Rheumatoid arthritis association at 6q23

Abstract

The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 × 10 -5 -5 × 10 -7 in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 × 10 -8 ) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-α-induced protein 3 (TNFAIP3).The WTCCC genome-wide association screen (GWA) of 1,860 rheumatoid arthritis cases and 2,938 healthy controls confirmed association with SNPs within the HLA region and the PTPN22 gene (P < 1 × 10 -7 ; ref. 1). Nine other loci showed strong evidence for association (P = 1 × 10 -5 -5 × 10 -7 ). SNPs at these loci were genotyped in an independent cohort of 5,063 rheumatoid arthritis cases and 3,849 healthy controls (Supplementary Methods and Supplementary Table 1 Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts www.sequenom.com), to establish whether they are genuinely associated with the disease. In this cohort, we had 80% power to detect most of the effect sizes reported in the initial study at P < 0.05 (Supplementary Table 2 online). We selected ten SNPs for genotyping; these included the known rheumatoid arthritis susceptibility variant rs2476601, mapping to the PTPN22 gene, and nine previously unknown SNPs identified by the WTCCC study1. A Bonferroni correction of 9 was applied to account for the previously unknown loci investigated, resulting in a P value threshold of P < 0.006 for claims of significance in this validation study. We regarded SNPs validated at P values between 0.05 and 0.006 as suggestive evidence.We detected strong association with the rheumatoid arthritis-causing SNP in the PTPN22 gene (rs2476601), as expected (odds ratio (OR) = 1.53, 95% CI = 1.39-1.68, trend P = 2.0 × 10 -18 ). This was not a completely independent replication, as association of rheumatoid arthritis with this locus has been reported in previous studies using some of the same samples included in the current study2-4. However, it confirmed the suitability of this cohort for validation studies. Of the nine newly identified SNPs tested, rs6920220 (G > A) showed association with rheumatoid arthritis in this cohort (OR for minor allele = 1.23, 95% CI = 1.15-1.33, trend P = 1.1 × 10 -8 ) (Table 1). For this SNP, the allele frequencies were similar across control groups tested in the WTCCC study and the healthy controls tested here (minor allele frequency (MAF) 0.22 and 0.21, respectively). We therefore undertook a combined analysis of the WTCCC data and the validation data, and we obtained strong statistical evidence for association between this SNP and rheumatoid arthritis (OR = 1.22, 95% CI = 1.15-1.29, trend P = 3.6 × 10 -12

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

“…The effects of the two SNPs were found to be independently associated with T1D using logistic regression analyses, as found in RA 13,16 (Table 2). More recently, this gene region has also been associated with SLE in two independent studies.…”

“…[1][2][3][4] Interestingly, several of these T1D susceptibility loci are shared with other immune-mediated diseases, namely PTPN22, CTLA4, IL2RA, IL2, IL7R and SH2B3 (see Table 1 for full gene names). 1,5,6 Therefore, we sought to test newly identified rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis, ankylosing spondylitis (AS) and Crohn's disease (CD) loci for association in T1D [7][8][9][10][11][12][13][14][15][16][17] with the assumption of an increased prior probability of association based on the previous evidence of overlapping risk alleles across autoimmune diseases. 18 We selected single nucleotide polymorphisms (SNPs) for genotyping that had shown a convincing evidence of association with at least one other autoimmune disease from genome-wide association scans published over the past 2 years.…”

“…18 We selected single nucleotide polymorphisms (SNPs) for genotyping that had shown a convincing evidence of association with at least one other autoimmune disease from genome-wide association scans published over the past 2 years. We genotyped SNPs from the genes: CD58 (rs12044852) which has been associated with multiple sclerosis; 8 STAT3 (rs3816769) which has been associated with CD; 7 IL1A (rs17561) and ERAP1, previously called ARTS1 (rs30187) which have been associated with AS; 15,17 MMEL1-TNFRSF14 (rs3890745), CDK6 (rs42041), the 7q23 gene desert (rs11761231), CCL21 (rs2812378), TRAF1/C5 (rs3761847), KIF5A(rs1678542) and CD40 (rs4810485), which have been associated with RA; 7,12,19 BANK1 (rs10516487), FAM167A previously called C8orf13 (rs13277113) and ITGAM (rs9888739) which have been associated with SLE [9][10][11]20 and STAT4 (rs7574865) and TNFAIP3 (rs6920220 and rs10499194) which have been associated with both RA and SLE 13,14,16,21,22 (See Table 1 for full gene names).…”

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

“…53 Indeed, at least five of the A20 SNPs associate with lower A20 expression or activity in homozygous or heterozygous carriers of minor alleles, and hence could recap A20 HET. [54][55][56][57][58][59] On the basis of HapMap (Haplotype mapping) data, minor allele frequency of some of these SNPs is far from being negligible, especially in certain populations. For instance, the percentage of homozygous carriers of rs610604 minor allele (prevalent in patients with psoriasis and predicting higher coronary artery disease in diabetic patients) reaches 18% in Europeans and 32-50% in Africans, while the percentage of homozygous carriers of rs661561minor allele (associated with Grave's disease) reaches 37% in Europeans and up to 50% in Asians.…”

Lack of evidence for association of two functional SNPs of CHI3L1 gene (HC-gp39) with rheumatoid arthritis

“…Several studies suggest roles of HLA-DRB1 [3] and PTPN22 [4][5][6] in RA pathogenesis. Three further RA risk loci have been identified recently, including the STAT4 gene [7][8][9], loci in the 6q23 [10][11] and TRAF1/C5 [12][13]. As RA is a major cause of disability and is even correlated with increased mortality in severe cases [14].…”