RESEARCH - TRAF1-C5 as a risk locus for RA - a genomewide study

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Published at www.nejm.org September 5, 2007 (10.1056/NEJMoa073491)

TRAF1-C5 as a Risk Locus for Rheumatoid Arthritis - A Genomewide Study

M. Plenge, M.D., Ph.D., Mark Seielstad, Ph.D., Leonid Padyukov, M.D.,

Ph.D., Annette T. Lee, Ph.D., Elaine F. Remmers, Ph.D., Bo Ding, Ph.D.,

Liew, M.S., Houman Khalili, B.S., Alamelu Chandrasekaran, Ph.D.,

Leela R.L. Davies, B.S., Wentian Li, Ph.D., K.S. Tan, M.Sc., Carine

Bonnard, M.Sc., Rick T.H. Ong, M.Sc., Anbupalam Thalamuthu, Ph.D., Sven

Pettersson, M.D., Ph.D., Chunyu Liu, Ph.D., Chao Tian, B.S., Wei V. Chen,

M.S., P. Carulli, Ph.D., Evan M. Beckman, M.D., Altshuler, M.D.,

Ph.D., Lars Alfredsson, Ph.D., Lindsey A. Criswell, M.D., M.P.H.,

I. Amos, Ph.D., F. Seldin, M.D., Ph.D., L.

Kastner, M.D., Ph.D., Lars Klareskog, M.D., Ph.D., and K. Gregersen,

M.D.

ABSTRACT

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<1x10-8) 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=4x10-14). 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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Read the entire article here:

http://content.nejm.org/cgi/content/full/NEJMoa073491

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