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Netz U, Carter JV, Eichenberger MR, Dryden GW, Pan J, Rai SN, Galandiuk S. Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn’s disease. World J Gastroenterol 2017; 23:4958-4967. [PMID: 28785150 PMCID: PMC5526766 DOI: 10.3748/wjg.v23.i27.4958] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/05/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate genetic factors that might help define which Crohn’s disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy.
METHODS This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria).
RESULTS 121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.
CONCLUSION The Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.
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Ma T, Wu S, Yan W, Xie R, Zhou C. A functional variant of ATG16L2 is associated with Crohn's disease in the Chinese population. Colorectal Dis 2016; 18:O420-O426. [PMID: 27611316 DOI: 10.1111/codi.13507] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 05/29/2016] [Indexed: 12/16/2022]
Abstract
AIM To determine whether genetic polymorphism of the ATG16L2 gene is functionally associated with the incidence of Crohn's disease (CD) in the Chinese population. METHOD The single nucleotide polymorphism (SNP) rs11235604 of the ATG16L2 gene was genotyped in 363 patients with CD and 486 healthy volunteers from the Chinese Han population. The distributions of the genotype and allele frequency were compared between patients and controls by the chi-square test. The mRNA expression of ATG16L2 in T cells was evaluated by real-time PCR. Comparisons of mRNA expression of ATG16L2 between patients and controls and between patients with genotype CC and genotype CT/TT were performed with the Student's t-test. RESULTS Compared with the controls, patients were found to have a significantly higher proportion of genotype TT (5.5% vs 2.5%, P = 0.04). Allele T was the risk allele for the disease (16.3% vs 12.3%, P = 0.02), with an odds ratio of 1.31 (95% CI 1.04-1.67). The ATG16L2 mRNA of the patients was significantly reduced when compared with the controls (0.0044 ± 0.0018 vs 0.0064 ± 0.0023, P < 0.001). Patients with genotype TT/CT had a significant lower level of ATG16L2 mRNA than patients with genotype CC (0.0036 ± 0.0016 vs 0.0053 ± 0.0028, P = 0.005). CONCLUSIONS ATG16L2 is a susceptibility gene for CD in the Chinese population. The rs11235604 SNP is remarkably associated with downregulation of the expression of ATG16L2. Further investigation into the gene's function is warranted for a comprehensive knowledge of the contribution of the variant to the development of CD.
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Affiliation(s)
- T Ma
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China
| | - S Wu
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China
| | - W Yan
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China
| | - R Xie
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China
| | - C Zhou
- Department of Gastroenterology, Huai'an First People's Hospital of Nanjing Medical University, Huai'an, China.
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Yang DH, Yang SK, Song K, Hong M, Park SH, Lee HS, Kim JB, Lee HJ, Park SK, Jung KW, Kim KJ, Ye BD, Byeon JS, Myung SJ, Kim JH, Shin US, Yu CS, Lee I. TNFSF15 is an independent predictor for the development of Crohn's disease-related complications in Koreans. J Crohns Colitis 2014; 8:1315-26. [PMID: 24835165 DOI: 10.1016/j.crohns.2014.04.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 03/22/2014] [Accepted: 04/04/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND Crohn's disease (CD) is a chronic idiopathic inflammatory bowel disease involving the whole gastrointestinal tract. TNFSF15 has been proved as a susceptibility gene for CD, but there are few reports about the association between TNFSF15 single nucleotide polymorphisms (SNPs) and the clinical course of CD. AIM To investigate the association between TNFSF15 genotypes and the clinical course of CD in Koreans. METHODS A total of 906 CD patients having TNFSF15 genotype data and clinical information were recruited from CD registry database of a tertiary referral center. The association between five TNFSF15 SNPs (rs4574921, rs3810936, rs6478108, rs6478109, and rs7848647) and various clinical parameters including stricture, non-perianal penetrating complications, bowel resection, and reoperation was investigated. RESULTS Among the five SNPs, rs6478108 CC genotype was associated with the development of stricture and non-perianal penetrating complications during follow-up (HR for stricture=1.706, 95% confidence interval 1.178-2.471, P=0.005; HR for non-perianal penetrating complications=1.667, 95% confidence interval 1.127-2.466, P=0.010), and rs4574921 CC genotype was associated with the development of perianal fistula (HR=2.386, 95% confidence interval 1.204-4.727, P=0.013) by multivariate analysis. However, there was no significant association of cumulative operation and reoperation rate with 5 SNPs of TNFSF15. CONCLUSION In Korean patients with CD, non-risk allele homozygotes of TNFSF15 SNPs rs6478108 and rs4574921 are independent genetic predictive factors for the development of strictures/non-perianal penetrating complications and perianal fistula, respectively.
