Targeted Exon Resequencing For Korean Rheumatoid Arthritis

Abstract

Background/Purpose: Rheumatoid arthritis (RA) is a systemic autoimmune disorder with heritability estimated at 65% characterized by arthritis and autoantibodies formation against citrullinated peptides (ACPA). Although there have been many efforts to identify underlying genetic causes of RA by common variants from genome-wide association studies (GWAS), most of around 60 loci identified have modest effect sizes and explained fully little of missing heritability. To discover functional and causal rare variants, we targeted genes outside of MHC region by for which there was reasonable evidence for involvement in Korean RA.

Methods: We performed targeted exon resequencing for 402 candidate genes in non-HLA region for 1,997 Korean RA cases-controls with Agilent’s SureSelect kit (target region = 1.36Mb) on the HiSeq2000 platform. The sequencing data was filtered by our quality control criteria. RA association was assessed by a logistic regression for common markers and by a gene-based analysis using both Score-Seq and SKAT-O for rare coding variants.

Results: A total of 10,590 high-quality single-nucleotide variants (SNVs) was found in 1,217 cases and 717 healthy controls after applying the quality criteria (minimal depth coverage = 20x). The majority of the variants had low or rare frequency (90.6%) and 7,208 SNV was not reported in public databases like the 1000 genome project data. There were no novel loci associated with RA susceptibility in a single-marker level but we identified a significant accumulation of rare nonsynonymous variants in gene A associated with RA (Score-Seq: P = 3.5 ×10−4, SKAT-O: P = 7.0 ×10−3).

Conclusion: The gene A involved in the differentiation and activation Th17 was associated with RA risk by gene-based approaches of rare coding variants.