Rioux John D, Xavier Ramnik J, Taylor Kent D, Silverberg Mark S, Goyette Philippe, Huett Alan, Green Todd, Kuballa Petric, Barmada M Michael, Datta Lisa Wu, Shugart Yin Yao, Griffiths Anne M, Targan Stephan R, Ippoliti Andrew F, Bernard Edmond-Jean, Mei Ling, Nicolae Dan L, Regueiro Miguel, Schumm L Philip, Steinhart A Hillary, Rotter Jerome I, Duerr Richard H, Cho Judy H, Daly Mark J, Brant Steven R
Université de Montréal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, Quebec H1T 1C8, Canada.
Nat Genet. 2007 May;39(5):596-604. doi: 10.1038/ng2032. Epub 2007 Apr 15.
We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.
我们开展了一项全基因组关联研究，研究对象为回肠克罗恩病，并进行了两项独立的重复研究，确定了几个与克罗恩病相关的新区域。具体而言，除了先前确定的CARD15和IL23R关联外，我们还发现10q21.1上的一个基因间区域以及ATG16L1中的一个编码变异与克罗恩病存在强关联且得到显著重复验证（合并P<10^(-10)），后者最近也被另一研究小组报道。我们还报告了与编码PHOX2B、NCF4的基因组区域变异以及16q24.1上的一个预测基因（FAM92B）存在强关联且得到独立重复验证。最后，我们证明ATG16L1在肠道上皮细胞系中表达，该基因的功能敲除可消除鼠伤寒沙门氏菌的自噬。这些发现共同表明，自噬和宿主细胞对细胞内微生物的反应参与了克罗恩病的发病机制。
