Differential microRNA regulation of HLA-C expression and its association with HIV control

Authors

Smita Kulkarni, SAIC-Frederick, Inc.
Ram Savan, NCI-Frederick
Ying Qi, Ragon Institute of Massachusetts General Hospital
Xiaojiang Gao, Ragon Institute of Massachusetts General Hospital
Yuko Yuki, Ragon Institute of Massachusetts General Hospital
Sara E. Bass, SAIC-Frederick, Inc.,
Maureen P. Martin, SAIC-Frederick, Inc.,
Peter Hunt, University of California - San Francisco
Steven G. Deeks, University of California - San Francisco
Amalio Telenti, University of Lausanne
Florencia Pereyra, Ragon Institute of Massachusetts General Hospital
David Goldstein, Duke University
Steven Wolinsky, Northwestern University
Bruce Walker, Ragon Institute of Massachusetts General Hospital
Howard A. Young, NCI-FrederickFollow
Mary Carrington, National Institutes of HealthFollow

Date of this Version

2011

Comments

Published in Nature (2011) vol. 472, 23 pp.; doi:10.1038/nature09914

Abstract

The HLA-C locus is distinct relative to the other classicalHLA class I loci in that it has relatively limited polymorphism1, lower expression on the cell surface, and more extensive ligand–receptor interactions with killer-cell immunoglobulin-like receptors. A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed -35) associates with control of HIV, and with levels of HLA-C messenger RNA transcripts and cell-surface expression, 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. Here we show that variation within the 39 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 39 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.