High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci

Abstract

Objective A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9,299 Korean and 45,790 European case-control samples. Results We identified 8 new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1–FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10−8), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the 7 new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusion This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.

Interactions Between Amino Acid–Defined Major Histocompatibility Complex Class II Variants and Smoking in Seropositive Rheumatoid Arthritis

“…The baseline characteristics including smoking information of each cohort are shown in Table 1. The Immunochip data have been reported by Eyre S et al (32) for EIRA, by Karlson EW et al (33) for NHS, and by Kim K et al (34) for Korean.…”

OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response

“…TNFSF4 (encoding OX40L) polymorphism has been found to confer susceptibility to SLE (Cunninghame Graham et al, 2008; Delgado-Vega et al, 2009) and other autoimmune diseases, such as Sjögren syndrome, and rheumatoid arthritis (Kim et al, 2015; Nordmark et al, 2011). Furthermore, copy number variations and/or polymorphism at the TLR7 locus has been shown to associate with SLE susceptibility (Shen et al, 2010).…”

History of narcolepsy at Stanford University

“…Other associated loci included the TCR beta-gene a partner of TCRα; TNFSF4 (also called OX40L) a costimulatory receptor for T-cell activation involved in Lupus [158], Crohn’s disease [159], rheumatoid arthritis [160], and celiac disease; Cathepsin H, an enzyme likely involved in antigen processing and associated with Type 1 diabetes [161]; ZNF365, a transcription factor associated with inflammatory bowel disease (IBD) [159] and atopic dermatitis [162]; IL10RB-IFNAR1, a region associated with IBD [163]. …”