Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13

Abstract

The WTCCC study identified 49 single nucleotide polymorphisms (SNPs) putatively associated with RA at p=1×10 -4 -1×10 -5 (Tier 3). Here, we show that 3 of these SNPs, mapping to chromosome 10p15 (rs4750316), 12q13 (rs1678542) and 22q13 (rs3218253), are also associated (trend p = 4×10 -5 , p=4×10 -4 and p=4×10 -4 , respectively) in a validation study of 4,106 RA cases and an expanded reference group of 11,238 subjects, confirming them as true susceptibility loci in Caucasians.Rheumatoid arthritis (RA) is a common autoimmune disease, affecting an estimated 475,000 adults in the UK, in which inflammation of synovial joints is characteristic. The WTCCC genome wide association screen of 1860 RA case and 2938 healthy control Caucasian samples confirmed association of SNPs with previously identified loci within the HLA region and the PTPN22 gene (Tier1, p<5×10 -7 )1. Nine loci were associated in the next tier of significance (Tier 2, p=1×10 -5 -5×10 -7 ) and association to one, on chromosome 6q23 has been replicated and confirmed in subsequent independent studies2, 3. Forty-nine SNPs were associated at p = 1 × 10 -4 -1 × 10 -5 (Tier 3) and we now describe investigation of these SNPs in an independent cohort of 4,106 RA samples (supplementary methods). Causal variants within this group of SNPs are likely to confer small effect sizes, by virtue of the fact that the evidence for association with them in the original WTCCC study was weaker than for those SNPs in Tiers 1 and 2. In order to maximise power to replicate true associations, genotype data from an independent cohort of 3,599 healthy controls was combined with that Table 1). In addition, we took the opportunity to reevaluate the evidence for association with the Tier 2 SNPs using the expanded reference group for comparison.Of the 49 novel Tier 3 SNPs tested, 3 showed association with RA: rs4750316 (C>G), mapping to chromosome 10p15 (OR minor allele =0.87, 95% CI 0.81-0.93, trend P = 4 × 10 -5 ); rs1678542 (G>C) mapping to chromosome 12q13 (OR minor allele = 0.91, 95% CI 0.86-0.96, trend P = 4 × 10 -4 ) and rs3218253 (C>T) mapping to chromosome 22 (OR minor allele = 1.11, 95% CI 1.05 -1.17, trend P = 4 × 10 -4 ) ( Table 1, supplementary Tables 2 and 3). For all SNPs, the allele frequencies were similar across the control group tested in the WTCCC study and the expanded reference group tested here (rs4750316 minor allele frequency (MAF) 0.20 and 0.20; rs1678542 MAF 0.37 and 0.37; rs3218254 MAF 0.25 and 0.26, respectively) and all satisfied Hardy-Weinberg expectations. Both combined analysis and meta-analysis of the WTCCC data and the validation data provided strong statistical evidence for association between RA and all 3 SNPs (combined analysis: OR rs4750316 = 0.85 95% CI 0.80-0.90, trend P = 1.3×10 -8 ; OR rs1678542 = 0.88, 95% CI 0.85-0.93, trend P = 1.3 × 10 -7 ; OR rs3218253 = 1.13, 95% CI 1.07-1.18, trend P = 1.3 × 10 -6 ) ( Table 1 and supplementary Table 2).RA is characterised by the presence of autoantibodies in some but not all patients. Previo...

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

“…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.…”

Members 6B and 14 of the TNF receptor superfamily in multiple sclerosis predisposition

“…A perfect proxy located at 60 kb from TNFRSF14 in 1p36 (rs3890745, r 2 ¼ 1) was found associated with rheumatoid arthritis by metaanalyses of two genome-wide studies; 6 the role of this gene in disease risk was also validated by a study of a strongly correlated variant (rs10910099, r 2 ¼ 0.96) in an independent cohort. 7 The TNFRSF14 gene is also known as herpes virus entry mediator (HVEM), and human herpes viruses have often been involved in the aetiology of multiple sclerosis (MS). 8 The entry of viruses into cells is a complex process, which is still incompletely understood.…”

Dissection of a complex disease susceptibility region using a Bayesian stochastic search approach to fine mapping

“…The region has provided some prime examples of evolving genetic research. Initially associated with T1D susceptibility using a candidate gene and tag SNP approach [15], further studies revealed association to other autoimmune diseases, including MS [16] and rheumatoid arthritis [17], and demonstrated that multiple genetic markers were needed to explain the T1D association [18]. Genotype to phenotype studies have demonstrated that disease-associated variants in the region also associate with IL2RA mRNA expression and CD25 protein expression on the surface of naive and memory CD4 + T cells [19][20][21] and sensitivity of memory CD4 + T and activated T regulatory cells to IL-2 [22].…”