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N Engl J Med DOI:10.1056/NEJMoa073491

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

Publication TypeJournal Article
Year of Publication2007
AuthorsPlenge, RM, Seielstad, M, Padyukov, L, Lee, AT, Remmers, EF, Ding, B, Liew, A, Khalili, H, Chandrasekaran, A, Davies, LRL, Li, W, Tan, AKS, Bonnard, C, Ong, RTH, Thalamuthu, A, Pettersson, S, Liu, C, Tian, C, Chen, WV, Carulli, JP, Beckman, EM, Altshuler, D, Alfredsson, L, Criswell, LA, Amos, CI, Seldin, MF, Kastner, DL, Klareskog, L, Gregersen, PK
JournalN Engl J Med
Volume357
Issue12
Pages1199-209
Date Published2007 Sep 20
ISSN1533-4406
KeywordsArthritis, Rheumatoid, Autoantibodies, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 9, Complement C5, Genetic Predisposition to Disease, Genotype, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Linkage Disequilibrium, Logistic Models, Peptides, Cyclic, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Protein Tyrosine Phosphatases, Risk Factors, Sequence Analysis, DNA, TNF Receptor-Associated Factor 1
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

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.

URLhttp://dx.doi.org/10.1056/NEJMoa073491
DOI10.1056/NEJMoa073491
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/17804836?dopt=Abstract

Alternate JournalN. Engl. J. Med.
PubMed ID17804836
PubMed Central IDPMC2636867
Grant ListK08-AI55314-3 / AI / NIAID NIH HHS / United States
N01AR22263 / AR / NIAMS NIH HHS / United States
M01 RR000079 / RR / NCRR NIH HHS / United States
R01-AI065841 / AI / NIAID NIH HHS / United States
R01 AR050267 / AR / NIAMS NIH HHS / United States
R01-AR44422 / AR / NIAMS NIH HHS / United States
K08 AI055314-03 / AI / NIAID NIH HHS / United States
M01 RR018535 / RR / NCRR NIH HHS / United States
R01 AR044422 / AR / NIAMS NIH HHS / United States
5-M01-RR-00079 / RR / NCRR NIH HHS / United States
M01-RR018535 / RR / NCRR NIH HHS / United States
K08 AI055314-02 / AI / NIAID NIH HHS / United States
R01 AI065841 / AI / NIAID NIH HHS / United States
N01-AR22263 / AR / NIAMS NIH HHS / United States
/ / Intramural NIH HHS / United States
K08 AI055314-01A1 / AI / NIAID NIH HHS / United States
K08 AI055314-05 / AI / NIAID NIH HHS / United States
R01-AR050267 / AR / NIAMS NIH HHS / United States
K24 AR002175 / AR / NIAMS NIH HHS / United States
K08 AI055314 / AI / NIAID NIH HHS / United States
K24-AR02175 / AR / NIAMS NIH HHS / United States
K08 AI055314-04 / AI / NIAID NIH HHS / United States