Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis

被引：1415

作者：

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.

机构：

[1] Univ Montreal, Montreal, PQ H1T 1C8, Canada

[2] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada

[3] MIT, Broad Inst, Cambridge, MA 02142 USA

[4] Harvard Univ, Cambridge, MA 02142 USA

[5] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA

[6] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA

[7] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[8] Cedars Sinai Med Ctr, Ctr Inflammatory Bowel Dis, Los Angeles, CA 90048 USA

[9] Univ Toronto, Mt Sinai Hosp, IBD Ctr, Toronto, ON M5G 1X5, Canada

[10] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[11] Johns Hopkins Univ, Dept Med, Harvey M & Lyn P Meyerhoff Inflammatory Bowel Dis, Baltimore, MD 21231 USA

[12] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA

[13] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada

[14] Univ Montreal, Montreal, PQ H2W 1V1, Canada

[15] CHUM, Hotel Dieu, Montreal, PQ H2W 1V1, Canada

[16] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[17] Univ Pittsburgh, Med Ctr, Sch Med, Dept Med,Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA

[18] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA

[19] Yale Univ, Dept Med, Div Gastroenterol, Inflammatory Bowel Dis Ctr, New Haven, CT 06519 USA

[20] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

来源：

NATURE GENETICS | 2007年 / 39卷 / 05期

关键词：

D O I：

10.1038/ng2032

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：596 / 604

页数：9

共 43 条

[1] Macrophages rapidly transfer pathogens from lipid raft vacuoles to autophagosomes [J].