<em>TRAF1-C5</em> as a Risk Locus for Rheumatoid Arthritis — A Genomewide Study

Robert Plenge

Mark Seielstad

Leonid Padyukov

Annette Lee

Alamelu Chandrasekaran+20 authors

Drs. Plenge and Seielstad contributed equally to this article. Drs. Klareskog and Gregersen contributed equally to this article as principal investigators for the Swedish Epidemiological Investigation of Rheumatoid Arthritis and the North American Rheumatoid Arthritis Consortium, respectively.

^{The authors' affiliations are listed in the Appendix. Address reprint requests to Dr. Gregersen at the Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030, or at}ude.shsn@gretep.

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<1×10^{) 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 = 4×10^{). 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.

Abstract

Rheumatoid arthritis is a common inflammatory arthritis of unknown cause, in which both genetic and environmental risk factors have been implicated.¹3 The genetic contribution to a susceptibility to rheumatoid arthritis has been shown in studies of twins⁴ and families⁵ and in genomewide linkage scans.⁶11

Two genes have shown a strong association with susceptibility: PTPN22¹²13 and HLA-DRB1.¹⁴ Variants of each gene elevate the risk primarily for a subgroup of severe rheumatoid arthritis characterized by the presence of autoantibodies against cyclic citrullinated peptide (anti-CCP-positive).¹²1516 We have recently reported a significant association at STAT4 on chromosome 2q.¹⁷ Several other promising candidate genes have been reported in the literature (e.g., CTLA4 and PADI4), but these genes have had more modest statistical evidence of association.¹⁸19 All of the alleles associated with rheumatoid arthritis are common in healthy persons of European ancestry (allele frequency, >5%). Therefore, it seems likely that additional common genetic variants with a modest effect size (e.g., odds ratio, <1.5 per copy) remain to be discovered.²⁰

Statistical tests based on allele frequencies in case-control studies (association analyses) have more power to identify common alleles that confer a modest risk than do tests based on chromosomal segregation in families (linkage analyses).²¹ Until recently, genetic association studies were limited to small regions of the genome containing biologic candidate genes or those identified through family-based linkage studies. Recent developments in understanding patterns of human genetic variation,²² together with cost-effective genotyping techniques and statistical methodology,²³24 have made it possible to test, in an unbiased manner, common variants across the entire genome for the risk of disease. Current genotyping platforms are estimated to represent more than two thirds of known common genetic variation throughout the genome, encompassing more than 20,000 human genes.²⁵ By comparison, fewer than 100 candidate genes have been tested for an association with the risk of rheumatoid arthritis.¹⁸

Our genomewide association study involved two groups of case subjects with anti-CCP-positive rheumatoid arthritis: one group who had been treated at rheumatology clinics across North America, the North American Rheumatoid Arthritis Consortium (NARAC), and another group from a Swedish population-based study, the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). In the NARAC study, case subjects were matched with control subjects according to self-reported ethnic background; in the EIRA study, case subjects were matched with control subjects according to age, sex, and geographic location.

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