Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

Abstract

Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10−12; T1D, P = 2.4 × 10−10; psoriasis, P = 5.9 × 10−6; celiac disease, P = 1.2 × 10−87). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10−3; T1D, P = 8.6 × 10−27; celiac disease, P = 6.0 × 10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.

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Figure 1: Disease associations of HLA and non-HLA variants.
Figure 2: Non-additive contribution of the HLA region to autoimmune disease risk.
Figure 3: Interaction effects among HLA haplotypes.

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Acknowledgements

This project was supported by grants from the German Research Foundation (DFG; LE 2593/1-1 and LE 2593/2-1 (T.L.L.), GO 1795/1-1 (I.G.), KN 378/2-1 (M.K.) and SCHU 1596/5-1 (J.S.)), by grants from the US National Institutes of Health (1R01AR062886 (P.I.W.d.B.), R01AR065183 (J.T.E.), 1R01AR063759-01A1 (S.R.), 5U01GM092691 (S.R.) and 1UH2AR067677-01 (S.R.)), by the IMI (European Union)–funded program BTCure (L.K.) and by the Netherlands Organization for Scientific Research (Vernieuwingsimpuls VIDI Award NWO project 016.126.354 (P.I.W.d.B.)). Sample collection for J.M. was supported by a grant from the Instituto de Salud Carlos III (RD12/0009). M.M.N. received support for this work from the Alfried Krupp von Bohlen und Halbach-Stiftung and is a member of the DFG-funded Excellence Cluster ImmunoSensation.

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T.L.L., A.J.D., S.R., P.I.W.d.B. and S.R.S. conceived the study, coordinated the study and wrote the initial version of the manuscript. T.L.L., A.J.D., S.R., B.H., X.H., Y.O., P.I.W.d.B. and S.R.S. contributed to the study design and analysis strategy. T.L.L., A.J.D. and S.R. conducted all analyses. The following authors organized and contributed subject samples and provided SNP genotype data: S.E., T.W.J.H., L.K., J.M., S.R.-D., J.W. and P.K.G. (rheumatoid arthritis); W.-M.C., S.O.-G. and S.S.R. (T1D); G.A., A.F., D.D.G., R.P.N., P.R., P.E.S., L.C.T. and J.T.E. (psoriasis); J.G.-A., D.A.v.H., A.Z. and C.W. (celiac disease); and J.B., G.E.B., I.G., M.K., M.M.N., M.M.W. and J.S. (achalasia). The following authors contributed to critical writing and review of the manuscript: X.H., D.A.v.H., M.K., S.E., S.S.R., L.K., A.Z., C.W., Y.O. and T.W.J.H. All authors contributed to the final manuscript.

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Correspondence to Paul I W de Bakker or Soumya Raychaudhuri.

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The authors declare no competing financial interests.

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Lenz, T., Deutsch, A., Han, B. et al. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nat Genet 47, 1085–1090 (2015). https://doi.org/10.1038/ng.3379

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