TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study.
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.
Plenge
Robert M
RM
Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, MA, USA.
Seielstad
Mark
M
Padyukov
Leonid
L
Lee
Annette T
AT
Remmers
Elaine F
EF
Ding
Bo
B
Liew
Anthony
A
Khalili
Houman
H
Chandrasekaran
Alamelu
A
Davies
Leela R L
LR
Li
Wentian
W
Tan
Adrian K S
AK
Bonnard
Carine
C
Ong
Rick T H
RT
Thalamuthu
Anbupalam
A
Pettersson
Sven
S
Liu
Chunyu
C
Tian
Chao
C
Chen
Wei V
WV
Carulli
John P
JP
Beckman
Evan M
EM
Altshuler
David
D
Alfredsson
Lars
L
Criswell
Lindsey A
LA
Amos
Christopher I
CI
Seldin
Michael F
MF
Kastner
Daniel L
DL
Klareskog
Lars
L
Gregersen
Peter K
PK
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003182:Complement C5 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D010456:Peptides, Cyclic / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics*