Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease.
Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease.
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DOI：
10.1038/ng.215
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发表时间：
2008-09
期刊：
影响因子：
30.8
通讯作者：
Xavier, Ramnik J.
中科院分区：
文献类型：
--
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.
随着最近全基因组关联研究的成功，人类遗传学的一个关键焦点是了解相关位点的遗传变异如何影响细胞和疾病过程。克罗恩病（CD）与IRGM周围的snp相关，但编码序列变异已被排除为这种关联的来源。我们发现了一个常见的，20 kb的缺失多态性，它位于IRGM的上游，与最强烈的cd相关SNP处于完美的连锁不平衡（r2 = 1.0），导致IRGM在具有两个不同上游序列的群体中分离。IRGM的缺失（CD风险）和参考（CD保护）单倍型表现出不同的表达模式。操纵IRGM表达水平可调节内化细菌的细胞自噬，这一过程与CD有关。这些结果表明，IRGM与CD的关联源于IRGM调节的改变，这影响了自噬的效力，并确定了一种常见的缺失多态性可能是一种因果变异。
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, but coding-sequence variation has been excluded as a source of this association. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 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.
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