Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31

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 , 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 ¼ 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 ¼ 0.019 and P ¼ 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.

Is FCRL3 a New General Autoimmunity Gene?

“…For the programmed cell death 1 (PDCD1; chromosome 2q37) gene, strong supporting evidences were observed in SLE and RA [2]. A role of the SLC22A4/SLC22A5 genomic region on chromosome 5q31 in the pathogenesis of RA and Crohn's disease was also supported by numerous population studies [2][3][4][5].…”

AMBIENCE: A Novel Approach and Efficient Algorithm for Identifying Informative Genetic and Environmental Associations With Complex Phenotypes

“…GGI analysis of interactions in chromosome 5: We assessed the effectiveness of the KWII and TCI spectra for identifying key interactions in a genotype data set from Daly et al (2001) containing 103 SNPs spanning a 616-kb region of chromosome 5q31 that has been linked to Crohn's disease Onnie et al 2006). The data set contains genotypes for 129 parent-child trios composed of 144 cases and 243 controls .…”

Association analysis of susceptibility candidate region on chromosome 5q31 for tuberculosis

“…24,31 It is possible that the same locus can be involved in susceptibility to several related phenotypes as reported in this study on different variants in SLC22A and SLC22A5 contributing to tuberculosis susceptibility. The genomic neighborhood surrounding the Th2 cytokine cluster is particularly important for their gene expression or activities.…”

“…Association analysis on the SNP rs17166050, located in intron 4 of RAD50, showed a significant association with Crohn's disease. 24 Thus, the unidentified SNPs in the 5q31 region may influence variation of gene function among populations and contribute to the risk of Crohn's disease and other infections and inflammatory diseases. The activation of Th2 cytokine genes has been suggested to correlate with extensive tuberculosis disease.…”