Session Title: Genetics and Genomics of Rheumatic Diseases
Session Type: Abstract Submissions (ACR)
Background/Purpose: One of the principal findings of genome wide association studies in autoimmune diseases has been the substantial overlap of genetic susceptibility loci identified. This has underpinned fine mapping initiatives such as the Immunochip (IC) project in which custom chips were designed to fine-map regions of associations common to a number of autoimmune diseases. Samples from patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and psoriatic arthritis (PsA) have been genotyped using IC; given that all are types of inflammatory arthritis (IA) which exhibit common pathology and some overlap of associated loci, the data emerging from IC provides a unique opportunity to identify novel overlapping regions and determine whether the causal variants within overlapping loci are the same or different for each disease.
Methods: As part of the IC project, genotyping, quality control and association analysis was performed for RA (11475 cases and 15870 controls), JIA (2816 polygoarticular and oligoarticular JIA cases and 13056 controls) and PsA (929 cases and 4537 controls). Some controls were shared between cohorts. For this analysis all SNPs with a minor allele frequency >1% which reached p<10-3 in any of the 3 diseases were first selected. IC regions were defined as including all SNPs from the 1000 Genomes Project CEU population (September 2009 release) that were in 0.1-cM (HapMap3 CEU) recombination blocks around each GWAS region lead marker. IC Regions which contained SNPs associated with more than one type of IA were considered overlapping.
Results: 49 regions showed association at p<10-3 with more than one type of IA, of these, in RA and JIA 4 loci (PTPN22 STAT4, ANKRD55 and TYK2) reached genome wide significance (5×10-8), with a further 7 associated at p<10-5 in both diseases. Interestingly 4 of these loci are also associated with PsA at p<10-3 (TNFAIP3, PTPN2. RUNX1 and TYK2). 6 of these loci have been previously associated with both RA and JIA (PTPN22, STAT4, AFF3, TNFAIP3, PTPN2 and IL2RA) whilst 5 are novel overlapping regions (DNASE1L3, ANKRD55, TYK2, RUNX1 and IL2RB). For the PTPN22, STAT4, DNASE1L3, ANKRD55, TYK2 and RUNX1 regions the RA and JIA associated SNPs are either identical or highly correlated (r2>0.8), the direction of effect is the same in both diseases and odds ratios similar. For AFF3, TNFAIP3 and PTPN2 the associated SNPs are different and weakly correlated (r2>0.4<0.8) but the direction of effect is similar for each disease. An interesting finding is that for IL2RA and IL2RB the pattern of association in the region is completely different.
Conclusion: These findings add to the body of evidence that there are shared susceptibility genes for inflammatory arthritis. Further investigation is required to fully explore whether the regions contain the same or different causal effect, including functional studies to determine whether, in overlapping loci with the same causal variant, the variant predisposes to disease by the same mechanism.
Rheumatoid Arthritis Consortium for Immunochip (RACI), Juvenile Arthritis Consortium for Immunochip (JACI), UK Psoriatic Arthritis Consortium
K. J. A. Steel,
C. D. Langefeld,
J. P. Haas,
J. F. Bohnsack,
S. D. Thompson,
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