1. Systematic approach demonstrates enrichment of multiple interactions between non- HLA risk variants and HLA-DRB1 risk alleles in rheumatoid arthritis.
- Author
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Diaz-Gallo LM, Ramsköld D, Shchetynsky K, Folkersen L, Chemin K, Brynedal B, Uebe S, Okada Y, Alfredsson L, Klareskog L, and Padyukov L
- Subjects
- Anti-Citrullinated Protein Antibodies genetics, Anti-Citrullinated Protein Antibodies immunology, Arthritis, Rheumatoid immunology, Cohort Studies, Epistasis, Genetic immunology, Epitopes genetics, Epitopes immunology, Female, HLA-DRB1 Chains immunology, Humans, Male, North America, Polymorphism, Single Nucleotide, Risk Factors, Sweden, Alleles, Arthritis, Rheumatoid genetics, Epistasis, Genetic genetics, Genetic Predisposition to Disease genetics, HLA-DRB1 Chains genetics
- Abstract
Objective: In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non- HLA single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact with SE alleles more frequently than expected by chance and if such genetic interactions influence the HLA-DRB1 SE effect concerning risk to ACPA-positive RA., Methods: We computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish epidemiological investigation of rheumatoid arthritis (EIRA) and the North American rheumatoid arthritis consortium (NARAC). Then, we tested for differences in the AP p value distributions observed for two groups of SNPs, non-associated and associated with disease. We also evaluated whether the SNPs in interaction with HLA-DRB1 were cis-eQTLs in the SE alleles context in peripheral blood mononuclear cells from patients with ACPA-positive RA (SE-eQTLs)., Results: We found a strong enrichment of significant interactions (AP p<0.05) between the HLA-DRB1 SE alleles and the group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both). Interestingly, 564 out of 1492 SNPs in consistent interaction for both cohorts were significant SE-eQTLs. Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after removal of the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581)., Conclusion: Our data demonstrate that there are massive genetic interactions between the HLA-DRB1 SE alleles and non- HLA genetic variants in ACPA-positive RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2018
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