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Affiliation(s)
- Dong-Hoon Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea.
| | - Myunghee Hong
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Ho-Su Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Ji-Beom Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Hyo Jeong Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Soo-Kyung Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Kee Wook Jung
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Kyung-Jo Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Byong Duk Ye
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jin-Ho Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Ui Sup Shin
- Department of Surgery, Korea Institute of Radiological and Medical Sciences, Korea Cancer Center Hospital, Seoul, South Korea
| | - Chang Sik Yu
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Inchul Lee
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
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Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, Mantzaris G, Reinisch W, Colombel JF, Vermeire S, Travis S, Lindsay JO, van Assche G. [Second European evidence-based Consensus on the diagnosis and management of ulcerative colitis Part 1: Definitions and diagnosis (Spanish version)]. REVISTA DE GASTROENTEROLOGIA DE MEXICO 2014; 79:263-289. [PMID: 25487134 DOI: 10.1016/j.rgmx.2014.10.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 10/23/2014] [Indexed: 02/07/2023]
Affiliation(s)
- A Dignass
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo.
| | - R Eliakim
- AD y RE contribuyeron de igual manera en este trabajo
| | - F Magro
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - C Maaser
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - Y Chowers
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - K Geboes
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - G Mantzaris
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - W Reinisch
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - J-F Colombel
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - S Vermeire
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - S Travis
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - J O Lindsay
- AD y GVA actuaron como coordinadores del Consenso; AD y RE contribuyeron de igual manera en este trabajo
| | - G van Assche
- AD y GVA actuaron como coordinadores del Consenso.
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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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Sarlos P, Varszegi D, Csongei V, Magyari L, Jaromi L, Nagy L, Melegh B. Susceptibility to ulcerative colitis in Hungarian patients determined by gene-gene interactions. World J Gastroenterol 2014; 20:219-227. [PMID: 24415875 PMCID: PMC3886011 DOI: 10.3748/wjg.v20.i1.219] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 09/17/2013] [Accepted: 10/14/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the inflammatory bowel disease-5 locus (IBD5) and interleukin-23 receptor (IL23R) gene variants in UC patients and test for gene-gene interaction.
METHODS: The study population (n = 625) was comprised of 320 unrelated ulcerative colitis (UC) patients with Caucasian origin and 316 age- and gender-matched, healthy controls. Five variants in the IBD5 locus (IGR2198a_1 rs11739135, IGR2096a_1 rs12521868, IGR2230a_1 rs17622208, SLC22A4 rs1050152 and SLC22A5 rs2631367) and two of the IL23R gene (rs1004819, rs2201841) were analysed. PCR and restriction fragment length polymorphism methods were used for genotyping, the SLC22A4 rs1050152 genotypes were determined by direct sequencing. Interactions and specific genotype combinations of the seven variants were tested by binary logistic regression analysis. The IL23R genotypes were stratified by IBD5 genotypes for further interaction analyses.
RESULTS: For the IL23R rs1004819 A allele we found significantly higher allele frequency (P = 0.032) in UC patients compared to control subjects. The SNP rs1004819 showed significant association with UC risk for carriers (P = 0.004, OR = 1.606; 95%CI: 1.160-2.223) and the SNP rs2201841 for homozygotes (P = 0.030, OR = 1.983; 95%CI: 1.069-3.678). Individually none of the IBD5 markers conferred risk to UC development. There was no evidence for statistical interaction either between IBD5 loci and IL23R genes using logistic regression analysis. After genotype stratification, we could detect a positive association on the background of rs1004819 A allele for SLC22A4 T, SLC22A5 C, IGR2198a_1 C or IGR2096a_1 T allele, the highest OR was calculated in the presence of SLC22A4 T allele (P = 0.005, OR = 2.015; 95%CI: 1.230-3.300). There was no association with UC for any combinations of rs1004819 and IGR2230a_1. The IL23R rs2201841 homozygous genotype and IBD5 carrier status together did not confer susceptibility for UC.
CONCLUSION: The present study has shown that UC susceptibility genes are likely to act in a complex interactive manner similar to CD.
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Safrany E, Szabo M, Szell M, Kemeny L, Sumegi K, Melegh BI, Magyari L, Matyas P, Figler M, Weber A, Tulassay Z, Melegh B. Difference of interleukin-23 receptor gene haplotype variants in ulcerative colitis compared to Crohn's disease and psoriasis. Inflamm Res 2013; 62:195-200. [PMID: 23093364 DOI: 10.1007/s00011-012-0566-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Revised: 07/19/2012] [Accepted: 10/09/2012] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Polymorphisms of the interleukin-23 receptor (IL23R) gene have been found to play a role in the development of several autoimmune diseases. Our aim was to examine the possible effect of not only simple individual variants, but of haplotypes composed of them. SUBJECTS We analysed 263 patients with psoriasis, 199 patients with Crohn's disease (CD), 282 patients with ulcerative colitis (UC), and 253 controls for rs1884444, rs11805303, rs7517847, rs2201841, rs10889677 and rs11209032 variants. METHODS The genotypes were determined by using PCR/RFLP assay. Logistic regression analysis was used to compare the genotype distribution of the polymorphisms and haplotypes between the examined autoimmune diseases and healthy controls. RESULTS Rs1884444 was found to confer risk for UC and psoriasis, rs10889677 for CD and psoriasis, while rs2201841 and rs7517847 had effect only in CD. Using these SNPs we could study the susceptibility haplotype profiles in these diseases with special attention to UC. Eight different haplotypes could be differentiated. We found that the SNPs exert their susceptibility character in specific haplotype blocks, and the frequency of one haplotype differed significantly in UC compared with both other diseases and also with healthy controls. This haplotype conferred risk for UC, even while it had a somewhat lower frequency in the other diseases than in controls. CONCLUSIONS The data presented here serve as evidence for the need of haplotype analysis instead of just single standing SNP analysis when susceptibility is interpreted.
