Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.

Figure 1

Linkage disequilibrium (D) between SNPs at the 20q13 locus in the control cohort together with the corresponding Haploview gene track. The association signal resides in a region of LD that harbors several genes, including TNFRSF6B.

Figure 2

Colonic TNFRSF6B expression and serum DCR3 concentration. (a) Colon biopsies were obtained from healthy controls (n = 11, Crohn’s disease histological index of severity (CDHIS):0) and affected segments from individuals with Crohn’s disease with ileo-colonic (n = 18, mean ± s.e.m. CDHIS: 4.1 ± 0.7) or colon-only (n = 14, mean ± s.e.m CDHIS: 4.9 ± 1) location and individuals with UC (n = 10, mean ± s.e.m. CDHIS: 7.2 ± 0.6, P < 0.05 vs. CD groups). We prepared RNA and determined the global pattern of gene expression using the Affymetrix GeneChip Human Genome HG-U133 Plus 2.0 array. Data were normalized to an internal control reference sample, and then to the median value of the healthy control samples, to allow for comparison of mRNA expression in the IBD colon samples relative to the healthy control samples. Results for TNFRSF6B mRNA expression relative to controls are shown. (b) We determined the serum concentration of the TNFRSF6B gene product, DCR3, by ELISA in healthy controls (n = 10), individuals with IBD with the TNFRSF6B GGGG genotype (n = 17, carrying the major allelic variants: G at rs2315008 and G at rs4809330) and individuals with IBD with the TNFRSF6B TGAG genotype (n = 11, carrying the minor allelic variants: T at rs2315008 and A at rs4809330). *P < 0.05, **P < 0.01 vs. control, ***P < 0.05 vs. TNFRSF6B GGGG genotype.