Systematic Approach Demonstrates Enrichment of Multiple Interactions Between Non- Risk Variants and Risk Alleles in Rheumatoid Arthritis

Overview

Journal Ann Rheum Dis

Specialty Rheumatology

Date 2018 Jul 4

PMID 29967194

Citations 10

Authors

Lina-Marcela Diaz-Gallo

Daniel Ramskold

Klementy Shchetynsky

Lasse Folkersen

Karine Chemin

Boel Brynedal

Steffen Uebe

Yukinori Okada

Lars Alfredsson

Lars Klareskog

Leonid Padyukov

Affiliations

Soon will be listed here.

Abstract

Objective: In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non- 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 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 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 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 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 SE alleles and non- genetic variants in ACPA-positive RA.

Citing Articles

Identification of epistatic SNP combinations in rheumatoid arthritis using LAMPLINK and Japanese cohorts.

Shibata M, Terada A, Kawaguchi T, Kamatani Y, Okada D, Nagashima K J Hum Genet. 2024; 69(10):541-547.

PMID: 39014190 DOI: 10.1038/s10038-024-01269-y.

Genetics of rheumatoid arthritis.

Padyukov L Semin Immunopathol. 2022; 44(1):47-62.

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Impact of Posttranslational Modification in Pathogenesis of Rheumatoid Arthritis: Focusing on Citrullination, Carbamylation, and Acetylation.

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Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis.

Roszkowski L, Ciechomska M Cells. 2021; 10(8).

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Interaction of HLA Class II rs9272219 and rs17028450 (Arg690Cys) Variants Affects Neuromyelitis Optica Spectrum Disorder Susceptibility in an Admixed Mexican Population.

Rosas-Madrigal S, Villarreal-Molina M, Flores-Rivera J, Rivas-Alonso V, Macias-Kauffer L, Ordonez G Front Genet. 2021; 12:647343.

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References

Sharon E, Sibener L, Battle A, Fraser H, Garcia K, Pritchard J . Genetic variation in MHC proteins is associated with T cell receptor expression biases. Nat Genet. 2016; 48(9):995-1002. PMC: 5010864. DOI: 10.1038/ng.3625. View

Hindorff L, Sethupathy P, Junkins H, Ramos E, Mehta J, Collins F . Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A. 2009; 106(23):9362-7. PMC: 2687147. DOI: 10.1073/pnas.0903103106. View

Seddighzadeh M, Korotkova M, Kallberg H, Ding B, Daha N, Kurreeman F . Evidence for interaction between 5-hydroxytryptamine (serotonin) receptor 2A and MHC type II molecules in the development of rheumatoid arthritis. Eur J Hum Genet. 2010; 18(7):821-6. PMC: 2987366. DOI: 10.1038/ejhg.2010.12. View

Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P . High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012; 44(12):1336-40. PMC: 3605761. DOI: 10.1038/ng.2462. View

Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L . A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 2004; 50(10):3085-92. DOI: 10.1002/art.20553. View

Raychaudhuri S, Sandor C, Stahl E, Freudenberg J, Lee H, Jia X . Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012; 44(3):291-6. PMC: 3288335. DOI: 10.1038/ng.1076. View

Ding B, Kallberg H, Klareskog L, Padyukov L, Alfredsson L . GEIRA: gene-environment and gene-gene interaction research application. Eur J Epidemiol. 2011; 26(7):557-61. PMC: 3143319. DOI: 10.1007/s10654-011-9582-5. View

Lekman M, Hossjer O, Andrews P, Kallberg H, Uvehag D, Charney D . The genetic interacting landscape of 63 candidate genes in Major Depressive Disorder: an explorative study. BioData Min. 2014; 7:19. PMC: 4181757. DOI: 10.1186/1756-0381-7-19. View

Klareskog L, Ronnelid J, Lundberg K, Padyukov L, Alfredsson L . Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol. 2008; 26:651-75. DOI: 10.1146/annurev.immunol.26.021607.090244. View

10.

Padyukov L, Seielstad M, Ong R, Ding B, Ronnelid J, Seddighzadeh M . A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann Rheum Dis. 2010; 70(2):259-65. PMC: 3015094. DOI: 10.1136/ard.2009.126821. View

11.

Plenge R, Cotsapas C, Davies L, Price A, de Bakker P, Maller J . Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet. 2007; 39(12):1477-82. PMC: 2652744. DOI: 10.1038/ng.2007.27. View

12.

Jawaheer D, Lum R, Amos C, Gregersen P, Criswell L . Clustering of disease features within 512 multicase rheumatoid arthritis families. Arthritis Rheum. 2004; 50(3):736-41. DOI: 10.1002/art.20066. View

13.

McAllister K, Eyre S, Orozco G . Genetics of rheumatoid arthritis: GWAS and beyond. Open Access Rheumatol. 2011; 3:31-46. PMC: 5074784. DOI: 10.2147/OARRR.S14725. View

14.

Lenz T, Deutsch A, Han B, Hu X, Okada Y, Eyre S . Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nat Genet. 2015; 47(9):1085-90. PMC: 4552599. DOI: 10.1038/ng.3379. View

15.

Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H . The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2013; 42(Database issue):D1001-6. PMC: 3965119. DOI: 10.1093/nar/gkt1229. View

16.

Kallberg H, Padyukov L, Plenge R, Ronnelid J, Gregersen P, van der Helm-van Mil A . Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet. 2007; 80(5):867-75. PMC: 1852748. DOI: 10.1086/516736. View

17.

Jawaheer D, Seldin M, Amos C, Chen W, Shigeta R, Monteiro J . A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am J Hum Genet. 2001; 68(4):927-36. PMC: 1275647. DOI: 10.1086/319518. View

18.

Rothman K, Greenland S, Walker A . Concepts of interaction. Am J Epidemiol. 1980; 112(4):467-70. DOI: 10.1093/oxfordjournals.aje.a113015. View

19.

Shim S, Lee W, Kim Y, Chang J, Song S, Jung Y . Role of S5b/PSMD5 in proteasome inhibition caused by TNF-α/NFκB in higher eukaryotes. Cell Rep. 2012; 2(3):603-15. DOI: 10.1016/j.celrep.2012.07.013. View

20.

Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K . Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014; 506(7488):376-81. PMC: 3944098. DOI: 10.1038/nature12873. View