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Wang J, Sun M, Liu X, Yan Q, Gao Q, Ni K, Yang J, Zhang S, Zhang C, Shan C. Transcriptome analysis identifies genetic risk markers and explores the pathogenesis for inflammatory bowel disease. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167013. [PMID: 38199515 DOI: 10.1016/j.bbadis.2023.167013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/30/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024]
Abstract
Inflammatory bowel disease (IBD) is an incurable and disabling bowel disease driven by multiple risk factors that severely limit patients' quality of life. We integrated the RNA-sequencing data of 1238 IBD patients, and investigated the pathogenesis of IBD by combining transcriptional element prediction analysis and immune-related analysis. Here, we first determined that KIAA1109 is inhibited in IBD patients. The expression of KIAA1109 and NOD2, the key receptor of NOD-like receptors, showed a negative correlation. The NOD-like receptor signaling pathway is activated and exerts transcriptional regulation on the chemokines CXCL1 and CXCL2 through the activation of the transcription factors NFκB and AP1. Analysis of immune infiltration revealed that the expression of chemokines CXCL1 and CXCL2 may regulate the inflammatory response induced by immune cells. These findings suggest that the KIAA1109-NOD2-NFκB/AP1-CXCL1/CXCL2 regulatory axis is the molecular mechanism of IBD pathogenesis, which will provide a new perspective for the diagnosis, treatment and management of IBD patients.
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Affiliation(s)
- Jiyan Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Mingming Sun
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Xu Liu
- Endoscopy Center, Tianjin Union Medical Center, Tianjin 300121, China
| | - Qi Yan
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Qingle Gao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China
| | - Kemin Ni
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Juze Yang
- Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China
| | - Shuai Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China; Tianjin Institute of Coloproctology, Tianjin 300121, China.
| | - Changliang Shan
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China.
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The role of NOD2 in intestinal immune response and microbiota modulation: A therapeutic target in inflammatory bowel disease. Int Immunopharmacol 2022; 113:109466. [DOI: 10.1016/j.intimp.2022.109466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/11/2022] [Accepted: 10/24/2022] [Indexed: 11/25/2022]
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Liu M, Zhu W, Wang J, Zhang J, Guo X, Wang J, Song J, Dong W. Interleukin-23 receptor genetic polymorphisms and ulcerative colitis susceptibility: A meta-analysis. Clin Res Hepatol Gastroenterol 2015; 39:516-25. [PMID: 25497273 DOI: 10.1016/j.clinre.2014.10.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/13/2014] [Accepted: 10/17/2014] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The interleukin-23 receptor (IL-23R) polymorphism has been implicated in susceptibility to ulcerative colitis (UC), but the results remain inconclusive. This study was designed to evaluate whether IL-23R polymorphisms were associated with UC susceptibility. METHODS CNKI, WanFang Data, PubMed, MEDLINE, Web of Science, Google Scholar, EBSCO, CBM database and EMBASE were searched until 31 June 2014 for eligible studies on eight IL-23R polymorphisms: rs11209026, rs7517847, rs1209032, rs2201841, rs1343151, rs1088967, rs1495965 and rs1004819. Meta-analysis from all eligible case-control studies was performed to assess the purported associations. Meta-analysis was performed by using the RevMan 5.2 software and STATA package version 12.0. RESULTS Sixteen studies with 5438 cases and 7380 controls were included. Overall, our analysis found that variant minor alleles for single nucleotide polymorphisms (SNPs) rs11209026 (Arg381Gln) (dominant model: GG+TG vs. TT, P=0.02, OR=0.71, 95%CI: 0.53-0.94); rs7517847 (recessive model: GG vs. TT, P=0.04, OR=0.80, 95%CI: 0.65-0.99) and rs11209032 [dominant model: GA+AA vs. GG (P=0.04, OR=1.31, 95% CI: 1.01-1.26); AA vs. GG: (P=0.04, OR=1.21, 95% CI: 1.01-1.45)] of IL-23R were associated with UC risk. In stratification analysis by ethnicity, we observed that the rs11209026 and rs7517847 polymorphism of IL-23R could protect against development of UC among Caucasian populations [rs11209026: dominant model (P=0.01, OR=0.69, 95%CI: 0.52-0.92); rs7517847: GG vs. TT (P=0.002, OR=0.69, 95%CI: 0.54-0.87); recessive model (P=0.004, OR=0.73, 95% CI: 0.59-0.90)]; the rs11209032 were associated with a greater risk for UC in Caucasian populations [dominant model (P=0.04, OR=1.13, 95%CI: 1.00-1.26)]; the rs1088967 were associated with a lower risk for UC among Asian populations [dominant model (P=0.04, OR=0.73, 95%CI: 0.54-0.99)]. Moreover, meta-analysis revealed no association between the four alleles of the rs2201841, rs1004819, rs1495965 and rs1343151 polymorphisms and the risk of developing UC in Caucasian and Asian populations. CONCLUSION Our meta-analysis supports that two polymorphisms (rs11209026 and rs7517847) in the IL-23 gene may be considered to be protective factors against developing UC among Caucasian populations; while the rs11209032 polymorphisms may increase the risk of UC among Caucasian populations; furthermore, the rs1088967 polymorphisms in the IL-23 gene may be considered to be protective factors against developing UC among Asian populations. Further large case-control studies especially concerning ethnicity differences and genotype-phenotype interaction should be performed to clarify possible roles of IL-23R in UC.
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Affiliation(s)
- Min Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Wenqian Zhu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Jun Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Xufeng Guo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Jing Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Jia Song
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China.
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Boukercha A, Mesbah-Amroun H, Bouzidi A, Saoula H, Nakkemouche M, Roy M, Hugot JP, Touil-Boukoffa C. NOD2/ CARD15 gene mutations in North Algerian patients with inflammatory bowel disease. World J Gastroenterol 2015; 21:7786-7794. [PMID: 26167078 PMCID: PMC4491965 DOI: 10.3748/wjg.v21.i25.7786] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 04/23/2015] [Accepted: 05/07/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyse allelic frequency of NOD2 gene variants and to assess their correlation with inflammatory bowel disease (IBD) in Algeria.
METHODS: We studied 132 unrelated patients diagnosed with IBD, 86 with Crohn’s disease (CD) and 46 with ulcerative colitis (UC). Data was prospectively collected between January 2011 and December 2013. The demographic and clinical characteristics were recorded for all the patients. A group of 114 healthy unrelated individuals were selected as controls. All groups studied originated from different regions of North Algeria and confirmed the Algerian origin of their parents and grandparents. Informed and written consent was obtained from each of the participants. All individuals were genotyped for the three CD-associated NOD2 variants (p.Arg702Trp, p.Gly908Arg and p.Leu1007fsinsC mutations) using the polymerase chain reaction-restriction fragment length polymorphism method. Allele and genotype frequencies in patients and control subjects were compared by χ2 test and Fisher’s exact test where appropriate. Odds ratios (OR) and 95% confidence intervals (95%CI) were also estimated. Association analyses were performed to study the influence of these variants on IBD and on clinical phenotypes.
