Brief Report: Identification of BACH2 and RAD51B as Rheumatoid Arthritis Susceptibility Loci in a Meta-Analysis of Genome-Wide Data.

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Abstract

OBJECTIVES: A dense fine-mapping study (Immunochip) for rheumatoid arthritis (RA) identified 14 validated genome-wide significant hits as well as a number of suggestive loci (P= 5x10(-05) < 5x10(-08) ), that have yet to be replicated. The aim of this study was to determine whether these suggestive loci were involved in RA pathogenesis and to explore whether they were associated with a specific RA serotype. METHODS: A total of 16 single nucleotide polymorphisms (SNPs) were selected for genotyping and association analysis in two independent validation cohorts comprising 6,106 RA cases and 4,290 controls. Meta-analysis across the Immunochip discovery and both validation cohorts was carried out for a combined total of 17,581 RA cases and 20,160 controls. Additionally stratified analysis was performed on patient subsets defined by their anti-cyclic citrullinated peptides (anti-CCP) antibody status. RESULTS: Six SNPs were replicated with a p-value <0.05 in the validation cohort. All SNPs in the validation showed odds ratios (ORs) in the same direction to the Immunochip discovery study. One SNP, rs72928038 mapping to an intron of BACH2, achieved genome-wide significance in the meta-analysis (p =1.2x10(-8) , OR 1.12) and a second SNP, rs911263 mapping to an intron of RAD51B, was significantly associated in the anti-CCP positive subgroup (p=4x10(-8) , OR 0.89) confirming them as RA susceptibility loci. CONCLUSIONS: This study provides robust evidence for association to genes involved in B-cell differentiation (BACH2) and DNA repair (RAD51B). The RAD51B gene exhibits different associations based on serological subtype, adding to the expanding knowledge base in defining subgroups of RA. © 2013 American College of Rheumatology.

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