Dechairo, Bryan Michael; (2001) Investigation of putative susceptibility regions to inflammatory bowel disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease of the intestine, commonly diagnosed as either ulcerative colitis (UC) or Crohn's disease (CD). Epidemiological studies have consistently shown that both genetic and environmental factors influence the pathogenesis of IBD. Recently, a number of linkage and association studies have been conducted in cohorts of IBD families to try and identify the genetic component of IBD. Several putative linked loci and associated polymorphisms have been identified, with varying significance and consistency between studies. In the present research, to further investigate and hopefully clarify previous linkage findings, a replication study on chromosome 6p (IBD3) and an extension study on chromosomes 3p were conducted. Short tandem repeat (STR) markers across each region were genotyped in 284 IBD affected sibling pairs (ASPs) from 234 families. A nonparametric peak multipoint LOD score of 3.0 was observed near D6S291, replicating the previous linkage to IBD3. No linkage was detected to the 3p locus. Concurrently, due to the initial detection of linkage to the chromosome 3 locus using a subset of the present IBD cohort, association analysis was conducted across the 3p region and 4 candidate genes within it, GNAI2, CCR5, CCR2 and CCRL2. STR markers used in the present 3p linkage study and several biallelic polymorphisms identified across each gene were genotyped in 333 additional IBD simplex families. Significant positive association (P = 0.005) was detected between UC and the CCR532 polymorphism, previously associated with HIV. No other significant associations were detected.

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