Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease

Abstract

The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it is widely accepted that immunologic, environmental and genetic components contribute to its etiology. To identify genetic susceptibility factors in CD, we performed a genome-wide association study in Japanese patients and controls using nearly 80,000 gene-based single nucleotide polymorphism (SNP) markers and investigated the haplotype structure of the candidate locus in Japanese and European patients. We identified highly significant associations (P = 1.71 x 10(-14) with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients. The association was confirmed in the study of two European IBD cohorts. Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups. Our results suggest that the genetic variations in the TNFSF15 gene contribute to the susceptibility to IBD in the Japanese and European populations.

No association between TNFSF15 and IL23R with ulcerative colitis in Koreans

“…[23][24][25][26] TNFSF15 (tumor necrosis factor ligand superfamily, member 15) was the first CD-susceptibility gene identified through a genome-wide association screening of 72 738 single-nucleotide polymorphisms (SNPs) in Japanese population. 10 The association was well replicated by several studies, including our previous study in a Korean cohort, 27 an independent Japanese cohort 28 and a US cohort, 29 and metaanalyses of genome-wide association studies in European populations, 22 although the association was less significant in Europeans than in Japanese or Korean individuals. 29,30 However, reports of an association of TNFSF15 with UC in Caucasians have been inconsistent.…”

“…10,16,[27][28][29][30] In fact, the association of TNFSF15 with CD is much stronger in Asians than in Caucasians. 29,30 The association of IL23R with CD is consistently observed in Caucasians, but among Asians, this association has been demonstrated only in Koreans.…”

“…[1][2][3][4] The incidence of IBD is relatively higher in Caucasian than in Asian populations; however, the incidence in Asia is increasing. 5,6 Of the two types of IBD, the genetic contribution to disease risk has been documented more extensively and clearly for CD [7][8][9][10][11][12][13][14][15][16][17] than for UC. [18][19][20][21] So far, linkage and genome-wide association studies have identified more than 30 CD-susceptibility loci in Caucasian populations.…”

Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach

“…Although the aetiology of these diseases is not fully understood, there is strong support for a genetic component based on findings of familial aggregation, higher concordance in monozygotic twins and ethnic differences in disease prevalence. 1,2 To date, different genetic studies have shown several genes playing a relevant role in these diseases, including NOD2/CARD15, 3 DGL5, 4 SLC22A4 and SLC22A5, 5,6 TNFSF15, 7,8 NOD1/CARD4 7 and IL23R. 9,10 NOD2/CARD15 is likely to be the major genetic factor contributing to CD.…”

The pursuit of genome-wide association studies: where are we now?

“…7,8 Subsequently, an additional candidate gene (that is, ELMO1) was also identified for diabetic nephropathy in 2005 using the same study design, and likewise, the identification of TNFSF15 for Crohn's disease (CD), and CALM1 for osteoarthritis where all the studies have genotyped around 80 000 SNPs. [9][10][11] The examples of these early days of GWAS were performed in Japanese populations by the same group of researchers. However, there are at least two major differences between these studies and the GWAS performed by Klein et al 1 In contrast to the GWAS of AMD, which used a commercial genotyping array; that is, Affymetrix Human Mapping 100K Set, the genotyping of all of the early versions of GWAS was not performed by microarray technologies, but instead by applying high-throughput multiplex PCR-Invader assay methods.…”