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Affiliation(s)
- Eniko Safrany
- Department of Medical Genetics, University of Pecs, Szigeti 12, 7624 Pecs, Hungary
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Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, Mantzaris G, Reinisch W, Colombel JF, Vermeire S, Travis S, Lindsay JO, Van Assche G. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis 2012; 6:965-90. [PMID: 23040452 DOI: 10.1016/j.crohns.2012.09.003] [Citation(s) in RCA: 638] [Impact Index Per Article: 49.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Accepted: 09/03/2012] [Indexed: 12/12/2022]
Affiliation(s)
- Axel Dignass
- Department of Medicine 1, Agaplesion Markus Hospital, Wilhelm-Epstein-Str. 4, D-60431 Frankfurt/Main, Germany.
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Repnik K, Potočnik U. Haplotype in the IBD5 region is associated with refractory Crohn's disease in Slovenian patients and modulates expression of the SLC22A5 gene. J Gastroenterol 2011; 46:1081-91. [PMID: 21695374 DOI: 10.1007/s00535-011-0426-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2011] [Accepted: 05/27/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND The IBD5 locus (OMIM ID 606348) on chromosome 5 was suggested to be one of the most important genetic factors involved in the pathogenesis of inflammatory bowel diseases (IBDs). However the main contributor from this region is still unknown. METHODS We investigated the possible association of the IBD5 locus with IBD in Slovenian patients and correlation between disease-associated single nucleotide polymorphisms (SNPs) and quantitative gene expression (eQTL) of candidate genes from the IBD5 locus in peripheral blood lymphocytes and colon tissue biopsies from IBD patients. We genotyped SNPs from the IBD5 locus in 312 healthy controls and 632 IBD patients. RESULTS We found statistically significant association of polymorphisms rs1050152 in gene SLC22A4 (p = 0.005, OR = 2.177, 95% CI = 1.270-3.526) and rs2631372 in gene SLC22A5 (p = 0.001, OR = 0.473, 95% CI = 0.307-0.731) and TC haplotype of both polymorphisms (p = 0.006, OR = 1,541, 95% CI = 1.130-2.100) with refractory Crohn's disease (CD) in Slovenian patients who do not respond to standard therapy, including patients who develop fistulas. We found decreased expression of SLC22A4 and SLC22A5 genes in peripheral blood lymphocytes from IBD patients compared to control group and decreased expression of SLC22A5 gene in inflamed tissue biopsies compared to noninflamed colon (p = 0.009). We found lower expression of SLC22A5 gene in IBD patients with disease-susceptible genotypes for both disease-associated SNPs. CONCLUSIONS Our data suggest that SNPs and haplotype in the IBD5 SLC22A4/SLC22A5 region contribute to the development of particularly refractory Crohn's disease in the Slovenian population, and expression studies in blood lymphocytes and colon tissue biopsies and eQTL analysis suggest that SLC22A5 is the main gene in the IBD5 region contributing to the IBD pathogenesis.
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Affiliation(s)
- Katja Repnik
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Slomškov Trg 15, 2000 Maribor, Slovenia
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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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Abstract
The intestinal barrier is one of the most dynamic surfaces of the body. It is here where a single layer of epithelial cells mediates the intricate encounters that occur between the host's immune system and a multitude of potential threats present in the intestinal lumen. Several key factors play an important role in the final outcome of this interaction, including the state of oxidative stress, the level of activation of the immune cells, and the integrity of the epithelial barrier. This chapter describes the main evidence demonstrating the impact that l-carnitine has on each of these factors. These findings, combined with the demonstrated safety profile of l-carnitine, underscore the potential therapeutic value of l-carnitine supplementation in humans suffering from intestinal inflammation and highlight the functional data supporting an association between Crohn's disease and mutations in the l-carnitine transporter genes.
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Mazor Y, Karban A, Nesher S, Weiss B, Leshinsky-Silver E, Levine A, Eliakim R. Granulomas in Crohn's disease: are newly discovered genetic variants involved? J Crohns Colitis 2010; 4:438-43. [PMID: 21122541 DOI: 10.1016/j.crohns.2010.02.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Revised: 01/25/2010] [Accepted: 02/19/2010] [Indexed: 12/23/2022]
Abstract
BACKGROUND Non-caseating granulomas exist in a substantial portion of patients with Crohn's disease (CD). Several single nucleotide polymorphisms (SNPs) have been identified as a having strong association with CD, including SNPs within the autophagy related 4 homolog A (ATG4A) gene and the neutrophil cytosolic factor 4 (NCF4) gene. We hypothesized a possible association between the presence of granulomas in CD patients and variants in the ATG4A and NCF4 genes. AIMS To investigate whether variants in the NCF4 and ATG4A genes are associated with granuloma formation in a cohort of Israeli patients with CD, exploring demographic and clinical characteristics that differ between granuloma positive and granuloma negative patients. METHODS 307 Israeli patients with CD were studied. Patients with CD who underwent biopsy or resection of the intestine were classified according to presence or absence of granulomas. Using PCR-RFLP we determined the allele frequency in SNP rs4821544 (NCF4 gene) and SNP rs807185 (ATG4A gene) for all patients. RESULTS Granulomas were found in 85 out of 307 CD patients (27%). There were no significant differences between patients with or without granulomas in allele frequency in SNPs rs4821544 and rs807185. CD Patients with granuloma were younger at diagnosis than patients without granuloma (mean age 19 vs. 27, respectively, P<0.0001) and were more likely to undergo surgery (55.3% vs. 34.8%, respectively, P=0.002). CONCLUSIONS No association was found between SNPs rs4821544 and rs807185 and the presence of granulomas in CD patients. Granuloma positive patients were more likely to be younger and to undergo surgery.
