Abstract
BackgroundGenetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique.MethodsExome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC), 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family.ResultsFrom the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV) c.374T>C (p.I125T) in exon 4 of discs large homolog 1 (DLG1), a gene has been reported to play mutiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1. ConclusionsWe have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.
Highlights
Crohn’s disease (CD) and ulcerative colitis (UC) are classified as chronic, idiopathic inflammatory bowel diseases (IBD) [1,2]
We have discovered novel genetic variants in the coding regions of discs large homolog 1 (DLG1) gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients
Numerous functional and deleterious variants in the population are at frequencies of 0.5 to 5% that are too low to be detected by GWAS [5,6]
Summary
Crohn’s disease (CD) and ulcerative colitis (UC) are classified as chronic, idiopathic inflammatory bowel diseases (IBD) [1,2]. High concordance in twins and a higher prevalence of the disease in a certain ethnic population imply a strong genetic influence on the risk of disease development [3,4]. Identifying the genetic loci or rare detrimental mutations in different populations or families with the disease will help elucidate the pathogenesis of these complex traits and facilitate the development of more targeted therapy. As predisposing variants will present at a much higher frequency in the affected relatives of an index case, family studies may facilitate the detection of the ‘missing heritability’ not identified by GWAS [7]. Genetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique
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