Systematic approach demonstrates enrichment of multiple interactions between non-HLA risk variants and HLA-DRB1 risk alleles in rheumatoid arthritis

Diaz-Gallo LM, Ramskold D, Shchetynsky K, Folkersen L, Chemin K, Brynedal B, Uebe S, Okada Y, Alfredsson L, Klareskog L, Padyukov L (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Book Volume: 77

Pages Range: 1454-1462

Journal Issue: 10

DOI: 10.1136/annrheumdis-2018-213412

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.

Authors with CRIS profile

Steffen Uebe Institute of Human Genetics

Involved external institutions

Karolinska Institute SE Sweden (SE) Osaka University / 大阪大学 JP Japan (JP) Sankt Hans Hospital / Psykiatrisk Center Sct. Hans DK Denmark (DK)

How to cite

APA:

Diaz-Gallo, L.-M., Ramskold, D., Shchetynsky, K., Folkersen, L., Chemin, K., Brynedal, B.,... Padyukov, L. (2018). Systematic approach demonstrates enrichment of multiple interactions between non-HLA risk variants and HLA-DRB1 risk alleles in rheumatoid arthritis. Annals of the Rheumatic Diseases, 77(10), 1454-1462. https://doi.org/10.1136/annrheumdis-2018-213412

MLA:

Diaz-Gallo, Lina-Marcela, et al. "Systematic approach demonstrates enrichment of multiple interactions between non-HLA risk variants and HLA-DRB1 risk alleles in rheumatoid arthritis." Annals of the Rheumatic Diseases 77.10 (2018): 1454-1462.

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