Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci

J D Rioux, M S Silverberg, M J Daly, A H Steinhart, R S McLeod, A M Griffiths, T Green, T S Brettin, V Stone, S B Bull, A Bitton, C N Williams, G R Greenberg, Z Cohen, E S Lander, T J Hudson, K A Siminovitch, J D Rioux, M S Silverberg, M J Daly, A H Steinhart, R S McLeod, A M Griffiths, T Green, T S Brettin, V Stone, S B Bull, A Bitton, C N Williams, G R Greenberg, Z Cohen, E S Lander, T J Hudson, K A Siminovitch

Abstract

The chronic inflammatory bowel diseases (IBDs)-Crohn disease (CD) and ulcerative colitis (UC)-are idiopathic, inflammatory disorders of the gastrointestinal tract. These conditions have a peak incidence in early adulthood and a combined prevalence of approximately 100-200/100,000. Although the etiology of IBD is multifactorial, a significant genetic contribution to disease susceptibility is implied by epidemiological data revealing a sibling risk of approximately 35-fold for CD and approximately 15-fold for UC. To elucidate the genetic basis for these disorders, we undertook a genomewide scan in 158 Canadian sib-pair families and identified three regions of suggestive linkage (3p, 5q31-33, and 6p) and one region of significant linkage to 19p13 (LOD score 4.6). Higher-density mapping in the 5q31-q33 region revealed a locus of genomewide significance (LOD score 3.9) that contributes to CD susceptibility in families with early-onset disease. Both of these genomic regions contain numerous genes that are important to the immune and inflammatory systems and that provide good targets for future candidate-gene studies.

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