Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans.

Nimmisha Govind,Ananyo Choudhury,Michèle Ramsay,Richard J Reynolds,Annette Lee,Bridget Hodkinson,Mohammed Tikly,S Louis Bridges,Scott Hazelhurst,Jacqueline Frost,Peter K Gregersen,Claudia Ickinger

doi:10.2119/molmed.2014.00097

Abstract

The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10(-5)). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.

Highlights

Rheumatoid arthritis (RA) is a complex autoimmune disease affecting 0.5% to 1% of the population worldwide
This study showed that variants of the PTPN22 gene do not confer risk for RA in black South Africans
Unlike in Caucasians, we found no associations with human leukocyte antigen (HLA) B or HLA DPB1 [34,35,36], our sample has limited statistical power to detect these secondary effects in the major histocompatibility (MHC)

Summary

Introduction

Rheumatoid arthritis (RA) is a complex autoimmune disease affecting 0.5% to 1% of the population worldwide. This is characterized by chronic inflammation of synovial joints resulting in progressive joint destruction. Genome-wide association studies (GWASs) have made great strides in identifying novel loci associated with RA. Despite these discoveries, less than 50% of the heritability can be explained. The Immunochip consortium designed a genotyping array, an Illumina Infinium array with ~196,000 single nucleotide polymorphisms (SNPs), from 186 loci previously associated with 12 autoimmune diseases identified from GWASs. The success of the Immunochip is evidenced by novel risk loci, not previously associated with a specific pheno-

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