ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 71

A Rare Coding Allele in IFIH1 is Protective for Psoriatic Arthritis

Ashley Budu-Aggrey1,2, John Bowes2, Philip E. Stuart3, Matthew Zawistowski4, Lam C. Tsoi4, Rajan P. Nair5, Eleanor Korendowych6, Neil J McHugh6, James T. Elder5, Anne Barton1,7,8 and Soumya Raychaudhuri9, 1NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust and University of Manchester, Manchester Academy of Health Sciences, Manchester, United Kingdom, 2Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK, Manchester, United Kingdom, 3Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, 4Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 5University of Michigan Medical School, Ann Arbor, MI, 6Royal National Hospital for Rheumatic Diseases and Dept Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom, 7Arthritis Research UK, Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, United Kingdom, 8The Kellgren Centre for Rheumatology, Central Manchester Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester, United Kingdom, 9Brigham and Women's Hospital, Boston, MA

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: ,

Session Information

Date: Sunday, November 13, 2016

Title: Genetics, Genomics and Proteomics - Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:  Psoriatic Arthritis (PsA) is an inflammatory arthritis associated with psoriasis estimated to present in approximately 14% of psoriasis patients in the UK. As a complex disease, PsA is influenced by both genetic and environmental factors. Genome-wide association studies (GWAS) have reported risk alleles for both PsA and psoriasis that are common, with a frequency > 5% in the population. However, association with rare coding alleles has not yet been reported for PsA alone.

Methods:  In this study, we attempt to identify rare coding variants (MAF < 5%) associated with PsA. We genotyped 41,267 variants in 1,980 PsA cases and 5,913 controls of Caucasian decent using the Infinium HumanExome-12 BeadChip (v1-0) (Illumina) and the Infinium HumanCoreExome-24 BeadChip (v1-0) (Illumina). We applied single-point analysis using the Fisher’s exact test in PLINK with all variants passing QC. We performed multiple-variant analysis with rare variants alone using the SKAT package in R. We then applied conditional analysis using PLINK to investigate independent effects. We also analysed an independent cohort of 2,234 PsA cases and 5,708 healthy controls of European descent, where we performed single-point analysis using Firth logistic regression. A meta-analysis of the discovery and independent summary statistics was performed using PLINK.

Results: Upon performing single-point analysis, we found the strongest association at the rs35667974 SNP (P=2.39×10-6, OR=0.47), mapping to the IFIH1 gene and encoding an Ile923Val missense mutation. We replicated this association within an independent North American dataset (P=2.5×10-5, OR=0.49), which was highly significant in meta-analysis with the discovery dataset (P=4.67×10-10). IFIH1 was also found to have a strong association when performing multiple-variant analysis (SKAT, P=6.77×10-6). The association of the rare coding allele was independent of the common PsA variant at the same locus (rs984971) when performing conditional logistic regression (P­cond=4.0×10-6) and conditional haplotype analysis (P=2.95×10-7).

Conclusion:  For the first time, we report a rare coding allele at IFIH1 to be protective for PsA. This association has been previously reported for psoriasis and type 1 diabetes, highlighting the relevance of this allele in immune-related diseases. The association that we identified in PsA provides strong evidence to suggest that IFIH1 is a causal gene. This finding could provide further insight into the mechanism of disease for PsA. The functional role of IFIH1 might be investigated in PsA using this coding change.

Disclosure: A. Budu-Aggrey, None; J. Bowes, None; P. E. Stuart, None; M. Zawistowski, None; L. C. Tsoi, None; R. P. Nair, None; E. Korendowych, None; N. J. McHugh, None; J. T. Elder, None; A. Barton, None; S. Raychaudhuri, None.

To cite this abstract in AMA style:

Budu-Aggrey A, Bowes J, Stuart PE, Zawistowski M, Tsoi LC, Nair RP, Korendowych E, McHugh NJ, Elder JT, Barton A, Raychaudhuri S. A Rare Coding Allele in IFIH1 is Protective for Psoriatic Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/a-rare-coding-allele-in-ifih1-is-protective-for-psoriatic-arthritis/. Accessed .

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