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Nat Genet. 2015 Sep;47(9):1085-90. doi: 10.1038/ng.3379. Epub 2015 Aug 10.

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

Author information

1
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
2
Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
3
Evolutionary Immunogenomics, Department of Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Ploen, Germany.
4
Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
5
Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.
6
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
7
Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA.
8
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
9
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
10
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
11
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
12
National Institute for Health Research (NIHR) Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.
13
Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
14
Genetics Department, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
15
Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.
16
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
17
Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
18
Institute of Human Genetics, University of Bonn, Bonn, Germany.
19
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
20
Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
21
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
22
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
23
Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
24
Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada.
25
Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada.
26
Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
27
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
28
Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
29
Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.
30
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
31
Department of Rheumatology, Umeå University, Umeå, Sweden.
32
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
33
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
34
Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
35
Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
36
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
37
Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands.

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.

PMID:
26258845
PMCID:
PMC4552599
DOI:
10.1038/ng.3379
[Indexed for MEDLINE]
Free PMC Article

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