Abstract
BackgroundThe inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage.MethodsUsing a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in a clinical homogeneous group of severely diseased patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression.ResultsSixteen polymorphisms in 13 genes involved in regulation of inflammation were associated with risk of CD and/or UC (p≤0.05). The polymorphisms TLR2 (rs1816702), NFKB1 (rs28362491), TNFRSF1A (rs4149570), IL6R (rs4537545), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk of CD and the polymorphisms TLR2 (rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFA (rs1800629), TNFRSF1A (rs4149570), IL10 (rs3024505), IL23R (rs11209026), PTPN22 (rs2476601) and PPARG (rs1801282) were associated with risk of UC. When including all patients (IBD) the polymorphisms TLR2 (rs4696480 and rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs187084), TNFRSF1A (rs4149570), IL6R (rs4537545), IL10 (rs3024505), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk. After Bonferroni correction for multiple testing, both the homozygous and the heterozygous variant genotypes of IL23R G>A(rs11209026) (ORCD,adj: 0.38, 95% CI: 0.21–0.67, p = 0.03; ORIBD,adj 0.43, 95% CI: 0.28–0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (ORCD,unadj 0.54, 95% CI: 0.41–0.72, p = 7*10−4; ORIBD,unadj: 0.61, 95% CI: 0.48–0.77, p = 0.001) were associated with reduced risk of CD.ConclusionThe biological effects of the studied polymorphisms suggest that genetically determined high inflammatory response was associated with increased risk of CD. The many SNPs found in TLRs suggest that the host microbial composition or environmental factors in the gut are involved in risk of IBD in genetically susceptible individuals.
Highlights
Chronic inflammatory bowel diseases (IBDs), Crohn’s disease (CD) and ulcerative colitis (UC), are complex diseases that result from the interaction of numerous genetic and environmental factors [1].Genetic association studies have identified innate immunity as a critical component in the development of IBD
The genotype distributions among the healthy controls deviated from Hardy-Weinberg equilibrium for TLR2 (216934 A.T) (p = 0.02), TLR4 (p = 0.03), TLR9 (1174 G.A) (p = 0.02), and TGFB1 (2509 C.T) (p = 0.02)
Polymorphisms associated with risk of CD The homozygous variant genotype of TLR2 C.T
Summary
Chronic inflammatory bowel diseases (IBDs), Crohn’s disease (CD) and ulcerative colitis (UC), are complex diseases that result from the interaction of numerous genetic and environmental factors [1].Genetic association studies have identified innate immunity as a critical component in the development of IBD. More than 163 IBD susceptibility polymorphisms have been confirmed, most of which are associated with both CD and UC, by candidate and genome wide association studies (GWAS) [2,3,4,5,6,7,8,9,10,11] These polymorphisms have been estimated to only account for 20% of the genetic heritage involved in IBD [12]. The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage
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