Early Inflammatory Bowel Disease Genetic Studies


Initial IBD genetic research consisted of candidate gene studies in which functionally plausible genes of interest were analyzed for the association of polymorphisms with IBD. Such studies were mostly notable for the findings of modest associations of the human leukocyte antigen (HLA) complex with both Crohn's disease and ulcerative colitis in different populations.[3] Subsequently, further analysis of the genetic basis of IBD was pursued using linkage studies, which reveal the approximate location of susceptibility genes on broad chromosomal regions by studying families with two or more IBD-affected members. Such studies led to the identification of several promising chromosomal regions, including linkage between Crohn's disease and a region on chromosome 16 (the IBD1 locus).[2-4] Subsequently, in 2001, two groups simultaneously identified an association between Crohn's disease and variants in the nucleotide-binding oligomerization domain 2 (NOD2) gene, also known as caspase recruitment domain 15 (CARD15) in the region of the IBD1 locus.[5,6] Three variants in this gene (Leu1007insC, Gly908Arg, and Arg702Trp) were found to be associated with Crohn's disease but not with ulcerative colitis. Patients carrying one of the NOD2 mutations have a two to four-fold increased risk of developing Crohn's disease, while those carrying two mutations have a 20 to 40-fold increased risk of developing Crohn's disease.[2,3] These three NOD2 variants, however, are carried by only 20-30% of all Crohn's disease patients, suggesting that other genes are involved in the development of this condition.[2,3] In addition, the lack of association of this gene with ulcerative colitis indicated that separate genes predispose the patient to this condition. In addition, suggestive linkage for a locus on chromosome 5q (IBD5) was found, and later studies demonstrated an association between Crohn's disease and a common haplotype spanning the 5q cytokine gene cluster.[7-9] Subsequently, functional polymorphisms in the SLC22A4 and SLC22A5 genes in this region were identified, but it remains unclear as to whether these are the causal genes.[10]