Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity
- University of Texas Southwestern Medical Center, United States
- Yale School of Medicine, United States
- Oklahoma Medical Research Foundation, United States
- Université catholique de Louvain, Belgium
- Penn State Medical School, United States
- Texas Scottish Rite Hospital for Children, United States
- Cincinnati Children's Hospital Medical Center, United States
- University of Southern California, United States
- University of California, Los Angeles, United States
Abstract
Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to >4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.
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Human subjects: All the study subjects gave their written informed consent for the study. All the research protocols and methods employed were approved by UT Southwestern Institutional Review Board.
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© 2016, Raj et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity
eLife 5:e12089.
https://doi.org/10.7554/eLife.12089
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