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14
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Yamamoto-Furusho JK. Genetic Susceptibility in Inflammatory Bowel Disease. Clin Rev Bone Miner Metab 2010. [DOI: 10.1007/s12018-009-9068-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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15
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Limdi JK, Siminovitch KA, Newman W. Genetic dissection of inflammatory bowel disease: unravelling etiology and improving diagnostics. Expert Rev Clin Immunol 2010; 1:609-17. [PMID: 20477602 DOI: 10.1586/1744666x.1.4.609] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Over the past 10 years, remarkable advances in the mapping and identification of genes involved in susceptibility to inflammatory bowel disease have been witnessed. Most notable among these advances has been the discovery of variants in the CARD15, DLG5, SLC22A4 and SLC22A5 genes, which are associated with increased risk of inflammatory bowel disease or specifically Crohn's disease. These discoveries have provided critical new insights into the molecular pathophysiology of inflammatory bowel disease and the pathways wherein genetic and environmental factors such as enteric bacterial flora may interact to trigger immune dysregulation and intestinal inflammation. This review will outline the discovery of these inflammatory bowel disease-related genes, describe future prospects for further inflammatory bowel disease gene identification, and consider the impact of a genetic understanding of inflammatory bowel disease on future clinical practice.
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Affiliation(s)
- Jimmy K Limdi
- Wythenshawe Hospital, South Manchester University Hospitals, NHS Trust, Manchester, UK.
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Talián G, Lakner L, Bene J, Komlósi K, Horváth K, Gasztonyi B, Miheller P, Figler M, Mózsik G, Tulassay Z, Melegh B. Plasma carnitine ester profiles in Crohn's disease and ulcerative colitis patients with different IGR2230a_1 genotypes. Int J Immunogenet 2009; 36:329-335. [PMID: 19735486 DOI: 10.1111/j.1744-313x.2009.00834.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
An association has been repeatedly demonstrated between inflammatory bowel disease (IBD) and the IBD5 locus in the 5q31 chromosomal region. The aim of the present study was to examine the prevalence of the IGR2230a_1 intronic nucleotide polymorphism of the slc22a5 gene (coding for the OCTN2 carnitine transporter protein) lying within this region, and its possible relationship with the carnitine metabolism in Hungarian IBD patients and controls. We genotyped by restriction fragment length polymorphism 200 Crohn's disease (CD) and 246 ulcerative colitis (UC) patients, as well as 187 healthy controls. From plasma samples we determined detailed carnitine ester profiles of 76 CD, 43 UC patients and 45 control persons using electrospray ionization triple quadruple tandem mass spectrometry. The distribution of the genotypes was not significantly different in the CD or the UC group compared with the controls. We found no significant alterations of the carnitine profile in the carrier/non-carrier or the homozygote/non-homozygote comparisons in both the CD and the UC groups, stratified by IGR2230a_1 genotype. Our data suggest that this polymorphism alone is not associated with CD and UC in the Hungarian population, and has no effect on the carnitine metabolism.
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Affiliation(s)
- G Talián
- Department of Medical Genetics and Child Development, University of Pécs, H-7624 Pécs, Hungary
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Rosenstiel P, Sina C, Franke A, Schreiber S. Towards a molecular risk map--recent advances on the etiology of inflammatory bowel disease. Semin Immunol 2009; 21:334-45. [PMID: 19926490 DOI: 10.1016/j.smim.2009.10.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2009] [Accepted: 10/14/2009] [Indexed: 12/11/2022]
Abstract
Recent advances have enabled a comprehensive understanding of the genetic architecture of inflammatory bowel disease (IBD) with over 30 identified and replicated disease loci. The pathophysiological consequences of disease gene variants in Crohn disease and ulcerative colitis, the two main subentities of IBD, so far are only understood on the single disease gene level, yet complex network analyses linking the individual risk factors into a molecular risk map are still missing. In this review, we will focus on recent pathways and cellular functions that emerged from the genetic studies (e.g. innate immunity, autophagy) and delineate the existence of shared (e.g. IL23R, IL12B) and unique (e.g. NOD2 for CD) risk factors for the disease subtypes. Ultimately, the defined molecular profiles may identify individuals at risk early in life and may serve as a guidance to administer personalized interventions for causative therapies and/or early targeted prevention strategies. Due to this comparatively advanced level of molecular understanding in the field, IBD may represent precedent also for future developments of individualized genetic medicine in other polygenic disorders in general.
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Affiliation(s)
- Philip Rosenstiel
- Institute for Clinical Molecular Biology, Christian-Albrechts University of Kiel, Schittenhelmstr. 12, D-24105 Kiel, Germany.
