Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis
Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis
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DOI：
10.1038/ng2032
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发表时间：
2007-05-01
期刊：
影响因子：
30.8
通讯作者：
Brant, Steven R.
中科院分区：
文献类型：
--
作者：
Rioux, John D.;Xavier, Ramnik J.;Brant, Steven R.
我们提出了一个回肠克罗恩病的全基因组关联研究和两个独立的复制研究，确定了几个新的区域的关联克罗恩病。具体来说，除了先前建立的CARD 15和IL 23 R相关性之外，我们还确定了与10q21.1上的基因间区域和ATG 16 L1中的编码变体的强且显著重复的相关性（组合P < 10（-10）），后者最近也由另一组报道。我们还报告了独立复制与编码PHOX 2B、NCF 4和16q24.1（FAM 92 B）预测基因的基因组区域变异的强相关性。最后，我们证明了ATG 16 L1在肠上皮细胞系中表达，并且该基因的功能性敲除消除了鼠伤寒沙门氏菌的自噬。总之，这些发现表明，自噬和宿主细胞对细胞内微生物的反应参与克罗恩病的发病机制。
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.