RESULTS: The p.Arg702Trp mutation showed the highest frequency in CD patients (8%) compared to UC patients (2%) (P = 0.09, OR = 3.67, 95%CI: 0.48-4.87) and controls (5%) (P = 0.4, OR = 1.47, 95%CI: 0.65-3.31). In CD patients allelic frequencies of p.Gly908Arg and p.Leu1007fsinsC variants compared to HC were 3% vs 2% (P = 0.5, OR = 1.67, 95%CI: 0.44-6.34); 2% vs 1% (P = 0.4 OR = 2.69 95%CI: 0.48-14.87 respectively). In UC patients, allelic frequencies of p.Gly908Arg and p.Leu1007fsinsC variants compared to HC were 1% vs 2% (P = 1, OR = 1.62, 95%CI: 0.17-4.74) and 2% vs 1% (P = 0.32, OR = 0.39, 95%CI: 0.05-2.87). The total frequency of the mutated NOD2 chromosomes was higher in CD (13%), than in HC (8%) and UC (5%). In addition, NOD2 variants were linked to a particular clinical sub-phenotype in CD in this Algerian cohort. As expected, the three NOD2 variants showed a significant association with CD but did not reach statistical significance, despite the fact that the allele frequency of NOD2 variants was in the range found in most of the European populations. This might be due to the non-exposure of the NOD2 carriers to environmental factors, required for the expression of the disease.
CONCLUSION: Further analyses are necessary to study genetic and environmental factors in IBD in the Algerian population, using larger patient groups.
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Abstract
: Restorative proctocolectomy with ileal pouch-anal anastomosis is commonly used in the management of ulcerative colitis. Inflammation of the ileal pouch reservoir, or pouchitis, is a common complication of ileal pouch-anal anastomosis that is incompletely understood. Risk factors including nonsmoker status and primary sclerosing cholangitis have been linked with pouchitis development, but the etiopathogenesis of pouchitis remains poorly defined. Pouchitis is more commonly a complication of ileal pouch-anal anastomosis performed in patients with ulcerative colitis, and similar to ulcerative colitis, chronic pouchitis is associated with extraintestinal manifestations and other diseases of immune origin, suggesting overlap in the disease pathogenesis. It is becoming apparent that pouchitis encompasses clinically distinct subtypes based on the response or lack of response to antibiotic therapy. There is also emerging evidence of the role of autoimmunity in a subgroup of patients with pouchitis, including patients with concurrent primary sclerosing cholangitis, seropositivity for immunoglobulin G4, or infiltration of immunoglobulin G4-expressing plasma cells in the pouch mucosa. The identification of underlying autoimmunity may have important clinical implications in the diagnosis, subclassification, and management of pouchitis.
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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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Almadi MA, Aljebreen AM, Sanai FM, Marcus V, Almeghaiseeb ES, Ghosh S. New insights into gastrointestinal and hepatic granulomatous disorders. Nat Rev Gastroenterol Hepatol 2011; 8:455-66. [PMID: 21818145 DOI: 10.1038/nrgastro.2011.115] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Numerous diseases that involve the gastrointestinal tract reveal the presence of granulomas on histological analysis. Granulomatous diseases can be either primary or secondary to environmental factors. Granulomas are dynamic structures composed of organized collections of activated macrophages, including epithelioid and multinucleated giant cells, surrounded by lymphocytes. The formation of granulomas is usually in response to antigenic stimulation and is orchestrated through cytokines, immune cells and host genetics. In this Review, the pathogenesis and etiologies of granulomas of the gastrointestinal tract and liver are discussed, as are the available diagnostic tools to help differentiate their various underlying etiologies. In addition, the role of granulomas in harboring latent tuberculosis is reviewed. The effects of tumor necrosis factor antagonists and interferon-α on the development of granulomas are also discussed.
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Affiliation(s)
- Majid A Almadi
- Department of Medicine, Gastroenterology Division, King Khalid University Hospital, King Saud University, PO Box 231494, Riyadh 11321, Saudi Arabia.
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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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Borzutzky A, Fried A, Chou J, Bonilla FA, Kim S, Dedeoglu F. NOD2-associated diseases: Bridging innate immunity and autoinflammation. Clin Immunol 2010; 134:251-61. [DOI: 10.1016/j.clim.2009.05.005] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2009] [Accepted: 05/06/2009] [Indexed: 11/25/2022]
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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; 36:329-35. [PMID: 19735486 DOI: 10.1111/j.1744-313x.2009.00834.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [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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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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Abstract
The nucleotide-binding and oligomerization domain, leucine-rich repeat (also known as NOD-like receptors, both abbreviated to NLR) family of intracellular pathogen recognition receptors are increasingly being recognized to play a pivotal role in the pathogenesis of a number of rare monogenic diseases, as well as some more common polygenic conditions. Bacterial wall constituents and other cellular stressor molecules are recognized by a range of NLRs, which leads to activation of the innate immune response and upregulation of key proinflammatory pathways, such as IL-1beta production and translocation of nuclear factor-kappaB to the nucleus. These signalling pathways are increasingly being targeted as potential sites for new therapies. This review discusses the role played by NLRs in a variety of inflammatory diseases and describes the remarkable success to date of these therapeutic agents in treating some of the disorders associated with aberrant NLR function.
