Dr. Kremer has received consulting fees, speaking fees, and/or honoraria from AbbVie, Bristol-Myers Squibb, Genentech, Lilly, and Pfizer (less than $10,000 each) and is an employee of the Consortium of Rheumatology Researchers of North America (CORRONA).
Brief Report: Identification of BACH2 and RAD51B as Rheumatoid Arthritis Susceptibility Loci in a Meta-Analysis of Genome-Wide Data
Version of Record online: 27 NOV 2013
© 2013 The Authors. Arthritis & Rheumatism is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Arthritis & Rheumatism
Volume 65, Issue 12, pages 3058–3062, December 2013
How to Cite
McAllister, K., Yarwood, A., Bowes, J., Orozco, G., Viatte, S., Diogo, D., Hocking, L. J., Steer, S., Wordsworth, P., Wilson, A. G., Morgan, A. W., UK Rheumatoid Arthritis Genetics Consortium, Rheumatoid Arthritis Consortium International, Kremer, J. M., Pappas, D., Gregersen, P., Klareskog, L., Plenge, R., Barton, A., Greenberg, J., Worthington, J. and Eyre, S. (2013), Brief Report: Identification of BACH2 and RAD51B as Rheumatoid Arthritis Susceptibility Loci in a Meta-Analysis of Genome-Wide Data. Arthritis & Rheumatism, 65: 3058–3062. doi: 10.1002/art.38183
- Issue online: 27 NOV 2013
- Version of Record online: 27 NOV 2013
- Accepted manuscript online: 10 SEP 2013 03:35PM EST
- Manuscript Accepted: 29 AUG 2013
- Manuscript Received: 29 MAY 2013
- Arthritis Research UK. Grant Number: 17552
- Innovative Medicines Initiative (Joint Undertaking project BeTheCure). Grant Number: 115142-2
- Wellcome Trust. Grant Number: Research Career Development Fellowship 095684/Z/11/A
- Swiss Foundation for Medical-Biological Scholarships
- Swiss National Science Foundation. Grant Number: SSMBS grant PASMP3_134380
- Donation from Novartis to the Foundation
- National Institute for Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit
- NIHR Manchester Musculoskeletal Biomedical Research Unit
A recent high-density fine-mapping (ImmunoChip) study of genetic associations in rheumatoid arthritis (RA) identified 14 risk loci with validated genome-wide significance, as well as a number of loci showing associations suggestive of significance (P = 5 × 10−5 < 5 × 10−8), but these have yet to be replicated. The aim of this study was to determine whether these potentially significant loci are involved in the pathogenesis of RA, and to explore whether any of the loci are associated with a specific RA serotype.
A total of 16 single-nucleotide polymorphisms (SNPs) were selected for genotyping and association analyses in 2 independent validation cohorts, comprising 6,106 RA cases and 4,290 controls. A meta-analysis of the data from the original ImmunoChip discovery cohort and from both validation cohorts was carried out, for a combined total of 17,581 RA cases and 20,160 controls. In addition, stratified analysis of patient subsets, defined according to their anti–cyclic citrullinated peptide (anti-CCP) antibody status, was performed.
A significant association with RA risk (P < 0.05) was replicated for 6 of the SNPs assessed in the validation cohorts. All SNPs in the validation study had odds ratios (ORs) for RA susceptibility in the same direction as those in the ImmunoChip discovery study. One SNP, rs72928038, mapping to an intron of BACH2, achieved genome-wide significance in the meta-analysis (P = 1.2 × 10−8, OR 1.12), and a second SNP, rs911263, mapping to an intron of RAD51B, was significantly associated in the anti-CCP–positive RA subgroup (P = 4 × 10−8, OR 0.89), confirming that both are RA susceptibility loci.
This study provides robust evidence for an association of RA susceptibility with genes involved in B cell differentiation (BACH2) and DNA repair (RAD51B). The finding that the RAD51B gene exhibited different associations based on serologic subtype adds to the expanding knowledge base in defining subgroups of RA.