Widespread Non-additive and Interaction Effects Within HLA Loci Modulate the Risk of Autoimmune Diseases

Overview

Journal Nat Genet

Specialty Genetics

Date 2015 Aug 11

PMID 26258845

Citations 92

Authors

Tobias L Lenz

Aaron J Deutsch

Buhm Han

Xinli Hu

Yukinori Okada

Stephen Eyre

Michael Knapp

Alexandra Zhernakova

Tom W J Huizinga

Goncalo Abecasis

Jessica Becker

Guy E Boeckxstaens

Wei-Min Chen

Andre Franke

Dafna D Gladman

Ines Gockel

Javier Gutierrez-Achury

Javier Martin

Rajan P Nair

Markus M Nothen

Suna Onengut-Gumuscu

Proton Rahman

Solbritt Rantapaa-Dahlqvist

Philip E Stuart

Lam C Tsoi

David A van Heel

Jane Worthington

Mira M Wouters

Lars Klareskog

James T Elder

Peter K Gregersen

Johannes Schumacher

Stephen S Rich

Cisca Wijmenga

Shamil R Sunyaev

Paul I W de Bakker

Soumya Raychaudhuri

Affiliations

Soon will be listed here.

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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References

de Bakker P, Raychaudhuri S . Interrogating the major histocompatibility complex with high-throughput genomics. Hum Mol Genet. 2012; 21(R1):R29-36. PMC: 3459647. DOI: 10.1093/hmg/dds384. View

Lipsitch M, Bergstrom C, Antia R . Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures. BMC Med Genet. 2003; 4:2. PMC: 149356. DOI: 10.1186/1471-2350-4-2. 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

Okada Y, Kim K, Han B, Pillai N, Ong R, Saw W . Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Hum Mol Genet. 2014; 23(25):6916-26. PMC: 4245039. DOI: 10.1093/hmg/ddu387. View

Parkes M, Cortes A, van Heel D, Brown M . Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet. 2013; 14(9):661-73. DOI: 10.1038/nrg3502. View

Wordsworth P, Pile K, Buckely J, Lanchbury J, Ollier B, Lathrop M . HLA heterozygosity contributes to susceptibility to rheumatoid arthritis. Am J Hum Genet. 1992; 51(3):585-91. PMC: 1682725. View

MacGregor A, Ollier W, Thomson W, Jawaheer D, Silman A . HLA-DRB1*0401/0404 genotype and rheumatoid arthritis: increased association in men, young age at onset, and disease severity. J Rheumatol. 1995; 22(6):1032-6. View

Carrington M, Nelson G, Martin M, Kissner T, Vlahov D, Goedert J . HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science. 1999; 283(5408):1748-52. DOI: 10.1126/science.283.5408.1748. View

So H, Gui A, Cherny S, Sham P . Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet Epidemiol. 2011; 35(5):310-7. DOI: 10.1002/gepi.20579. View

10.

Clop A, Bertoni A, Spain S, Simpson M, Pullabhatla V, Tonda R . An in-depth characterization of the major psoriasis susceptibility locus identifies candidate susceptibility alleles within an HLA-C enhancer element. PLoS One. 2013; 8(8):e71690. PMC: 3747202. DOI: 10.1371/journal.pone.0071690. View

11.

Woelfing B, Traulsen A, Milinski M, Boehm T . Does intra-individual major histocompatibility complex diversity keep a golden mean?. Philos Trans R Soc Lond B Biol Sci. 2008; 364(1513):117-28. PMC: 2666699. DOI: 10.1098/rstb.2008.0174. View

12.

Gjuvsland A, Plahte E, Adnoy T, Omholt S . Allele interaction--single locus genetics meets regulatory biology. PLoS One. 2010; 5(2):e9379. PMC: 2826424. DOI: 10.1371/journal.pone.0009379. View

13.

Horton R, Wilming L, Rand V, Lovering R, Bruford E, Khodiyar V . Gene map of the extended human MHC. Nat Rev Genet. 2004; 5(12):889-99. DOI: 10.1038/nrg1489. View

14.

Penn D, Damjanovich K, Potts W . MHC heterozygosity confers a selective advantage against multiple-strain infections. Proc Natl Acad Sci U S A. 2002; 99(17):11260-4. PMC: 123244. DOI: 10.1073/pnas.162006499. View

15.

Stahl E, Wegmann D, Trynka G, Gutierrez-Achury J, Do R, Voight B . Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nat Genet. 2012; 44(5):483-9. PMC: 6560362. DOI: 10.1038/ng.2232. View

16.

Okada Y, Han B, Tsoi L, Stuart P, Ellinghaus E, Tejasvi T . Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. Am J Hum Genet. 2014; 95(2):162-72. PMC: 4129407. DOI: 10.1016/j.ajhg.2014.07.002. View

17.

Miyadera H, Ohashi J, Lernmark A, Kitamura T, Tokunaga K . Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA. J Clin Invest. 2014; 125(1):275-91. PMC: 4382229. DOI: 10.1172/JCI74961. View

18.

Holoshitz J . The rheumatoid arthritis HLA-DRB1 shared epitope. Curr Opin Rheumatol. 2010; 22(3):293-8. PMC: 2921962. DOI: 10.1097/BOR.0b013e328336ba63. View

19.

Jia X, Han B, Onengut-Gumuscu S, Chen W, Concannon P, Rich S . Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One. 2013; 8(6):e64683. PMC: 3675122. DOI: 10.1371/journal.pone.0064683. View

20.

Koeleman B, Lie B, Undlien D, Dudbridge F, Thorsby E, de Vries R . Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease. Genes Immun. 2004; 5(5):381-8. DOI: 10.1038/sj.gene.6364106. View