Abstract
Chromosome 5q31 contains a cluster of genes involved in immune response, including a 250 kb risk haplotype associated with Crohn's disease (CD) susceptibility. Recently, two functional variants in SLC22A4 and SLC22A5 (L503F and G-207C), encoding the cation transporters OCTN1 and OCTN2, were proposed as causal variants for CD, but with conflicting genetic evidence regarding their contribution. We investigated this locus by resequencing the coding regions of 10 genes in 24 CD cases and deriving a linkage disequilibrium (LD) map of the 27 single nucleotide polymorphisms (SNPs) detected. Ten SNPs representative of the LD groups observed, were tested for CD association. L503F in SLC22A4 was the only nonsynonymous SNP significantly associated with CD (P=0.003), but was not associated with disease in the absence of other markers of the 250 kb risk haplotype. Two other SNPs, rs11242115 in IRF1 and rs17166050 in RAD50, lying outside the 250 kb risk haplotype, also showed CD association (P=0.019 and P=0.0080, respectively). The RAD50 gene contains a locus control region regulating expression of the Th2 cytokine genes at this locus. Other as yet undiscovered SNPs in this region may therefore modulate gene expression and contribute to the risk of CD, and perhaps of other inflammatory phenotypes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Loftus EV . Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 2004; 126: 1504–1517.
Mathew CG, Lewis CM . Genetics of inflammatory bowel disease: progress and prospects. Hum Mol Genet 2004; 13: R161–R168 (Special Issue 1).
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599–603.
Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R et al. A frameshift mutation in Nod2 associated with susceptibility to Crohn's disease. Nature 2001; 411: 603–606.
Hampe J, Cuthbert A, Croucher P, Mirza MM, Mascheretti S, Fisher S et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 2001; 357: 1925–1928.
Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, McLeod RS, Griffiths AM et al. Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet 2000; 66: 1863–1870.
Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001; 29: 223–228.
Mirza MM, Fisher SA, King K, Cuthbert AP, Hampe J, Sanderson J et al. Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease. Am J Hum Genet 2003; 72: 1018–1022.
Giallourakis C, Stoll M, Miller K, Hampe J, Lander E, Daly M et al. IBD5 is a general risk factor for inflammatory bowel disease: replication of association with Crohn's disease and identification of a novel association with Ulcerative Colitis. Am J Hum Genet 2003; 78: 205–211.
Negoro K, McGovern DPB, Kinouchi Y, Takahashi S, Lench NJ, Shimosegawa T et al. Analysis of the IBD5 locus and potential gene–gene interactions in Crohn's disease. Gut 2003; 52: 541–546.
Daly MJ, Rioux JD, Schaffner SE, Hudson TJ, Lander ES . High-resolution haplotype structure in the human genome. Nat Genet 2001; 29: 229–232.
Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q, Gu X et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 2004; 36: 471–475.
Török HP, Glas J, Tonenchi L, Lohse P, Müller-Myhsok B, Limbersky O et al. Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn's disease. Gut 2005; 54: 1354–1357.
Vermeire S, Pierik M, Hlavaty T, Claessens G, van Shuerbeeck N, Joossens S et al. Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD. Gastroenterology 2005; 129: 1845–1853.
Noble CL, Nimmo ER, Drummond H, Ho GT, Tenesa A, Smith L et al. The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease. Gastroenterology 2005; 129: 1854–1864.
Trinh TT, Rioux JD . Understanding association and causality in the genetic studies of inflammatory bowel disease. Gastroenterology 2005; 129: 2106–2110.
Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 1999; 21: 91–94.
Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 2003; 35: 341–348.
Donfack J, Schneider DH, Tan Z, Kirz T, Dubchak I, Frazer KA et al. Variation in conserved non-coding sequences on chromosome 5q and susceptibility to asthma and atopy. Resp Res 2005; 6: 145.
Ho P, Bruce IN, Silman A, Symmons D, Newman B, Young H et al. Evidence for common genetic control in pathways of inflammation for Crohn's disease and psoriatic arthritis. Arthritis Rheum 2005; 52: 3596–3602.
Frazer KA, Ueda Y, Zhu Y, Gifford VR, Garofalo MR, Mohandas N et al. Computational and biological analysis of 680 kb of DNA sequence from the human 5q31 cytokine gene cluster region. Genome Res 1997; 7: 495–512.
Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE, Kel OV et al. Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res 1998; 26: 362–367.
Ardle KG, Kruglyak L, Seielstad M . Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 2002; 3: 299–309.
Luoni G, Forton J, Jallow M, Akha ES, Sisay-Joof F, Pinder M et al. Population-specific patterns of linkage disequilibrium in the human 5q31 region. Genes Immun 2005; 6: 723–727.
Newman B, Gu X, Wintle R, Cescon D, Yazdanpanah M, Liu X et al. A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn's disease. Gastroenterology 2005; 128: 260–269.
Sallusto F, Reiner SL . Sliding doors in the immune response. Nat Immunol 2005; 6: 10–12.
Lennard-Jones JE . Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl 1989; 170: 2–6.
King K, Moody A, Fisher SA, Mirza MM, Cuthbert AP, Hampe J et al. Genetic variation in the IGSF6 gene and lack of association with inflammatory bowel disease. Eur J Immunogenet 2003; 30: 187–190.
Fisher SA, Moody A, Mirza MM, Cuthbert AP, Hampe J, MacPherson A et al. Genetic variation at the chromosome 16 chemokine gene cluster: development of a strategy for association studies in complex disease. Ann Hum Genet 2003; 67: 377–390.
Cuthbert AP, Fisher SA, Sanderson J, Forbes A, Lewis CM, Mathew CG . Genetic association between EPHX1 and Crohn's disease: population stratification, genotyping error or random chance? Gut 2004; 53: 1386.
Mirza MM, Fisher SA, Lewis CM, Mathew CG . Failure to replicate the association of a functional NFκB1 promoter polymorphism with ulcerative colitis in a British case control cohort. Gut 2005; 54: 1206.
Lewontin R . The Interaction of Selection and Linkage. II. Optimum models. Genetics 1964; 50: 757–782.
Devlin B, Risch N . A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 1995; 29: 311–322.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.
Zhao JH, Curtis D, Sham PC . Model-free analysis and permutation tests for allelic associations. Hum Hered 2000; 50: 133–139.
Acknowledgements
This work was supported by CORE, the 5th Framework Programme of the European Commission, and the Wellcome Trust.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Onnie, C., Fisher, S., King, K. et al. Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31. Genes Immun 7, 359–365 (2006). https://doi.org/10.1038/sj.gene.6364307
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gene.6364307
Keywords
This article is cited by
-
Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia
BMC Cancer (2013)
-
Replication of genetic loci for sarcoidosis in US black women: data from the Black Women’s Health Study
Human Genetics (2013)
-
A genome-wide admixture scan for ancestry-linked genes predisposing to sarcoidosis in African-Americans
Genes & Immunity (2011)
-
Association analysis of susceptibility candidate region on chromosome 5q31 for tuberculosis
Genes & Immunity (2010)
-
The interaction index, a novel information-theoretic metric for prioritizing interacting genetic variations and environmental factors
European Journal of Human Genetics (2009)