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Affiliation(s)
- Rebeccah J Mathews
- Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
| | - Michael B Sprakes
- Department of Gastroenterology, Leeds General Infirmary, Great George Street, Leeds, LS1 3EX, UK
| | - Michael F McDermott
- Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, St. James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
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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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Juyal G, Amre D, Midha V, Sood A, Seidman E, Thelma BK. Evidence of allelic heterogeneity for associations between the NOD2/CARD15 gene and ulcerative colitis among North Indians. Aliment Pharmacol Ther 2007; 26:1325-32. [PMID: 17892524 DOI: 10.1111/j.1365-2036.2007.03524.x] [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: 12/12/2022]
Abstract
BACKGROUND Three common disease susceptibility variants in the NOD2 gene are associated with inflammatory bowel disease in Caucasians, but not in Asians. Aim To screen for NOD2 variants and examine susceptibility for inflammatory bowel disease in North Indians. METHODS A case-control study was carried out in Punjab, India. Confirmed cases of ulcerative colitis and Crohn's disease and healthy controls matched for age (+/-10 years) and ethnicity were studied. Besides genotyping the three disease susceptibility variants (SNP8, SNP12 and SNP13), all 12 exons were resequenced to determine other potential single nucleotide polymorphisms. RESULTS Two hundred and ninety-eight ulcerative colitis, 25 Crohn's disease and 262 controls were investigated. Median age (range) at diagnosis was 39 (7-78) years for ulcerative colitis and 40 (32-58) years for Crohn's disease. All three disease susceptibility variants were either monomorphic or rare in the population. Sequencing (n = 30) revealed two single nucleotide polymorphisms: SNP5 (268 Pro/Ser) and rs2067085 (178 Ser/Ser). The frequency of SNP5 was higher among ulcerative colitis (17% vs. 12% in controls, P = 0.016) and Crohn's disease cases (20% vs. 12%, P = 0.28). SNP5 carriers had elevated risks for ulcerative colitis (OR = 1.72, 95% CI = 1.17-2.52, P = 0.005). CONCLUSIONS The absence of known inflammatory bowel disease susceptibility variants and potential associations between SNP5 and ulcerative colitis in North Indians suggests the presence of allelic heterogeneity for ulcerative colitis susceptibility.
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Affiliation(s)
- G Juyal
- Department of Genetics, University of Delhi, South Campus, New Delhi, India
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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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McKinnon RA, Ward MB, Sorich MJ. A critical analysis of barriers to the clinical implementation of pharmacogenomics. Ther Clin Risk Manag 2007; 3:751-9. [PMID: 18473000 PMCID: PMC2376080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Over recent decades, basic research has yielded a large volume of data on many potentially clinically relevant genetic determinants of drug efficacy and toxicity. Until recently, most examples involved genes encoding drug-metabolizing enzymes, particularly the cytochromes P450. More recently, rapid advances in genomic technologies have enabled broader, genome-wide searches for determinants of drug response. In parallel with these pharmacogenetic studies, a new drug discovery platform, termed pharmacogenomics, has emerged which utilises genetic information to guide the selection of new drugs most likely to survive increasingly demanding safety and efficacy assessments. Together, these advances are widely promoted as the basis of a new era of drug-based therapeutics tailored to the individual. The extent to which individualized or personalized medicine will emerge as a sustainable new therapeutic paradigm is, however, the topic of much debate. It is clear that an increasingly complex series of barriers must be overcome if we are to successfully harness genomic advances in the clinical setting. Potential barriers may include cost-effectiveness of the test, ethical concerns over the use of DNA, and required educational and equipment infrastructure. Although long overdue, many of these potential barriers are now being subjected to closer examination and as a result, a framework for successful clinical uptake of pharmacogenomics is emerging.
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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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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; 13:1221-9. [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] [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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20
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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: 49] [Impact Index Per Article: 2.7] [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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21
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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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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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23
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Silverberg MS, Duerr RH, Brant SR, Bromfield G, Datta LW, Jani N, Kane SV, Rotter JI, Philip Schumm L, Hillary Steinhart A, Taylor KD, Yang H, Cho JH, Rioux JD, Daly MJ. Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn's disease. Eur J Hum Genet 2007; 15:328-35. [PMID: 17213842 DOI: 10.1038/sj.ejhg.5201756] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Although the general association of the inflammatory bowel disease (IBD) 5 region on chromosome 5q31 to Crohn's disease (CD) has been replicated repeatedly, the identity of the precise causal variant within the region remains unknown. A recent report proposed polymorphisms in solute carrier family 22, member 4 (SLC22A4) organic cation transporter 1(OCTN1) and solute carrier family 22, member 5 (SLC22A5) (OCTN2) as responsible for the IBD5 association, but definitive, large-sample comparison of those polymorphisms with others known to be in strong linkage disequilibrium was not performed. We evaluated 1879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for six IBD5 tag single nucleotide polymorphisms (SNPs) to evaluate association localization and ethnic and subphenotypic specificity. We confirm association to the IBD5 region (best SNP IGR2096a_1/rs12521868, P<0.0005) and show this association to be exclusive to the non-Jewish (NJ) population (P=0.00005) (risk allele undertransmitted in Ashkenazi Jews). Using Phase II HapMap data, we demonstrate that there are a set of polymorphisms, spanning genes from prolyl 4-hydroxylase (P4HA2) through interferon regulatory factor 1 (IRF1) with equivalent statistical evidence of association to the reported SLC22A4 variant and that each, by itself, could entirely explain the IBD5 association to CD. Additionally, the previously reported SLC22A5 SNP is rejected as the potential causal variant. No specificity of association was seen with respect to disease type and location, and a modest association to ulcerative colitis is also observed. We confirm the importance of IBD5 to CD susceptibility, demonstrate that the locus may play a role in NJ individuals only, and establish that IRF1, PDLIM, and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.
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Affiliation(s)
- Mark S Silverberg
- Department of Medicine, Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada
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24
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Russell RK, Drummond HE, Nimmo ER, Anderson NH, Noble CL, Wilson DC, Gillett PM, McGrogan P, Hassan K, Weaver LT, Bisset WM, Mahdi G, Satsangi J. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease. Gut 2006; 55:1114-23. [PMID: 16469794 PMCID: PMC1856267 DOI: 10.1136/gut.2005.082107] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Revised: 01/15/2006] [Accepted: 02/01/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The OCTN1 (SLC22A4 1672C-->T) and OCTN2 (SLC22A5 -207G-->C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn's disease (CD), but their contribution in children has not been examined. METHODS These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a_1, IGR2198a_1, and IGR2230a_1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls. RESULTS All SNPs were in strong linkage disequilibrium (D' >0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (p<0.04). The homozygous mutant OCTN1/2 haplotype was increased in IBD (24.3% v 16.1%, p = 0.02) and UC (28.2% v 16.1%, p = 0.02) compared with controls. The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility. Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight, height, and BMI centile (<9(th) centile) at diagnosis (weight: 87.9% v 67.3% (p = 0.002), odds ratio (OR) = 3.52 (95% confidence interval, 1.51 to 8.22); height: 84.1% v 68.4% (p<0.05), OR = 2.44 (1.00 to 5.99); BMI: 79.6% v 61.1% (p = 0.02), OR = 2.49 (1.14 to 5.44)), and lower weight centile at follow up (87.5% v 64.6% (p = 0.03), OR = 3.83 (1.03 to 14.24)). Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis (p = 0.02, OR = 3.41 (1.20 to 9.66)). CONCLUSIONS These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis.
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Affiliation(s)
- R K Russell
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, UK.
