The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism1, lower expression on the cell surface2,3, and more extensive ligand–receptor interactions with killer-cell immunoglobulin-like receptors4. A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed −35) associates with control of HIV5,6,7, and with levels of HLA-C messenger RNA transcripts8 and cell-surface expression7, 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-C7. 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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This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contracts HHSN261200800001E, N02-CP-55504, R01-DA04334 and R01-DA12568. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the Cancer Inflammation Program Project Award for the year 2009, a grant from the Bill & Melinda Gates Foundation as part of the Collaboration for AIDS Vaccine Discovery, and the Mark and Lisa Schwartz Foundation. We would also like to thank the patients and investigators involved in the Multicenter AIDS Cohort Study (the MACS is funded by the National Institute of Allergy and Infectious Diseases, with supplemental funding from the National Cancer Institute and the National Heart, Lung and Blood Institute (grants UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613 and UO1-AI-35041), the Swiss HIV Cohort Study (see Supplementary Note 4 for the list of members), supported by the Swiss National Science Foundation grant number 33CSC0-108787, and the SCOPE study, which was funded by the UL1 RR024131 (Clinical and Translational Sciences Award) and P30 AI27763 (Center for AIDS Research) grants. We thank S. Anderson, G. O’Connor and R. Thomas for advice, A. Kronfli and K. Ramakrishnan for assistance in plasmid and genomic DNA preparations, A. McFarland for western blots, V. Braud for the DT9 antibody, R. Johnson and G. Nelson for statistical advice and T. Covell for administrative assistance.
The file contains Supplementary Figures 1-10 with legends, Supplementary Tables 1-4, Supplementary Notes and additional references.