Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans

Maria I Danila,Qi Yan,Richard J Reynolds,Vincent A Laufer,Nianjun Liu,Peter K Gregersen,Marlena Kern,Carl D Langefeld,S Louis Bridges,Donna K Arnett,Annette Lee

doi:10.2119/molmed.2017.00081

Abstract

More than 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody-positive RA and 933 African American controls on the Immunochip (iChip) array. Using multivariable regression, we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (odds ratio = 1.97, p = 1.28 × 10−15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11 and TNFSF18 loci were suggestively associated (10−4 < p < 3.1 × 10−6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants, including rs9653442, rs7608424 and rs6712515, as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1 and ETS1 — but no variants within the major histocompatibility complex — were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we used the dense genotyping of the iChip array and the unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1 and IL2RA.

Highlights

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by synovial joint inflammation, with disease phenotype ranging from mild joint involvement to severe joint destruction and permanent disability [1]
In contrast to other reports, we find that single nucleotide polymorphism (SNP) in the major histocompatibility complex (MHC) region do not appear to be associated with radiographic severity of RA in African Americans
Our study demonstrates the utility of ethnic-specific analysis of genetic data

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by synovial joint inflammation, with disease phenotype ranging from mild joint involvement to severe joint destruction and permanent disability [1]. To replicate and fine map risk loci identified in genome-wide association studies (GWAS) of autoimmune and inflammatory disorders such as RA, the Immunochip Consortium designed the Immunochip (iChip), a custom Illumina Infinium high-density array that has been used to study RA in patients of several racial and ethnic backgrounds [4,5,6,7,8]. Using the iChip and many other arrays, 100 RA risk loci of genome-wide significance (p < 5 × 10–8) have been identified in individuals of European and AFRICAN AMERICAN RA: MAPPING AUTOIMMUNE LOCI. The PTPN22 risk allele containing rs2476601, which has the highest effect size on RA susceptibility of any locus outside the major histocompatibility complex (MHC) in European populations, is essentially absent from the Yoruban population and is present in Asian and African American populations in low frequency [12]

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