Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP

被引：217

作者：

Zhernakova, Alexandra ^{[1
]}

Festen, Eleanora M. ^{[3
,4
]}

Franke, Lude ^{[1
,4
]}

Trynka, Gosia ^{[4
]}

van Diemen, Cleo C. ^{[4
]}

Monsuur, Alienke J. ^{[1
]}

Bevova, Marianna ^{[1
]}

Nijmeijer, Rian M. ^{[2
]}

van't Slot, Ruben ^{[1
]}

Heijmans, Roel ^{[7
]}

Boezen, H. Marike ^{[5
,6
]}

van Heel, David A. ^{[9
]}

van Bodegraven, Adriaan A. ^{[8
]}

Stokkers, Pieter C. F. ^{[10
]}

Wijmenga, Cisca ^{[1
,4
]}

Crusius, J. Bart A. ^{[7
]}

Weersma, Rinse K. ^{[3
]}

机构：

[1] Univ Med Ctr Utrecht, Dept Med Genet, Complex Genet Sect, Utrecht, Netherlands

[2] Univ Med Ctr Utrecht, Dept Surg, Utrecht, Netherlands

[3] Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, NL-9713 AV Groningen, Netherlands

[4] Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands

[5] Univ Med Ctr Groningen, Dept Epidemiol, NL-9713 AV Groningen, Netherlands

[6] Univ Groningen, Groningen, Netherlands

[7] Vrije Univ Med Ctr, Dept Pathol, Lab Immunogenet, Amsterdam, Netherlands

[8] Vrije Univ Med Ctr, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands

[9] Barts & London Queen Marys Sch Med & Dent, Inst Cell & Mol Sci, London, England

[10] Acad Med Ctr, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2008年 / 82卷 / 05期

关键词：

D O I：

10.1016/j.ajhg.2008.03.016

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The two main phenotypes of inflammatory bowel disease (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IBD. In phase 1, we typed 354 SNPs from 85 innate immunity genes in 520 Dutch IBD patients (284 CD, 236 UC) and 808 controls. In phase 11, ten autosomal SNPs showing association at p < 0.006 in phase I were replicated in a second cohort of 545 IBD patients (326 CD, 219 UC) and 360 controls. In phase 111, four SNPs with p < 0.01 in the combined phase I and phase 11 analysis were genotyped in an additional 786 IBD samples (452 CD, 334 UC) and 768 independent controls. Joint analysis of 1851 IBD patients (1062 CD, 789 UC) and 1936 controls demonstrated strong association to the IL18RAP rs917997 SNP for both CD and UC (p(IBD) 1.9 x 10(-8); OR 1.35). Association in CD is independently supported by the Crohn's disease dataset of the Wellcome Trust Case Control Consortium (imputed SNP rs917997, p = 9.19 x 10(-4)). In addition, an association of the CARD9 rs10870077 SNP to CD and UC was observed (p(IBD) = 3.25 x 10(-5); OR 1.21). Both genes are located in extended haplotype blocks on 2q11-2q12 and 9q34.3, respectively. Our results indicate two IBD loci and further support the importance of the innate immune system in the predisposition to both CD and UC.

引用

页码：1202 / 1210

页数：9

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