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18
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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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Braun J, Targan SR. Multiparameter analysis of immunogenetic mechanisms in clinical diagnosis and management of inflammatory bowel disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 579:209-18. [PMID: 16620020 DOI: 10.1007/0-387-33778-4_13] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The integrity of the intestinal mucosa depends on a functional coordination of the epithelium, lumenal microorganisms, and the local immune system. The mammalian immune system is superbly organized for innate and adaptive recognition of microbial antigens, a defensive capacity that must be balanced against the tissue damage produced by immune activity to preserve normal intestinal function. Inflammatory bowel disease (IBD) is generally thought to reflect an impairment in this balance, due to a combination of host genetic traits that shift the balance of immune and epithelial function to commensal microbiota, and perhaps the composition or activity of certain microbial elements as well. There has been much progress defining the fundamental disorders of these host traits, immunologic processes, and microbial targets in inflammatory bowel disease. Other fields of clinical and geologic microbiology are teaching us about the dynamic interaction of commensal bacteria with their host environment. These lines of investigation have revealed not only important insights about inflammatory bowel disease (IBD) pathogenesis, but also defined technologies and tools useful for its diagnosis and clinical management. This review focuses on these advances at the translational interface. We will first consider the innate anti-microbial response, centering on the utility of NOD2 genotyping for predicting disease susceptibility, prognosis, and therapeutic response profile. We will then turn to the adaptive anti-microbial response, focusing on the application of antibodies to fungal and bacterial species and products for Crohn's disease (CD) diagnosis and prognosis, and immunogenetics of T cell immunosuppression management. Finally, we will describe autoimmune mechanisms in IBD, with particular attention to autoantibodies in IBD diagnosis and infliximab responsiveness. We will conclude with the concept of multiparameter analysis of patients, to refine patient characterization and stratification in diagnosis and clinical management.
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Affiliation(s)
- Jonathan Braun
- UCLA Hospital Center for Health Sciences, Los Angeles, CA, USA
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20
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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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21
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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: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [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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Porter CK, Tribble DR, Aliaga PA, Halvorson HA, Riddle MS. Infectious gastroenteritis and risk of developing inflammatory bowel disease. Gastroenterology 2008; 135:781-6. [PMID: 18640117 DOI: 10.1053/j.gastro.2008.05.081] [Citation(s) in RCA: 132] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2008] [Revised: 05/20/2008] [Accepted: 05/30/2008] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Infectious gastroenteritis (IGE) is known to exacerbate previously diagnosed inflammatory bowel disease (IBD). However, limited data are available describing a causal link between IGE and incident IBD. METHODS By using a medical encounter data repository of active duty military personnel, a study was conducted to assess IBD risk in subjects with an antecedent case of IGE. RESULTS Between 1999 and 2006, there were 3019 incident IBD cases and 11,646 matched controls who were evaluated in a conditional logistic regression model. To control for potential misclassification, IGE episodes within 6 months of IBD diagnosis were excluded as exposures. After adjusting for potential confounders, an episode of IGE increased the risk of IBD (odds ratio, 1.40; 95% confidence interval, 1.19-1.66). The risk was slightly higher for Crohn's disease compared with ulcerative colitis. In addition, there was an approximate 5-fold increase in IBD risk for persons with a previous irritable bowel syndrome diagnosis. CONCLUSIONS These data support theories that the initiation of IBD is a multifactorial process that might include the disruption of normal gut homeostatic mechanisms. Further studies are warranted to evaluate the pathogen-specific risks, identify susceptible populations, and better understand the pathophysiologic relationship between IGE and IBD.
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Affiliation(s)
- Chad K Porter
- Enteric Diseases Department, Naval Medical Research Center, Silver Spring, Maryland 20910-7500, USA.
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Braun J, Wei B. Body traffic: ecology, genetics, and immunity in inflammatory bowel disease. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2008; 2:401-29. [PMID: 18039105 DOI: 10.1146/annurev.pathol.1.110304.100128] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The abundant bacteria and other microbial residents of the human intestine play important roles in nutrient absorption, energy metabolism, and defense against microbial pathogens. The mutually beneficial relationship of host and commensal microbiota represents an ancient and major coevolution in composition and mutual regulation of the human mucosa and the resident microbial community. Inflammatory bowel disease (IBD) is a set of chronic, relapsing inflammatory intestinal diseases in which rules of normal host-microbial interaction have been violated. This review considers the components of this host-microbial mutualism and the ways in which it is undermined by pathogenic microbial traits and by host immune and epithelial functions that confer to them susceptibility in patients with IBD. Recent advances in understanding the genetics of IBD and the immunology of host-microbial interaction are opening new strategies for treatments that target host susceptibility, candidate microbial pathogens, and intestinal ecology.
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Affiliation(s)
- Jonathan Braun
- David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
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Abstract
PURPOSE OF REVIEW Genetic factors play an important role in the pathogenesis of inflammatory bowel disease. In this review, we will provide an update on the rapid advances in the discovery of inflammatory bowel disease, primarily Crohn's disease, associated genes. RECENT FINDINGS Seven recently published Crohn's disease genome-wide association studies have confirmed prior findings related to the nucleotide-binding oligomerization domain 2 (NOD2) gene and the IBD5 locus. In addition, 10 novel loci have been identified and well replicated. SUMMARY 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 microflora in the pathogenesis of inflammatory bowel disease.
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25
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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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26
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Stange EF, Travis SPL, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, Feakins R, Fléjou JF, Herfarth H, Hommes DW, Kupcinskas L, Lakatos PL, Mantzaris GJ, Schreiber S, Villanacci V, Warren BF. European evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis. J Crohns Colitis 2008; 2:1-23. [PMID: 21172194 DOI: 10.1016/j.crohns.2007.11.001] [Citation(s) in RCA: 370] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2007] [Accepted: 11/23/2007] [Indexed: 02/06/2023]
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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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Abstract
Autoimmune diseases in general are complex genetic diseases where genes and environment interact in unknown ways. In recent years technologies have advanced our knowledge and new genes are being identified very rapidly. We can expect that most genes of major importance for the various autoimmune diseases will be discovered in the coming 5 years. The real challenge comes when we try to understand the mechanisms through which these genes confer disease susceptibility and how the interaction with environment takes place such that clinical expression of the disease results.
