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

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.

Figure 1. Results of the Genomewide Association Study

Panels A and B show results for 297,086 polymorphic SNPs genotyped in samples from 1522 case subjects with rheumatoid arthritis who were seropositive for autoantibodies against cyclic citrullinated peptide (anti-CCP-positive) and 1850 control subjects from the combined data sets from the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Panel A shows a comparison of distributions of observed versus expected P values generated by Cochran-Mantel-Haenszel stratified analysis and corrected for residual inflation by genomic control. Black data points represent the inclusion of SNPs from the major-histocompatibility-complex (MHC) locus; blue data points represent the exclusion of MHC. The most significant non-MHC SNPs are at PTPN22 and the TRAF1-C5 locus. Panel B shows SNPs plotted according to chromosomal location, with the -log₁₀ P values corrected with the use of genomic control. The blue horizontal line indicates SNPs that are significant at a genomewide level (P = 5×10^-8). SNPs at PTPN22 and within the MHC locus, where the HLA-DRB1 gene resides, reach genomewide significance. Multiple SNPs across the TRAF1-C5 locus on chromosome 9 (e.g., rs3761847; P = 2×10^-8 have a significant association.

Figure 2. (facing page) Case-Control Association Results and Linkage Disequilibrium Structure in the> TRAF1-C5 Locus

Panel A shows results for SNPs genotyped across 1 Mb as part of the original genomewide association scan in samples from 1522 case subjects with anti-CCP-positive rheumatoid arthritis and 1850 control subjects. Each diamond indicates a genotyped SNP; the color of each diamond is based on the correlation coefficient (r²) with the CEU HapMap with the most significant SNP in our study (rs3761847). The blue diamond indicates the P value for all samples in our study (the original scan plus replication samples), as determined by the Cochran-Mantel-Haenszel method in both NARAC and EIRA samples. The recombination rate (in centimorgans per megabase) with the CEU HapMap is shown in light blue along the x axis; the red arrow indicates the block of linkage disequilibrium shown in Panel B. The blue arrows indicate gene location. Panel B shows the linkage-disequilibrium (LD) structure across 200 kb of the TRAF1-C5 locus, based on pairwise r² with the CEU HapMap. The intron-exon structure of each gene is at the top of the figure. Putative functional SNPs in linkage disequilibrium with either rs3761847 or rs2900180 are indicated by hatched bars, in which red indicates r²>0.80 and pink indicates r² = 0.20 to 0.80; the specific SNPs, frequency, pairwise r² with the CEU HapMap, and the putative annotated function are listed at the bottom of the figure. CpG denotes cytidine and guanosine joined by a phosphodiester bond.