The association between the HLA-DRB1 shared epitope alleles and the risk of rheumatoid arthritis is influenced by massive gene-gene interactions.

Diaz-Gallo, L. M.; Ramsköld, D.; Shchetynsky, K.; Folkersen, L.; Chemin, K.; Brynedal, B.; Uebe, S.; Okada, Y.; Alfredsson, L.; Klareskog, L.; Padyukov, L.

doi:10.1101/221416

bioRxiv · 10.1101/221416

The association between the HLA-DRB1 shared epitope alleles and the risk of rheumatoid arthritis is influenced by massive gene-gene interactions.

Diaz-Gallo, L. M.·Ramsköld, D.·Shchetynsky, K.·Folkersen, L.·Chemin, K.·Brynedal, B.·Uebe, S.·Okada, Y.·Alfredsson, L.·Klareskog, L.·Padyukov, L.

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Abstract

In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope alleles (SE), is the highest genetic risk factor. Here, we aimed to investigate whether gene-gene interactions influence this HLA-DRB1 related major disease risk; specifically, we set out to test if non-HLA SNPs, conferring low diseases risk on their own, can modulate the HLA-DRB1 SE effect to develop ACPA-positive RA.\n\nTo address this question, we computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish EIRA and the North American NARAC. We found a strong enrichment of significant interactions (AP p-values<0.05) between the HLA-DRB1 SE alleles and a group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov [KS] test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both). Interestingly, 201 out of 1,492 SNPs in consistent interaction for both cohorts, were eQTLs in SE alleles context in PBMCs from ACPA-positive RA patients. Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after discounting the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581, AP FDR corrected p <0.05).\n\nOur data demonstrate that the association between the HLA-DRB1 SE alleles and the risk of ACPA-positive RA is modulated by massive genetic interactions with non-HLA genetic variants.

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Diaz-Gallo, L. M., Ramsköld, D., Shchetynsky, K., Folkersen, L., Chemin, K., Brynedal, B., Uebe, S., Okada, Y., Alfredsson, L., Klareskog, L., Padyukov, L.. 2017-11-17. The association between the HLA-DRB1 shared epitope alleles and the risk of rheumatoid arthritis is influenced by massive gene-gene interactions.. https://doi.org/10.1101/221416

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