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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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Rodríguez-Bores L, Fonseca GC, Villeda MA, Yamamoto-Furusho JK. Novel genetic markers in inflammatory bowel disease. World J Gastroenterol 2007; 13:5560-70. [PMID: 17948929 PMCID: PMC4172734 DOI: 10.3748/wjg.v13.i42.5560] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9. Nucleotide oligomerization domain (NOD2) and human leukocyte antigen (HLA) genes are the most extensively studied genetic regions (IBD1 and IBD3 respectively) in IBD. Mutations of the NOD2 gene are associated with Crohn's disease (CD) and several HLA genes are associated with ulcerative colitis (UC) and CD. Toll like receptors (TLRs) have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns. Studying single-nucleotide polymorphisms (SNPs) in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD: NOD1/Caspase-activation recruitment domains 4 (CARD4), Chemokine ligand 20 (CCL20), IL-11, and IL-18 among others. The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.
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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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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: 120] [Impact Index Per Article: 6.7] [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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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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Cummings JRF, Ahmad T, Geremia A, Beckly J, Cooney R, Hancock L, Pathan S, Guo C, Cardon LR, Jewell DP. Contribution of the novel inflammatory bowel disease gene IL23R to disease susceptibility and phenotype. Inflamm Bowel Dis 2007; 13:1063-8. [PMID: 17508420 DOI: 10.1002/ibd.20180] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND A North American genome-wide single nucleotide polymorphism (SNP) association study identified IL23R as a novel inflammatory bowel disease (IBD) susceptibility gene. Association was reported with multiple risk variants in the centromeric portion of IL23R in 3 large independent cohorts. The aims of this study were to replicate the association of IL23R with Crohn's disease (CD), examine subphenotype relationships, and look for evidence of epistasis with the known CD susceptibility gene CARD15 and susceptibility haplotype IBD5 in a large collection of CD patients. We further investigated the relationship between IL23R and ulcerative colitis (UC). METHODS In all, 604 CD and 647 UC patients who had been rigorously phenotyped and who had been recruited from a single UK center were used in this study. Controls were either spouses of patients (141) or were recruited from well-person clinics (993). Eight SNPs were genotyped using MassArray (Sequenom). All 8 SNPs genotyped were significantly associated with CD. RESULTS The association with the nonsynonymous SNP rs11209026 was confirmed (P=6.65x10(-6), odds ratio [OR], 0.43, 95% confidence interval [CI]: 0.29-0.64). The most significant SNP in our study was rs7517847 (P=4.9x10(-9), OR 0.65, 0.56-0.75), which is statistically independent of rs11209026. Preliminary evidence suggests an epistatic interaction with the IBD5 risk haplotype. The effects of mutations in this IL23R appear weaker in UC (P=0.008, OR 0.63, 0.45-0.89 and 0.005 OR, 0.81, 0.71-0.94, respectively). No subphenotype associations were identified. CONCLUSIONS We confirmed the findings that IL23R is a susceptibility gene for IBD with suggestive epistasis with the IBD5 locus in the CD population.
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Affiliation(s)
- J R Fraser Cummings
- Wellcome Trust Centre for Human Genetics, University of Oxford, and Gastroenterology Unit, Gibson Laboratories, Radcliffe Infirmary, Oxford, UK.
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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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Greenhall JA, Zapala MA, Cáceres M, Libiger O, Barlow C, Schork NJ, Lockhart DJ. Detecting genetic variation in microarray expression data. Genome Res 2007; 17:1228-35. [PMID: 17609390 PMCID: PMC1933513 DOI: 10.1101/gr.6307307] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The use of high-density oligonucleotide arrays to measure the expression levels of thousands of genes in parallel has become commonplace. To take further advantage of the growing body of data, we developed a method, termed "GeSNP," to mine the detailed hybridization patterns in oligonucleotide array expression data for evidence of genetic variation. To demonstrate the performance of the algorithm, the hybridization patterns in data obtained previously from SAMP8/Ta, SAMP10/Ta, and SAMR1/Ta inbred mice and from humans and chimpanzees were analyzed. Genes with consistent strain-specific and species-specific hybridization pattern differences were identified, and approximately 90% of the candidate genes were independently confirmed to harbor sequence differences. Importantly, the quality of gene expression data was also improved by masking the probes of regions with putative sequence differences between species and strains. To illustrate the application to human disease groups, data from an inflammatory bowel disease study were analyzed. GeSNP identified sequence differences in candidate genes previously discovered in independent association and linkage studies and uncovered many promising new candidates. This approach enables the opportunistic extraction of genetic variation information from new or pre-existing gene expression data obtained with high-density oligonucleotide arrays.
