrier. METHODS We studied 128 patients with quiescent CD, 129 first degree relatives (CD-R), 66 non-related household members (CD-NR), and 96 healthy controls. The three most common CARD15 polymorphisms (R702W, G908R, and 3020insC) were analysed and intestinal permeability was determined by the lactulose/mannitol ratio. RESULTS Intestinal permeability was significantly increased in CD and CD-R groups compared with CD-NR and controls. Values above the normal range were seen in 44% of CD and 26% of CD-R but only in 6% of CD-NR, and in none of the controls. A household community with CD patients, representing a common environment, was not associated with increased intestinal permeability in family members. However, 40% of CD first degree relatives carrying a CARD15 3020insC mutation and 75% (3/4) of those CD-R with combined 3020insC and R702W mutations had increased intestinal permeability compared with only 15% of wild-types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability. CONCLUSIONS In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD.
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Affiliation(s)
- S Buhner
- Department of Gastroenterology, Hepatology, and Endocrinology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Schumannstr 20-21, 10117 Berlin, Germany.
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49
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Abstract
The field of inflammatory bowel disease genetics plays a leading role in the genetics of complex traits. One of the first genetic loci for a complex trait to be identified by genome-wide linkage scans and confirmed by multiple studies was IBD1 for Crohn's disease. Shortly after this initial success, a second susceptibility locus, the IBD5 risk haplotype, was discovered and unequivocally replicated. In this review, we examine the genetics and potential functional implications of the IBD5 locus on disease susceptibility, prognosis, classification, and treatment. In addition, we discuss the challenges faced when the region identified by association contains multiple genes that are not easily separated by recombination-the primary tool of the human geneticist.
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Affiliation(s)
- Claudia Reinhard
- Montreal Heart Institute, Université de Montréal, Montréal, Canada
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50
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Palmieri O, Latiano A, Valvano R, D'Incà R, Vecchi M, Sturniolo GC, Saibeni S, Peyvandi F, Bossa F, Zagaria C, Andriulli A, Devoto M, Annese V. Variants of OCTN1-2 cation transporter genes are associated with both Crohn's disease and ulcerative colitis. Aliment Pharmacol Ther 2006; 23:497-506. [PMID: 16441470 DOI: 10.1111/j.1365-2036.2006.02780.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Two variants in the organic cation transporter gene cluster have been recently reported to confer susceptibility to Crohn's disease (CD). AIM To investigate these variants in CD and ulcerative colitis (UC), and their interaction with CARD15 gene and correlation to clinical subphenotypes. METHODS Case-control association analysis was performed in 899 patients (444 CD and 455 UC) and 611 controls. The organic cation transporter gene cluster single nucleotide polymorphisms G207G-->C and 1672C-->T, the IGR2198a_1 single nucleotide polymorphism in the IBD5 locus, and the R702W, G908R and L1007finsC variants of CARD15 gene were genotyped by ABI-7700, restriction fragment length polymorphic analysis and multiplex pyrosequencing, respectively. RESULTS The 1672TT and -207CC genotype frequencies were increased in both CD (OR = 1.5, P = 0.011; OR = 1.6, P = 0.002), and UC (OR = 1.5, P = 0.017; OR = 1.4, P = 0.033), respectively. Compared with controls, the TC haplotype frequency was increased in both CD (36% vs. 44%, P < or = 0.01) and UC (36% vs. 45%, P < or = 0.01). The frequency of the TC haplotype was 43% in CARD15-positive and 44% in CARD15-negative CD, respectively. Similar results were found in UC. In CD a significant association of the TC haplotype was found with presence of perianal fistulae (P = 0.007) and steno-fistulizing behaviour (P = 0.037). In UC, the TC haplotype was more frequent in patients with more extensive disease (P = 0.015), and those on immunosuppressives (P = 0.004). CONCLUSIONS Organic cation transporter gene cluster variants may confer susceptibility to both CD and UC, and the TC haplotype may influence some clinical features of IBD, but does not interact with CARD15 variants.
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Affiliation(s)
- O Palmieri
- Divisione di Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
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