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25
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Abstract
In 2004, an association of genetic variation in the discs large homolog 5 (DLG5) gene with inflammatory bowel disease (IBD) was described in two large European study samples. The initial report of DLG5 as a novel IBD susceptibility gene sparked a multitude of studies investigating its effect on CD and IBD, respectively, leading to controversial findings and ongoing discussions concerning the validity of the initial association finding and its role in the aetiology of Crohn disease. This review aims to summarize the current state of knowledge and to place the reported findings in the context of current concepts of complex diseases. This includes aspects of statistical power, phenotype differences and genetic heterogeneity between different populations as well as gene-gene and gene-environment interactions.
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Affiliation(s)
- Frauke Friedrichs
- Genetic Epidemiology of vascular disorders, Leibniz-Institute for Arteriosclerosis Research at the University of Muenster, Germany
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26
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Abstract
Crohn’s disease and ulcerative colitis are inflammatory disorders of the gastrointestinal tract with a substantial heritable component. The IBD5 region on chromosome 5q31 is one of only two loci widely confirmed to be associated with Crohn’s disease in multiple independent cohorts. Although many populations have demonstrated association with IBD5, there remains uncertainty as to the causal variant within the region. A recent report identified polymorphisms in SLC22A4 (OCTN1) and SLC22A5 (OCTN2) as being responsible for the IBD5 association, however, these findings have not been replicated. This review discusses the data evaluating the IBD5 locus and the OCTN genes and their relationship to inflammatory bowel disease. Several other genes, including IRF1 and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.
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Affiliation(s)
- Mark-S Silverberg
- Mount Sinai Hospital IBD Centre, Department of Medicine, Toronto, Ontario, Canada.
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27
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Waller S, Tremelling M, Bredin F, Godfrey L, Howson J, Parkes M. Evidence for association of OCTN genes and IBD5 with ulcerative colitis. Gut 2006; 55:809-14. [PMID: 16361305 PMCID: PMC1856215 DOI: 10.1136/gut.2005.084574] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Genetic association between Crohn's disease (CD) and OCTN1 (SLC22A4) C1672T/OCTN2 (SLC22A5) G-207C variants in IBD5 has recently been reported. These genes encode solute carriers and the association was suggested to be distinct from the background IBD5 risk haplotype. There have been conflicting reports of the association between markers in the IBD5 region and ulcerative colitis (UC) and interaction (epistasis) between this locus and CARD15. Our aim was to ascertain the contribution of OCTN variants to UC and CD in a large independent UK dataset, to seek genetic evidence that the OCTN association is distinct from the IBD5 risk haplotype and to identify interactions between the IBD5 and CARD15 loci. METHODS A total of 1104 unrelated Caucasian subjects with inflammatory bowel disease (IBD) (496 CD, 512 UC, 96 indeterminate) and 750 ethnically matched controls were genotyped for three single nucleotide polymorphisms (SNPs) in the CD associated genes (OCTN1+1672, OCTN2-207, and IGR2230), and two flanking IBD5 tagging SNPs, IGR2096 and IGR3096. Data were analysed by logistic regression methods within STATA. RESULTS OCTN variants were as strongly associated with UC and IBD overall as they were with CD (p = 0.0001; OR 1.3 (95% confidence interval 1.1-1.5)). OCTN variants were in tight linkage disequilibrium with the extended IBD5 risk haplotype D' 0.79 and 0.88, and r2 = 0.62 and 0.72 for IGR2096 and 3096, respectively. There was no deviation from a multiplicative model of interaction between CARD15 and IBD5 on the penetrance scale. CONCLUSIONS The OCTN variants were associated with susceptibility to IBD overall. The effect was equally strong in UC and CD. Although OCTN variants may account for the increased risk of IBD associated with IBD5, a role for other candidate genes within this extended haplotype was not excluded. There was no statistical evidence of interaction between CARD15 and either OCTN or IBD5 variants in susceptibility to IBD.
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Affiliation(s)
- S Waller
- IBD Researcg Group, Department of Medicine, University of Cambridge, Cambridge, UK
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28
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Abstract
Recent advances in the field of inflammatory bowel disease (IBD) genetics have enabled the definition and refinement of multiple IBD susceptibility loci and the identification of gene variants within such regions showing association with Crohn's disease (CD) and/or ulcerative colitis (UC). Most notable among the newly defined genetic determinants of IBD are specific variants in the CARD15 gene, which have been shown widely to influence both susceptibility and phenotype in CD. These genetic data have inspired intensive studies of CARD15 biologic functions and the information emerging from these analyses has already substantively enhanced understanding of the signaling pathways coupling bacterial pathogens to the host immune response. Genetic data implicating various other signaling effectors in IBD susceptibility have similarly focused attention on the molecular pathways driven or regulated by these proteins and the biochemical events linking effector/pathway dysfunction to intestinal inflammation and disease. In this review, progress in defining the genetic determinants of IBD is described with an emphasis on the impact of such knowledge on understanding of IBD molecular pathophysiology.
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Affiliation(s)
- Katherine Anne Siminovitch
- Department of Medicine, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld and Toronto General Hospital Research Institutes, 600 University Avenue, Room 778D, Toronto, Ont., Canada M5G 1X5.
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29
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Abstract
The chronic inflammatory bowel diseases Crohn's disease and ulcerative colitis are common causes of gastrointestinal disease in northern Europe, affecting as many as one in 250 people. Although mortality is low, morbidity associated with these diseases is substantial. We review the recent advances in the genetics of inflammatory bowel disease, with particular emphasis on the data that have been generated since the discovery of the CARD15 (NOD2) gene in 2001.
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Affiliation(s)
- Daniel R Gaya
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
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30
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Achkar JP, Dassopoulos T, Silverberg MS, Tuvlin JA, Duerr RH, Brant SR, Siminovitch K, Reddy D, Datta LW, Bayless TM, Zhang L, Barmada MM, Rioux JD, Steinhart AH, McLeod RS, Griffiths AM, Cohen Z, Yang H, Bromfield GP, Schumm P, Hanauer SB, Cho JH, Nicolae DL. Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus. Am J Gastroenterol 2006; 101:572-80. [PMID: 16542294 DOI: 10.1111/j.1572-0241.2006.00451.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p < 0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.
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Affiliation(s)
- Jean-Paul Achkar
- Center for Inflammatory Bowel Disease, Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH, USA
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31
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Abstract
The field of inflammatory bowel disease genetics plays a leading role in the genetics of complex traits. One of the first genetic loci for a complex trait to be identified by genome-wide linkage scans and confirmed by multiple studies was IBD1 for Crohn's disease. Shortly after this initial success, a second susceptibility locus, the IBD5 risk haplotype, was discovered and unequivocally replicated. In this review, we examine the genetics and potential functional implications of the IBD5 locus on disease susceptibility, prognosis, classification, and treatment. In addition, we discuss the challenges faced when the region identified by association contains multiple genes that are not easily separated by recombination-the primary tool of the human geneticist.
