U.S. Department of Health and Human Services

Rare Genetic Variants Identified for Inflammatory Bowel Disease

New technologies have enabled scientific researchers to uncover important rare genetic mutations associated with inflammatory bowel disease (IBD). Crohn’s disease (CD) and ulcerative colitis (UC), the two major forms of IBD, are complex diseases attributed to errant immune responses caused by a combination of genetic variants and environmental factors. Some variants are unique to either CD or UC, while others are shared. Using genome-wide association studies (GWAS) technology, as of November 2012, scientists had identified 163 genomic regions with variants that contribute to IBD. The variants that are known, however, account for only a small portion of IBD disease risk, and scientists have not yet identified the disease-associated gene within many of the implicated genomic regions. Scientists from several IBD research consortia and teams around the world have now used pooled “next-generation” sequencing technologies to examine 56 genes located in CD-associated genomic regions that had been identified by GWAS. Using pooled DNA samples from 350 CD patients and 350 healthy volunteers collected by the NIDDK IBD Genetics Consortium, IBD risk-related gene regions were sequenced using high-throughput sequencing technology. The scientists developed computer software to analyze the IBD sequencing data, which led to discovery of important rare variants. They further examined these variants in over 16,000 people with CD and 12,000 with UC, in comparison with more than 17,000 healthy individuals. A highly significant variant that confers IBD protection was identified in the CARD9 gene. Two additional rare protective variants were identified in the IL23R gene and one in the CUL2 gene. Five CD risk variants were identified in the NOD2 gene. Two of the NOD2 variants are more common in people of Ashkenazi Jewish ancestry—a population that is at high risk for CD—and one of the two variants is found only in the Ashkenazi population. In addition, associations in other gene coding regions were identified. This research has led to the discovery of multiple genetic variants conferring disease risk or protection in a number of IBD-associated genes previously identified by GWAS. These variants will provide valuable insights into the mechanisms by which these genes influence susceptibility to IBD. In addition, the identification of the CARD9 variant, which offers disease protection, has the potential to lead to new therapeutic models for IBD prevention and treatment.

Rivas MA, Beaudoin M, Gardet A, et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43: 1066-1073, 2011.​