Common variants at CD40 and other loci confer risk of rheumatoid arthritis

Abstract

To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls1,2. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 × 10−9 overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 × 10−7 overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 × 10−7 overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 × 10−6 overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 × 10−6 overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 × 10−8 overall).

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

“…7 The association with MMEL1-TNFRSF14 was initially demonstrated in a meta-analysis of three GWAS of approximately 4000 European patients and 12 000 European controls, whereas it had not been detected in any of the smaller individual GWAS. 14 In that study, the minor allele was also shown to have a protective effect on disease development (OR ¼ 0.86), which is similar to what we detect in the current study. The modeling we performed suggested that the homozygous state for the major allele conferred the highest risk, and that the presence of the minor allele was indeed protective in a dominant manner.…”

“…These were selected on the basis of previously published genome wide association data, indicating SNP association with RA. 13,14 Genotyping was undertaken in the laboratory of Dr Katherine Siminovitch at the University of Toronto, and the multiplexed SNP assays were performed on the Sequenom Mass Array iPLEX platform (Sequenom, Inc., San Diego, CA, USA). Allele-specific extension products were plated onto a SpectroCHIP (Sequenom, Inc.) subjected to mass spectrometric analysis, and the genotypes were identified using SpectroCALLER software (Sequenom, Inc.).…”

“…These have included PTPN22, CTLA4, TRAF1-C5, STAT4, TNFAIP3, CD40, MMEL1-TNFRSF14 and REL. 13,14 Interestingly, these studies have suggested ethnic differences in the patterns of genetic susceptibility, necessitating confirmation of associations in different populations. [15][16][17] Examples are a PTPN22-R620W polymorphism which is strongly associated with RA and other autoimmune diseases in Caucasian populations, but is absent in Orientals, and an association with PADI4 SNP found in Japanese populations which is not detected in most Caucasian populations, despite the presence of these gene polymorphisms.…”

The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis

“…However, it did not withstand correction for multiple testing, and the risk allele obtained in the present study was contrary to the one reported in the original RA study. 18 We observed a lack of association of IL1A, BANK1, ERAP1 (ARTS1), FAM167A-BLK, CCL21, PTPN2, STEAP1, HERC1 and STAT2 variants with MS. The STEAP and HERC1 variants have been associated with MS in a recent GWAS carried out by the Wellcome Trust Case-Control Consortium based on 12 374 non-synonymous SNPs, 22 but were not validated in our sample set.…”

“…29 The association of rs1678542/KIF5A variant with MS, uncovered for the first time in this work, was first associated with RA in European populations. 18,30 The rs1678542/KIF5A is located 194 kb apart from the rs703842/methyltransferase-like protein 1 3 0 UTR with a linkage disequilibrium r 2 of 0.184. The latter polymorphism is the most strongly associated SNP with MS in the locus in the GWAS carried out by the Australia and New Zealand Multiple Sclerosis Genetics Consortium.…”