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Affiliation(s)
- Jennifer A. Greenhall
- The Salk Institute for Biological Studies, La Jolla, California 92037, USA
- Neurosciences Graduate Program, School of Medicine, University of California, San Diego, California 92093, USA
| | - Matthew A. Zapala
- Biomedical Sciences Graduate Program, School of Medicine, University of California, San Diego, California 92093, USA
- Polymorphism Research Laboratory, Department of Psychiatry, University of California, San Diego, California 92093, USA
| | - Mario Cáceres
- The Salk Institute for Biological Studies, La Jolla, California 92037, USA
- Genes and Disease Program, Center for Genomic Regulation (CRG-UPF), Barcelona 08003, Spain
| | - Ondrej Libiger
- Polymorphism Research Laboratory, Department of Psychiatry, University of California, San Diego, California 92093, USA
| | - Carrolee Barlow
- The Salk Institute for Biological Studies, La Jolla, California 92037, USA
- Brain Cells, Inc., San Diego, California 92121, USA
| | - Nicholas J. Schork
- Biomedical Sciences Graduate Program, School of Medicine, University of California, San Diego, California 92093, USA
- Polymorphism Research Laboratory, Department of Psychiatry, University of California, San Diego, California 92093, USA
| | - David J. Lockhart
- The Salk Institute for Biological Studies, La Jolla, California 92037, USA
- Amicus Therapeutics, Cranbury, New Jersey 08512, USA
- Corresponding author.E-mail ; fax (609) 662-2001
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Plenge R, Rioux JD. Identifying susceptibility genes for immunological disorders: patterns, power, and proof. Immunol Rev 2007; 210:40-51. [PMID: 16623763 DOI: 10.1111/j.0105-2896.2006.00372.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
There is a genetic basis to the most common immune-mediated diseases. Identifying disease susceptibility genes, however, has been a challenge. Only a few genes have been consistently replicated across multiple studies. These convincing examples provide insight into a genetic approach to common immune diseases as well as insight into disease pathogenesis. Here, we discuss several important concepts of a genetic study -- patterns, power, and proof -- and why these are germane in testing inherited variation for influence on disease. Recent developments in the fields of human genetics and genomics are overcoming limitations within the field, and we anticipate many exciting discoveries in the near future.
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Affiliation(s)
- Robert Plenge
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA
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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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Abstract
The inflammatory bowel diseases (IBD) are comprised of two major subphenotypes, Crohn's disease (CD) and ulcerative colitis (UC). A significant role for genetic factors in IBD was established from epidemiologic studies and, more recently, the identification of well-established disease associations, notably the association of Nod2 (CARD15) polymorphisms with CD. The mapping to CD of Nod2 variants that alter protein function represents one of the earliest, most well-established, associations in complex genetic disorders. Since the initial discovery, genotype-phenotype correlations, definition of Nod2 expression and signaling pathways, association studies in other, related disorders, and features of Nod2 deficiency in murine models have been reported. Taken together, the Nod2 association to CD provides an illustrative model of the role of single gene variants in disease pathogenesis for common, complex multigenic disorders. Here we review general aspects of IBD genetics with particular focus on the role of Nod2 in CD.
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Affiliation(s)
- Judy H Cho
- Department of Medicine, Yale University, New Haven, Connecticut 06510, USA.
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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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Magyari L, Bene J, Komlósi K, Talián G, Faragó B, Csöngei V, Járomi L, Sáfrány E, Sipeky C, Lakner L, Varga M, Gasztonyi B, Melegh B. Prevalence of SLC22A4 1672T and SLC22A5 −207C combination defined TC haplotype in Hungarian ulcerative colitis patients. Pathol Oncol Res 2007; 13:53-6. [PMID: 17387389 DOI: 10.1007/bf02893441] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2006] [Accepted: 12/15/2006] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract. The aim of this study was to verify the prevalence rate of the haplotype called TC, determined by combination of two functional alleles of OCTN cation transporter genes (SLC22A4 1672T and SLC22A5 -207C combination variants) in ulcerative colitis patients and unrelated healthy controls. The "TC haplotype" has recently been suggested to confer risk for UC. A total of 121 unrelated Hungarian subjects with UC and 110 matched controls were genotyped for the two single nucleotide polymorphisms. The genotypes were determined by using PCR/RFLP assay and direct sequencing. The SLC22A4 1672T allele frequency was 46.7% in the patients with UC and 46.4% in the controls, whereas the SLC22A5 -207C allele occurred in 48.8% of the patients and 51.4% of the controls. The prevalence of the TC haplotype was 19% in the patient group and 22.7% in controls. Since there was no accumulation of the TC haplotype in the patient group, our observation suggests that carrying the TC haplotype is not associated with a higher risk for UC in the Hungarian population.
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Affiliation(s)
- Lili Magyari
- Department of Medical Genetics and Child Development, University of Pécs, Pécs, H-7624, Hungary
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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: 26] [Impact Index Per Article: 1.4] [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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Brant SR, Wang MH, Rawsthorne P, Sargent M, Datta LW, Nouvet F, Shugart YY, Bernstein CN. A population-based case-control study of CARD15 and other risk factors in Crohn's disease and ulcerative colitis. Am J Gastroenterol 2007; 102:313-23. [PMID: 17100976 DOI: 10.1111/j.1572-0241.2006.00926.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Multiple established Crohn's disease (CD) and ulcerative colitis (UC) risk factors including family history, tobacco use, Jewish ethnicity, urban residency, and CARD15/NOD2 mutations have been evaluated singly and in hospital-based observational studies. The goal of this study was to assess the relative contributions of all these risk factors jointly in a nonreferral, population-based cohort derived from a population epidemiologic database. METHODS CD (N = 232) and UC (N = 121) subjects were ascertained from our population-based IBD Registry derived from Manitoba Health, the single provincial insurer. Healthy controls (HC) (N = 336) were recruited via a 10:1 mailing matched for age, sex, and postal code. Ethnicity, tobacco use, family history, residency, and CARD15/NOD2 genotype status were determined. RESULTS In both univariate analyses and analyses adjusted for all risk factors, CD was influenced independently by CARD15/NOD2 heterozygote and homozygote/compound-heterozygote status (adjusted odds ratios [OR] 3.7 and 40.0, respectively), Jewish ethnicity (OR 18.5), CD family history (OR 6.2), and smoking (OR 3.0 current and 1.7 ex-smoker, respectively). Penetrance for homozygote/compound-heterozygotes was 4.9%, heterozygotes 0.54%, and wild types 0.184%. Population attributable risk for CARD15 was 26.7% and current tobacco use was 46.8%. A tobacco-CARD15 interaction was not observed. UC was influenced by Jewish ethnicity (OR 37.1), and by family history (OR 2.6), ex-smoker status (OR 1.9), and CARD15/NOD2 heterozygote or homozygote/compound-heterozygote status (OR 1.9 and 6.4, respectively) in adjusted analyses only. CONCLUSIONS CARD15/NOD2, family history, smoking, and Jewish ethnicity are independent risk factors for CD. Examination of these risk factors together in a single population-based cohort has provided initial data for population epidemiological characterization and genetic counseling uses.