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Affiliation(s)
- Claudia Reinhard
- Montreal Heart Institute, Université de Montréal, Montréal, Canada
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32
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Gazouli M, Mantzaris G, Archimandritis AJ, Nasioulas G, Anagnou NP. Single nucleotide polymorphisms of OCTN1, OCTN2, and DLG5 genes in Greek patients with Crohn's disease. World J Gastroenterol 2006; 11:7525-30. [PMID: 16437728 PMCID: PMC4725165 DOI: 10.3748/wjg.v11.i47.7525] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To validate novel single nucleotide polymorphisms (SNPs) in Greek patients with Crohn's disease (CD). METHODS A total of 120 patients with CD, 85 patients with UC, and 100 unrelated healthy controls were genotyped. Genotyping was performed by allele-specific PCR or by PCR-RFLP analysis. RESULTS Our results showed that the 1672T and -207C alleles were obviously over-represented in CD patients only (P<0.01 and P<0.05, respectively) compared to the control population. The G113A polymorphism was completely absent in our studied population. The odds ratio for the carriage of the TC haplotype was 2.21 for CD patients as compared with controls. Additionally, the frequency of the TC haplotype was increased in patients with ileocolitis or colitis, and was mainly associated with the fibrostenotic phenotype of the disease. Furthermore, when the TC haplotype was compared jointly with the carriage of at least one mutation of the NOD2/CARD15 gene, there was an increased risk for CD, but not for UC, compared to controls. Regarding the location of the disease, the concomitant presence of the TC haplotype and NOD2/CARD15 mutations was mainly associated with ileocolitis or ileitis. CONCLUSION Collectively, our results suggest that the 1672T variant of the OCTN1 gene and the -207C variant of the OCTN2 gene represent risk factors for CD in the Greek population.
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Affiliation(s)
- Maria Gazouli
- Department of Biology, School of Medicine, University of Athens, Athens 11527, Greece
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Palmieri O, Latiano A, Valvano R, D'Incà R, Vecchi M, Sturniolo GC, Saibeni S, Peyvandi F, Bossa F, Zagaria C, Andriulli A, Devoto M, Annese V. Variants of OCTN1-2 cation transporter genes are associated with both Crohn's disease and ulcerative colitis. Aliment Pharmacol Ther 2006; 23:497-506. [PMID: 16441470 DOI: 10.1111/j.1365-2036.2006.02780.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Two variants in the organic cation transporter gene cluster have been recently reported to confer susceptibility to Crohn's disease (CD). AIM To investigate these variants in CD and ulcerative colitis (UC), and their interaction with CARD15 gene and correlation to clinical subphenotypes. METHODS Case-control association analysis was performed in 899 patients (444 CD and 455 UC) and 611 controls. The organic cation transporter gene cluster single nucleotide polymorphisms G207G-->C and 1672C-->T, the IGR2198a_1 single nucleotide polymorphism in the IBD5 locus, and the R702W, G908R and L1007finsC variants of CARD15 gene were genotyped by ABI-7700, restriction fragment length polymorphic analysis and multiplex pyrosequencing, respectively. RESULTS The 1672TT and -207CC genotype frequencies were increased in both CD (OR = 1.5, P = 0.011; OR = 1.6, P = 0.002), and UC (OR = 1.5, P = 0.017; OR = 1.4, P = 0.033), respectively. Compared with controls, the TC haplotype frequency was increased in both CD (36% vs. 44%, P < or = 0.01) and UC (36% vs. 45%, P < or = 0.01). The frequency of the TC haplotype was 43% in CARD15-positive and 44% in CARD15-negative CD, respectively. Similar results were found in UC. In CD a significant association of the TC haplotype was found with presence of perianal fistulae (P = 0.007) and steno-fistulizing behaviour (P = 0.037). In UC, the TC haplotype was more frequent in patients with more extensive disease (P = 0.015), and those on immunosuppressives (P = 0.004). CONCLUSIONS Organic cation transporter gene cluster variants may confer susceptibility to both CD and UC, and the TC haplotype may influence some clinical features of IBD, but does not interact with CARD15 variants.
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Affiliation(s)
- O Palmieri
- Divisione di Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
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Latiano A, Palmieri O, Valvano RM, D'Incà R, Vecchi M, Ferraris A, Sturniolo GC, Spina L, Lombardi G, Dallapiccola B, Andriulli A, Devoto M, Annese V. Contribution of IBD5 locus to clinical features of IBD patients. Am J Gastroenterol 2006; 101:318-25. [PMID: 16454837 DOI: 10.1111/j.1572-0241.2006.00389.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIM The aim of this study was to investigate the influence of the IBD5 locus on clinical features of inflammatory bowel disease (IBD) patients, and its possible interaction with the CARD15 gene. PATIENTS AND METHODS A cohort of 1,199 IBD patients (570 with CD and 629 with ulcerative colitis [UC]), and 357 healthy subjects were investigated. Information on clinical features was fully available for 855 IBD patients. Two SNPs in the IBD5 locus (IGR2198a_1 and IGR2096a_1) and the three major variants of CARD15 gene were genotyped in patients and controls. RESULTS Homozygous carriers of risk alleles were significantly more frequent in CD (22.6% for IGR2198a_1, OR = 1.6, p = 0.015; 21.9% for IGR2096a_1, OR = 1.6, p = 0.012) compared to controls (16.8% and 15.7%, respectively). The homozygote frequency was also increased in UC patients, but not significantly. No significant gene-gene interaction was detected between IBD5 and CARD15. A univariate analysis detected association between IBD5 and steno/fistulizing behavior in CD patients (OR = 1.9; p = 0.004), and presence of more extensive colitis in UC patients (OR = 1.7; p = 0.01). Results from multiple logistic regression, after correction for covariates, showed that the influence of IBD5 on clinical outcome of CD was completely masked by that of CARD15, while the influence on more extensive colitis in UC patients was confirmed. CONCLUSIONS Our study shows that presence of the IBD5 risk alleles, particularly in the homozygous state, is associated with IBD and especially with CD, without a significant epistasis with CARD15. The contribution of CARD15 risk alleles to CD clinical features is prominent on that of IBD5.
