Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci

被引：293

作者：

Zhernakova, Alexandra ^{[1
,2
,3
]}

Stahl, Eli A. ^{[3
,4
]}

Trynka, Gosia ^{[5
,6
]}

Raychaudhuri, Soumya ^{[3
,4
,7
,8
]}

Festen, Eleanora A. ^{[5
,6
]}

Franke, Lude ^{[5
,6
,9
]}

Westra, Harm-Jan ^{[5
,6
]}

Fehrmann, Rudolf S. N. ^{[5
,6
]}

Kurreeman, Fina A. S. ^{[1
,3
,4
]}

Thomson, Brian ^{[4
]}

Gupta, Namrata ^{[4
]}

Romanos, Jihane ^{[5
,6
]}

McManus, Ross ^{[10
,11
]}

Ryan, Anthony W. ^{[10
,11
]}

Turner, Graham ^{[10
,11
]}

Brouwer, Elisabeth ^{[6
,12
]}

Posthumus, Marcel D. ^{[6
,12
]}

Remmers, Elaine F. ^{[13
]}

Tucci, Francesca ^{[14
]}

Toes, Rene ^{[1
]}

Grandone, Elvira ^{[15
]}

Mazzilli, Maria Cristina ^{[16
]}

Rybak, Anna ^{[17
]}

Cukrowska, Bozena ^{[18
]}

Coenen, Marieke J. H. ^{[19
]}

Radstake, Timothy R. D. J. ^{[20
]}

van Riel, Piet L. C. M. ^{[20
]}

Li, Yonghong ^{[21
]}

de Bakker, Paul I. W. ^{[3
,4
,22
,23
]}

Gregersen, Peter K. ^{[24
]}

Worthington, Jane ^{[25
]}

Siminovitch, Katherine A. ^{[26
,27
]}

Klareskog, Lars ^{[28
]}

Huizinga, Tom W. J. ^{[1
]}

Wijmenga, Cisca ^{[5
,6
]}

Plenge, Robert M. ^{[3
,4
,8
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands

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

[3] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA

[4] Broad Inst, Cambridge, MA USA

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

[6] Univ Groningen, Groningen, Netherlands

[7] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[8] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

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

[10] St James Hosp, Trinity Coll, Dept Clin Med, Trinity Ctr Hlth Sci, Dublin, Ireland

[11] St James Hosp, Trinity Coll, Inst Mol Med, Trinity Ctr Hlth Sci, Dublin, Ireland

[12] Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9713 AV Groningen, Netherlands

[13] NIAMSD, Genet & Genom Branch, NIH, Bethesda, MD 20892 USA

[14] Univ Naples Federico 2, European Lab Food Induced Dis, Naples, Italy

[15] IRCCS Casa Sollievo Sofferenza, Unita Aterosclerosi & Trombosi, Foggia, Italy

[16] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy

[17] Childrens Mem Hlth Inst, Dept Gastroenterol Hepatol & Immunol, Warsaw, Poland

[18] Childrens Mem Hlth Inst, Dept Pathol, Warsaw, Poland

[19] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[20] Radboud Univ Nijmegen, Dept Rheumatol, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[21] Celera, Alameda, CA USA

[22] Harvard Univ, Brigham & Womens Hosp, Div Genet, Dept Med,Med Sch, Boston, MA 02115 USA

[23] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[24] N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA

[25] Univ Manchester, Arthrit Res Campaign Epidemiol Unit, Manchester, Lancs, England

[26] Univ Toronto, Mt Sinai Hosp, Dept Med, Toronto, ON M5G 1X5, Canada

[27] Univ Hlth Network, Toronto, ON, Canada

[28] Karolinska Inst, Rheumatol Unit, Dept Med, Karolinska Univ Hosp Solna, Stockholm, Sweden

来源：

PLOS GENETICS | 2011年 / 7卷 / 02期

基金：

爱尔兰科学基金会;

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; SUSCEPTIBILITY LOCI; RISK LOCUS; TYROSINE-PHOSPHATASE; AUTOIMMUNE-DISEASES; GENETIC-VARIANTS; CROHNS-DISEASE; COMMON; ACTIVATION; EXPRESSION;

D O I：

10.1371/journal.pgen.1002004

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P < 5 x 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined) = 1.2 x 10(-12)), rs864537 near CD247 (P(combined) = 2.2 x 10(-11)), rs2298428 near UBE2L3 (P(combined) = 2.5 x 10(-10)), and rs11203203 near UBASH3A (P(combined) = 1.1 x 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 x 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.

引用

页数：13

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