Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease

作者：McCarroll Steven A; Huett Alan; Kuballa Petric; Chilewski Shannon D; Landry Aimee; Goyette Philippe; Zody Michael C; Hall Jennifer L; Brant Steven R; Cho Judy H; Duerr Richard H; Silverberg Mark S; Taylor Kent D; Rioux John D; Altshuler David; Daly Mark J^*; Xavier Ramnik J

来源：Nature Genetics, 2008, 40(9): 1107-1112.

DOI：10.1038/ng.215

Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn's disease (CD) is associated with SNPs around IRGM(1,2), but coding-sequence variation has been excluded as a source of this association(2). We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r(2) = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.

• 出版日期2008-9
• 单位河北医科大学