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Affiliation(s)
- Anna Latiano
- Divisione di Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
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Friedrichs F, Brescianini S, Annese V, Latiano A, Berger K, Kugathasan S, Broeckel U, Nikolaus S, Daly MJ, Schreiber S, Rioux JD, Stoll M. Evidence of transmission ratio distortion of DLG5 R30Q variant in general and implication of an association with Crohn disease in men. Hum Genet 2006; 119:305-11. [PMID: 16446977 DOI: 10.1007/s00439-006-0133-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2005] [Accepted: 12/24/2005] [Indexed: 12/12/2022]
Abstract
Recently, we described the association of genetic variation in the discs large homolog 5 (DLG5) gene with inflammatory bowel disease (IBD) in a large European study sample (Stoll et al. in Nat Genet 36:476-480, 2004). Here, we report that the R30Q variant constitutes a susceptibility factor for Crohn disease (CD) in men [odds ratio (OR)=2.49, 95% confidence interval (CI) 1.53-4.06, P<0.001] but not women (OR=1.01, 95% CI=0.70-1.45, P=0.979) using multivariate logistic regression analyses in a unified study sample from Germany, Italy and Quebec. R30Q is a significant predictor for CD in men even when accounting for CARD15 and IBD5 risk variants (adjusted OR=2.41, 95% CI=1.41-4.12, P=0.001). The observed association is driven by a gender-dependent transmission ratio distortion (TRD) among healthy controls (frequency of Q allele: men 5.2%, women 11.3%), an effect that is offset in CD patients (frequency of Q allele: men 10.1%, women 10.9%). This finding is further substantiated by two non-IBD study samples, one of which consists of a newborn screening sample (newborn males 7.1%; newborn females 11%, P=0.036). Further investigation of the observed TRD may contribute towards enlightening the role of DLG5 in physiological processes influencing transmission of chromosomes to the surviving offspring, which, in turn, may help in understanding its implication in the development of CD among men.
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Affiliation(s)
- Frauke Friedrichs
- Leibniz-Institute for Arteriosclerosis Research, Domagkstr. 3, 48149, Muenster, Germany
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Abstract
The research on genetic susceptibility of inflammatory bowel diseases (IBD) has been tremendous and over 10 chromosomal regions have been identified by genome-wide scanning. Further fine mapping as well as candidate gene studies have already led to the identification of a number of susceptibility genes including CARD15, DLG5, OCTN1 and 2, NOD1, HLA, and TLR4. The CARD15 gene is undoubtedly replicated most widely and most understood at present. CARD15 is involved in the recognition of bacterial peptidoglycan-derived muramyl dipeptide (MDP) and will stimulate secretion of antimicrobial peptides including alpha-defensins (also called cryptdins) to protect the host from invasion. Genetic research in IBD has advanced our understanding of the clinical heterogeneity of the disease and has started to tackle the complex interactions between genetic risk factors and environmental risk factors in IBD. Genes also interfere with the metabolization of drugs and may influence the clinical response and the drug-related toxicity. Interesting pharmacogenetic data with respect to steroids, azathioprine, and infliximab have been generated in IBD. Overall, it is anticipated that genetic markers in the future will be implemented in an integrated molecular diagnostic and prognostic approach of our patients.
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Affiliation(s)
- S Vermeire
- University Hospital Gasthuisberg Leuven, Division of Gastroenterology-Herestraat, Leuven 49-3000, Belgium.
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Tosa M, Negoro K, Kinouchi Y, Abe H, Nomura E, Takagi S, Aihara H, Oomori S, Sugimura M, Takahashi K, Hiwatashi N, Takahashi S, Shimosegawa T. Lack of association between IBD5 and Crohn's disease in Japanese patients demonstrates population-specific differences in inflammatory bowel disease. Scand J Gastroenterol 2006; 41:48-53. [PMID: 16373276 DOI: 10.1080/00365520510023864] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Population-specific differences in the genetic susceptibility to inflammatory bowel disease (IBD) are indicated by the fact that Crohn's disease (CD) in Japanese patients does not have any of the common CARD15 variants that are associated with CD in Caucasians. Recently, the disease-causing mutation in the IBD5 haplotype was identified. The TC haplotype, composed of L503F in SLC22A4 and -207G/C in SLC22A5 promoters, was reported to alter the function of the organic cation transporter and to be associated with CD in Caucasians. To determine whether the TC haplotype is also associated with IBD in a Japanese population, we genotyped L503F and -207G/C variants in Japanese subjects. Furthermore, we also performed a case-control association study with all representative single nucleotide polymorphisms (SNPs) in IBD5 using previous information of linkage disequilibrium extension reported in Japanese patients to determine whether there were variants in IBD5 specifically associated with IBD in Japanese patients. MATERIAL AND METHODS A total of 758 Japanese individuals, 241 patients with CD, 247 patients with ulcerative colitis (UC) and 270 healthy controls, were analyzed in this study. Genotyping for SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS We found L503F and -207G/C to be very rare (<1% frequency) in CD, UC and HC in the Japanese population. Furthermore, we also found that none of the representative SNPs in IBD5 was associated with CD or UC in the Japanese subjects. CONCLUSIONS In contrast to Caucasians, IBD5 is not a major component of the susceptibility to IBD in the Japanese population.
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Affiliation(s)
- Masaki Tosa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Ho P, Bruce IN, Silman A, Symmons D, Newman B, Young H, Griffiths CEM, John S, Worthington J, Barton A. Evidence for common genetic control in pathways of inflammation for Crohn's disease and psoriatic arthritis. ACTA ACUST UNITED AC 2005; 52:3596-602. [PMID: 16255050 DOI: 10.1002/art.21393] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Clinical, pharmacologic, and epidemiologic evidence supports the hypothesis that common genetic pathways may underlie inflammatory diseases. In a previous study, a Crohn's disease gene, CARD15, was demonstrated to be associated with psoriatic arthritis (PsA). Recently, a functional haplotype of 2 single-nucleotide polymorphisms (SNPs) mapping to the organic cation transporter (OCTN) genes, SLC22A4 and SLC22A5, was identified as a second Crohn's disease susceptibility locus. The SLC22A4 gene has also been associated with rheumatoid arthritis. This study was undertaken to further elucidate associations of PsA with Crohn's disease susceptibility genes. METHODS Association with CARD15 and OCTN was investigated in UK Caucasian patients with PsA (n = 472) and population controls (n = 594), using 5' allelic discrimination assays (TaqMan). Two SNPs in OCTN, forming a haplotype previously associated with Crohn's disease, were also tested in patients with psoriasis (n = 218) and patients with early undifferentiated inflammatory arthritis (n = 386). Allele and estimated haplotype frequencies were compared between patients and controls. RESULTS No association of PsA with CARD15 was detected. In contrast, a functional SNP mapping to the promoter region of SLC22A5 (rs2631367) was associated with PsA (for CC versus GG, odds ratio 1.65, 95% confidence interval 1.13-2.41, uncorrected P = 0.005). In addition, the haplotype associated with Crohn's disease was also associated with PsA (P = 0.001). No association was detected in the cohort with psoriasis alone or in the cohort with undifferentiated inflammatory arthritis. CONCLUSION The OCTN haplotype previously associated with Crohn's disease is also associated with PsA, suggesting that these 2 diseases may share some common genetic control in pathways of inflammation.
