Abstract
Inflammatory bowel disease (IBD) is characterized by multigenic inheritance. Defects in autophagy related genes are considered to show genetic heterogeneity between populations. We evaluated the association of several single nucleotide polymorphisms (SNPs) in the autophagy related 16 like 1 (ATG16L1) gene with IBD in Indians. The ATG16L1 gene was genotyped for ten different SNPs using DNA extracted from peripheral blood of 234 patients with Crohn’s disease (CD), 249 patients with ulcerative colitis (UC) and 393 healthy controls The SNPs rs2241880, rs4663396, rs3792106, rs10210302, rs3792109, rs2241877, rs6737398, rs11682898, rs4663402 and rs4663421 were genotyped using the Sequenom MassArray platform. PLINK was used for the association analysis and pairwise linkage disequilibrium (LD) values. Haplotype analysis was done using Haploview. All SNPs were in Hardy Weinberg equilibrium in cases and controls. The G allele at rs6737398 exhibited a protective association with both CD and UC. The T allele at rs4663402 and C allele at rs4663421 were positively associated with CD and UC. The T allele at rs2241877 exhibited protective association with UC only. The AA genotype at rs4663402 and the GG genotype at rs4663421 were protectively associated with both CD and UC. Haplotype analysis revealed that all the SNPs in tight LD (D’ = 0.76–1.0) and organized in a single haplotype block. Haplotype D was positively associated with IBD (P = 5.8 x 10−6 for CD and 0.002 for UC). SNPs in ATG16L1 were associated with IBD in Indian patients. The relevance to management of individual patients requires further study.
Highlights
Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is considered to result from abnormal immune reactions to gut luminal microbiota in genetically predisposed individuals [1,2,3]
The discovery that CD was associated with mutations in the NOD2 gene [4,5] provided the first indication of the important role played by innate immunity in inflammation and disease progression
The diagnosis of CD and UC was based on a composite of clinical, radiological, endoscopic, and histopathological findings according to the consensus criteria of the Indian Society of Gastroenterology [22,23]
Summary
Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is considered to result from abnormal immune reactions to gut luminal microbiota in genetically predisposed individuals [1,2,3]. The genetic predisposition is contributed by multiple genes through common variants (single nucleotide polymorphisms or SNPs) that each appear to exert a small influence. A coding SNP, named rs2241880, in the ATG16L1 was found to have a disease association with CD and this was responsible for threonine to alanine substitution (T300A) at amino acid 300 of protein. This SNP appeared to account for all of the disease risk exerted by the ATG16L1 locus. In light of the conflicting findings and ethnic differences in aforementioned studies we aimed at analyzing various polymorphisms in ATG16L1 gene for its association with CD and UC in Indian population
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