TRAF1-C5 as a risk locus for rheumatoid arthritis - A genomewide study

被引:619
作者
Plenge, Robert M.
Seielstad, Mark
Padyukov, Leonid
Lee, Annette T.
Remmers, Elaine F.
Ding, Bo
Liew, Anthony
Khalili, Houman
Chandrasekaran, Alamelu
Davies, Leela R. L.
Li, Wentian
Tan, Adrian K. S.
Bonnard, Carine
Ong, Rick T. H.
Thalamuthu, Anbupalam
Pettersson, Sven
Liu, Chunyu
Tian, Chao
Chen, Wei V.
Carulli, John P.
Beckman, Evan M.
Altshuler, David
Alfredsson, Lars
Criswell, Lindsey A.
Amos, Christopher I.
Seldin, Michael F.
Kastner, Daniel L.
Klareskog, Lars
Gregersen, Peter K.
机构
[1] Univ Calif San Francisco, San Francisco, CA 94143 USA
[2] Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA
[3] Massachusetts Gen Hosp, Boston, MA 02114 USA
[4] Univ Calif Davis, Rowe Program, Davis, CA 95616 USA
[5] Biogen Idec Inc, Cambridge, MA USA
[6] NIAMSD, Bethesda, MD 20892 USA
[7] N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY 11030 USA
[8] Karolinska Inst, Stockholm, Sweden
[9] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA
[10] Genome Inst Singapore, Singapore, Singapore
[11] Brigham & Womens Hosp, Boston, MA 02115 USA
[12] MIT, Cambridge, MA 02139 USA
[13] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA
关键词
D O I
10.1056/NEJMoa073491
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. Methods We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1 x 10(-8)) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). Results We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P=4 x 10(-14)). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). Conclusions A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis.
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页码:1199 / 1209
页数:11
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