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Affiliation(s)
- Pauline Ho
- University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
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39
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Vermeire S, Pierik M, Hlavaty T, Claessens G, van Schuerbeeck N, Joossens S, Ferrante M, Henckaerts L, Bueno de Mesquita M, Vlietinck R, Rutgeerts P. Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD. Gastroenterology 2005; 129:1845-53. [PMID: 16344053 DOI: 10.1053/j.gastro.2005.10.006] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2004] [Accepted: 07/27/2005] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Three years after the identification of NOD2/CARD15, 2 more genes for inflammatory bowel diseases (IBDs) were reported. The carnitine/organic cation transporter (OCTN) on 5q31 (IBD5) is associated with Crohn's disease (CD) and DLG5 (10q23), a member of membrane-associated guanylate kinase (MAGUK) family, with IBD. We studied mutation prevalence, assessed phenotypic expression, and performed conditional analysis to examine evidence for gene-gene interactions. METHODS A cohort of 2032 individuals was genotyped for disease-associated OCTN and DLG5 variants, including 981 patients with IBD (CD, n = 769; ulcerative colitis, n = 186; indeterminate colitis, n = 26) followed up at a tertiary IBD center. For 373 patients, DNA from both parents was available (cohort 1) for transmission disequilibrium testing analysis; case-control analysis was performed in 608 patients and 305 controls (cohort 2). RESULTS There was no distortion of transmission toward affected offspring for any of the variant alleles. Case-control analysis also failed to shown an association. A higher frequency of DLG5 113A was observed in CARD15-positive patients (12.2%) compared with CARD15-negative patients (8.7%; P = .033). The OCTN-TC risk haplotype was associated with penetrating disease (odds ratio, 1.474; 95% confidence interval, 1.028-2.114; P = .035). For DLG5, there were no associations with a particular phenotype. CONCLUSIONS DLG5 and OCTN do not play a role in the susceptibility to IBD, CD, or ulcerative colitis in the Flemish population but play a role in the phenotypic expression of the disease. OCTN variants were associated with perianal and penetrating CD. More studies in independent populations are urgently needed to assess the validity of DLG5 and OCTN in the pathogenesis of IBD.
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40
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Török HP, Glas J, Tonenchi L, Lohse P, Müller-Myhsok B, Limbersky O, Neugebauer C, Schnitzler F, Seiderer J, Tillack C, Brand S, Brünnler G, Jagiello P, Epplen JT, Griga T, Klein W, Schiemann U, Folwaczny M, Ochsenkühn T, Folwaczny C. Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn's disease. Gut 2005; 54:1421-7. [PMID: 15955786 PMCID: PMC1774699 DOI: 10.1136/gut.2005.066340] [Citation(s) in RCA: 118] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Recent data suggest identification of causal genetic variants for inflammatory bowel disease in the DLG5 gene and in the organic cation transporter (OCTN) cluster, both situated in previously described linkage regions. PATIENTS AND METHODS The polymorphisms in DLG5 (113 G-->A, 4136 C-->A, and DLG5_e26), SLC22A4 (1672 C-->T), and SLC22A5 (-207 G-->C) were assessed in 625 patients with Crohn's disease (CD), 363 patients with ulcerative colitis (UC), and 1012 healthy controls. Association with disease susceptibility, clinical phenotypes, and possible genetic interactions of these polymorphisms with disease associated CARD15/NOD2 mutations was analysed. RESULTS No significant association of DLG5 polymorphisms with CD or UC was observed. Homozygosity for the OCTN-TC haplotype was associated with an increased CD risk (OR = 1.65), which was even greater in the presence of CARD15 mutations. Genotype-phenotype analysis revealed that this association was particularly strong in patients with colonic disease. The TC haplotype was associated with non-fistulising non-fibrostenotic disease, an earlier age of disease onset, and reduced need for surgery. CONCLUSION Our observations argue against a role of DLG5 polymorphisms in the susceptibility for inflammatory bowel disease, whereas the OCTN polymorphisms are associated with CD. However, due to the comparable weak association observed herein, extended linkage disequilibrium analyses of these variants with the IBD5 haplotype tagged single nucleotide polymorphims might be advisable before definitive conclusions about their causative role in CD can be drawn.
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Affiliation(s)
- H-P Török
- Chirurgische Klinik und Poliklinik-Standort Innenstadt, and Medizinische Poliklinik-Standort Innenstadt, Ludwig-Maximilians-Universität München, Germany
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41
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Schreiber S, Rosenstiel P, Albrecht M, Hampe J, Krawczak M. Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nat Rev Genet 2005; 6:376-88. [PMID: 15861209 DOI: 10.1038/nrg1607] [Citation(s) in RCA: 242] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Chronic inflammatory disorders such as Crohn disease, atopic eczema, asthma and psoriasis are triggered by hitherto unknown environmental factors that function on the background of some polygenic susceptibility. Recent technological advances have allowed us to unravel the genetic aetiology of these and other complex diseases. Using Crohn disease as an example, we show how the discovery of susceptibility genes furthers our understanding of the underlying disease mechanisms and how it will, ultimately, give rise to new therapeutic developments. The long-term goal of such endeavours is to develop targeted prophylactic strategies. These will probably target the molecular interaction on the mucosal surface between the products of the genome and the microbial metagenome of a patient.
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Affiliation(s)
- Stefan Schreiber
- Institute for Clinical Molecular Biology, Center for Conservative Medicine, Christian-Albrechts-University Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany.
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Abstract
Nods are cytosolic proteins that contain a nucleotide-binding oligomerization domain (NOD). These proteins include key regulators of apoptosis and pathogen resistance in mammals and plants. A large number of Nods contain leucine-rich repeats (LRRs), hence referred to as NOD-LRR proteins. Genetic variation in several NOD-LRR proteins, including human Nod2, Cryopyrin, and CIITA, as well as mouse Naip5, is associated with inflammatory disease or increased susceptibility to microbial infections. Nod1, Nod2, Cryopyrin, and Ipaf have been implicated in protective immune responses against pathogens. Together with Toll-like receptors, Nod1 and Nod2 appear to play important roles in innate and acquired immunity as sensors of bacterial components. Specifically, Nod1 and Nod2 participate in the signaling events triggered by host recognition of specific motifs in bacterial peptidoglycan and, upon activation, induce the production of proinflammatory mediators. Naip5 is involved in host resistance to Legionella pneumophila through cell autonomous mechanisms, whereas CIITA plays a critical role in antigen presentation and development of antigen-specific T lymphocytes. Thus, NOD-LRR proteins appear to be involved in a diverse array of processes required for host immune reactions against pathogens.
