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

Nat Genet
Authors
Keywords
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.

Year of Publication
2015
Journal
Nat Genet
Volume
47
Issue
9
Pages
1085-90
Date Published
2015 Sep
ISSN
1546-1718
URL
DOI
10.1038/ng.3379
PubMed ID
26258845
PubMed Central ID
PMC4552599
Links
Grant list
1R01AR062886 / AR / NIAMS NIH HHS / United States
R01 AR042742 / AR / NIAMS NIH HHS / United States
1R01AR063759-01A1 / AR / NIAMS NIH HHS / United States
U19 AI111224 / AI / NIAID NIH HHS / United States
R01AR065183 / AR / NIAMS NIH HHS / United States
G1001158 / Medical Research Council / United Kingdom
U01 GM092691 / GM / NIGMS NIH HHS / United States
5U01GM092691 / GM / NIGMS NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
R01 AR062886 / AR / NIAMS NIH HHS / United States
UH2 AR067677 / AR / NIAMS NIH HHS / United States
MANMKBRU-2012-1 / Department of Health / United Kingdom
R01 AR065183 / AR / NIAMS NIH HHS / United States
R01 AR063611 / AR / NIAMS NIH HHS / United States
1UH2AR067677-01 / AR / NIAMS NIH HHS / United States