Journal
NATURE
Volume 472, Issue 7344, Pages 495-U548Publisher
NATURE PORTFOLIO
DOI: 10.1038/nature09914
Keywords
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Categories
Funding
- National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E, N02-CP-55504, R01-DA04334, R01-DA12568]
- NIH, National Cancer Institute, Center for Cancer Research
- Cancer Inflammation Program Project Award
- Bill & Melinda Gates Foundation
- Mark and Lisa Schwartz Foundation
- National Institute of Allergy and Infectious Diseases
- National Cancer Institute
- National Heart, Lung and Blood Institute [UO1-AI-35042, 5-MO1-RR-00722, UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041]
- Swiss HIV Cohort Study
- Swiss National Science Foundation [33CSC0-108787]
- [UL1 RR024131]
- [P30 AI27763]
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The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism(1), lower expression on the cell surface(2,3), and more extensive ligand-receptor interactions with killer-cell immunoglobulin-like receptors(4). A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed -35) associates with control of HIV5-7, and with levels of HLA-C messenger RNA transcripts(8) and cell-surface expression(7), but the mechanism underlying its varied expression is unknown. We proposed that the -35 SNP is not the causal variant for differential HLA-C expression, but rather is marking another polymorphism that directly affects levels of HLA-C-7. Here we show that variation within the 3' untranslated region (UTR) of HLA-C regulates binding of the microRNA hsa-miR-148 to its target site, resulting in relatively low surface expression of alleles that bind this microRNA and high expression of HLA-C alleles that escape post-transcriptional regulation. The 3' UTR variant associates strongly with control of HIV, potentially adding to the effects of genetic variation encoding the peptide-binding region of the HLA class I loci. Variation in HLA-C expression adds another layer of diversity to this highly polymorphic locus that must be considered when deciphering the function of these molecules in health and disease.
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