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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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McGovern DPB, Hysi P, Ahmad T, van Heel DA, Moffatt MF, Carey A, Cookson WOC, Jewell DP. Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Hum Mol Genet 2005; 14:1245-50. [PMID: 15790594 DOI: 10.1093/hmg/ddi135] [Citation(s) in RCA: 257] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The identification of the role of genetic variants within NOD2 (CARD15) in Crohn's disease and ulcerative colitis susceptibility highlight the role of the innate immune system in inflammatory bowel disease (IBD) pathogenesis. NOD1 (CARD4) is located on chromosome 7p14.3, in a region of known linkage to IBD and encodes an intracellular bacterial pathogen-associated molecular pattern receptor that is closely related to NOD2. We have identified strong association between haplotypes in the terminal exons of NOD1 and IBD (multi-allelic P = 0.0000003) in a panel of 556 IBD trios. The deletion allele of a complex functional NOD1 indel polymorphism (ND(1) + 32656*1) was significantly associated with early-onset IBD (P = 0.0003) in unrelated cases and controls. ND1 + 32656*1 was also associated with extra-intestinal manifestations of IBD (P = 0.04). These findings in two independent populations provide strong evidence for a role for NOD1 variants in IBD susceptibility and reinforce the role of the innate immune system in IBD pathogenesis.
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Affiliation(s)
- Dermot P B McGovern
- Thw Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.
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45
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Kinouchi Y, Negoro K, Takagi S, Takahashi S, Shimosegawa T. Genotype and phenotype relation in inflammatory bowel disease. J Gastroenterol 2005; 40 Suppl 16:21-4. [PMID: 15902959 DOI: 10.1007/bf02990574] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Genotype-phenotype analysis helps us to discriminate among various subgroups of IBD and consequently helps us to understand the etiology and pathogenesis as well as develop effective treatments for each subgroup of IBD.
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Affiliation(s)
- Yoshitaka Kinouchi
- Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai 980-8574 Japan
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46
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Newman B, Gu X, Wintle R, Cescon D, Yazdanpanah M, Liu X, Peltekova V, Van Oene M, Amos CI, Siminovitch KA. A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn's disease. Gastroenterology 2005; 128:260-9. [PMID: 15685536 DOI: 10.1053/j.gastro.2004.11.056] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Previously, we identified 2 functionally relevant polymorphisms in the SLC22A4 / 22A5 genes at the IBD5 locus that alter gene/protein function and comprise a 2-allele haplotype ( SLC22A -TC) associated with increased risk for Crohn's disease (CD). Here we examine the contribution of this susceptibility haplotype alone and in combination with CARD15 variants to CD subphenotypes and to susceptibility to ulcerative colitis (UC). METHODS Phenotype-genotype associations were evaluated in a Canadian cohort including 507 patients with CD, 216 patients with UC, and 352 ethnically matched controls genotyped for SLC22A4 C1672T, SLC22A5 G-207C, and the major CD-associated CARD15 variants. RESULTS The SLC22A -TC haplotype was strongly associated ( P < .0001) with CD in the non-Jewish subgroup of this cohort, and the combination of SLC22A -TC homozygosity and one or more of the common CARD15 disease susceptibility alleles engendered a 7.5-fold increase in risk for CD ( P = 9 x 10 -8 ) and a 4.5-fold increase in risk for ileal disease ( P = .001). The risk haplotype showed only a suggestive association with CD in the Jewish subgroup and no association with UC in the cohort or in subgroups stratified by CARD15 genotypes. CONCLUSIONS The SLC22A -TC haplotype acts together with CARD15 disease susceptibility alleles to increase risk for CD and ileal disease among CD patients but does not contribute to risk for UC in this Canadian cohort. The association of the SLC22A -TC haplotype and CARD15 alleles with ileal disease suggests that these variants have biologically intertwined effects in the pathogenesis of CD.
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Affiliation(s)
- Bill Newman
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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47
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Abstract
The genetic revolution has been with us for over a decade now. We have yet to see this impacting the care of patients except in a few rare examples. However, progress has been made in the field of inflammatory bowel disease (IBD) that could soon be translated to the bedside, both in terms of predicting the disease course as well as in the response to therapy. IBD traditionally has been classified as ulcerative colitis and Crohn's disease, with 10% of patients classified as having indeterminate colitis on the basis of clinical, radiologic, endoscopic, and histologic findings. However, this traditional view is now being challenged. Developments in genetics and serological markers, as well as an appreciation of the disease course, have led to an understanding that IBD is a heterogeneous group of diseases with some common genetic and environmental factors but different clinical manifestations in terms of disease behavior, location, and response to treatment. Data are now emerging that may allow us to more objectively select the correct therapy for the correct patient, rather than the current approach, which is based on clinical experience backed up by a less-than-perfect evidence base. In this article, we will review the evidence for this.
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Affiliation(s)
- J R Fraser Cummings
- Gastroenterology Unit, University of Oxford, Gibson Laboratories Radcliffe Infirmary, Oxford, UK.
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48
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49
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Nebert DW, Vesell ES. Advances in pharmacogenomics and individualized drug therapy: exciting challenges that lie ahead. Eur J Pharmacol 2004; 500:267-80. [PMID: 15464039 DOI: 10.1016/j.ejphar.2004.07.031] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2004] [Indexed: 12/16/2022]
Abstract
Between the 1930s and 1990s, several dozen predominantly monogenic, high-penetrance disorders involving pharmacogenetics were described, fueling the crusade that gene-drug interactions are quite simple. Then, in 1990, the Human Genome Project was established; in 1995, the term pharmacogenomics was introduced; finally, the complexities of determining an unequivocal phenotype, as well as an unequivocal genotype, have recently become apparent. Since 1965, more than 1000 reviews on this topic have painted an overly optimistic picture-suggesting that the advent of individualized drug therapy used by the practicing physician is fast approaching. For many reasons listed here, however, we emphasize that these high expectations must be tempered. We now realize that the nucleotide sequence of the genome represents only a starting point from which we must proceed to a more difficult stage: knowledge of the function encoded and how this affects the phenotype. To achieve individualized drug therapy, a high level of accuracy and precision is required of any clinical test proposed in human patients. Finally, we suggest that metabonomics, perhaps in combination with proteomics, might complement genomics in eventually helping us to achieve individualized drug therapy.
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Affiliation(s)
- Daniel W Nebert
- Division of Human Genetics, Department of Pediatrics and Molecular Developmental Biology, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056, USA.
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