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Affiliation(s)
- Steven R Brant
- Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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Abstract
At this moment, few confirmed associations between NOD2 mutations and diseases other than Crohn's disease (CD) and Blau syndrome (BS) have been reported, but research is ongoing in several fields where a genetic susceptibility factor and/or a role for the innate immune system is suspected. Whether the Crohn's-associated CARD15 mutations lead to a loss or gain of function of the NOD2 receptor is subject to controversy, and by which mechanisms this change in function might increase the susceptibility to CD is still under investigation. The possible involvement of NOD2/CARD15 in the pathogenesis of certain diseases with already (partially) unraveled pathophysiologic mechanisms might contribute to our further understanding of NOD2/CARD15 and its function in CD. We review studies on the association of CARD15 variants with diseases other than CD. The association of NOD2/CARD15 mutations with CD and BS, and possibly also early onset sarcoidosis, suggests a role for the gene in the development of granulomata and granulomatous diseases, possibly by inappropriate activation of the immune system. The data from the oncology field suggest that this inappropriate activation might even lead to uncontrolled proliferation of certain cell types. The studies in allergic diseases and atopy are the largest so far, and the association of NOD2/CARDI5 mutations with atopic phenotypes might be an indication that CARD15 also plays a role in the Th2 pathway. Finally, transplantation studies indicate that the genetic background of a patient should be taken into account when considering hematopoietic stem cell transplantation, given the increased risk of mortality and graft versus host disease observed. Whether NOD2 variants are also associated with an increased risk for infections and sepsis in patients receiving immunosuppressive therapies is unclear.
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Törkvist L, Noble CL, Lördal M, Sjöqvist U, Lindforss U, Nimmo ER, Löfberg R, Russell RK, Satsangi J. Contribution of the IBD5 locus to Crohn's disease in the Swedish population. Scand J Gastroenterol 2007; 42:200-6. [PMID: 17340776 DOI: 10.1080/00365520600842278] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Recent data have controversially suggested that variants of the organic cation transport genes SLC22A4 (OCTN1) and SLC22A5 (OCTN2) are responsible for the contribution of IBD5 to disease susceptibility in Crohn's disease (CD). The objective of this study was to assess the contribution of the SLC22A4 variant (1672T) and SLC22A5 variant (-207C) together with three IBD5 haplotype markers in the previously uninvestigated Swedish CD population. MATERIAL AND METHODS The study comprised 178 CD patients and 143 healthy controls (HC). Genotyping for IBD5 single nucleotide polymorphisms (SNPs) IGR2096a_1, IGR2198a_1, IGR2230a_1, SLC22A4 1672T and SLC22A5 -207C was carried out using the TaqMan system. Associations with disease susceptibility and disease phenotype were investigated. RESULTS Strong linkage disequilibrium was observed between the investigated SNPs (D prime >0.92). IGR2096a_1 allelic frequency and homozygosity rates were associated with CD (44% CD versus 33.8% HC, p=0.008, OR=1.55 and 20% CD versus 12% HC, p=0.04, OR=1.93, respectively). Variant allelic frequency of SLC22A4, 1672T (44% versus 36%, p=0.03, OR=1.4) and homozygosity for the SLC22A4, SLC22A5 TC haplotype (1672T, -207C) (21.3% versus 12%, p=0.03, OR=1.78, population attributable risk (PAR)=11%) were associated with CD. There was no association between the allelic frequency of SLC22A5 and CD (46.6% CD versus 41.5% HC, p=0.82). The association of the TC haplotype with CD was not independent of the SNPs representing the extended IBD5 linkage interval. CONCLUSIONS The IBD5 locus is associated with CD in the Swedish population. The strongest association is with the marker SNP IGR2096a_1, lying p-telomeric to SLC22A4 and SLC22A5. The effect of the TC haplotype was not an independent determinant in this population.
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Affiliation(s)
- Leif Törkvist
- Department of Medical & Surgical Gastroenterology, Karolinska University Hospital, Stockholm, Sweden
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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: 62] [Impact Index Per Article: 3.4] [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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Brescianini S, Trinh T, Stoll M, Schreiber S, Rioux JD, Daly MJ. IBD5 is associated with an extensive complicated Crohn's disease feature: implications from genotype-phenotype analysis. Gut 2007; 56:149-50. [PMID: 17172589 PMCID: PMC1856659 DOI: 10.1136/gut.2006.102723] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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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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