Journal
ARTHRITIS AND RHEUMATISM
Volume 65, Issue 12, Pages 3058-3062Publisher
WILEY
DOI: 10.1002/art.38183
Keywords
-
Categories
Funding
- Arthritis Research UK [17552]
- Innovative Medicines Initiative (Joint Undertaking project BeTheCure) [115142-2]
- Wellcome Trust [095684/Z/11/A]
- Swiss Foundation for Medical-Biological Scholarships [PASMP3_134380]
- Novartis
- National Institute for Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit
- NIHR Manchester Musculoskeletal Biomedical Research Unit
- AbbVie
- Bristol-Myers Squibb
- Genentech
- Lilly
- Pfizer
- Eli Lilly
- Wellcome Trust [095684/Z/11/A] Funding Source: Wellcome Trust
Ask authors/readers for more resources
ObjectiveA 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 x 10(-5) < 5 x 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. MethodsA 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. ResultsA 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 x 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 x 10(-8), OR 0.89), confirming that both are RA susceptibility loci. ConclusionThis 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available