title: Differential microRNA regulation of HLA-C expression and its association with HIV control.
abstract: The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism, 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 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.
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Ram
authors.initials: R
authors.lastname: Savan
authors.forename: Ying
authors.initials: Y
authors.lastname: Qi
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Gao
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yuki
authors.forename: Sara E
authors.initials: SE
authors.lastname: Bass
authors.forename: Maureen P
authors.initials: MP
authors.lastname: Martin
authors.forename: Peter
authors.initials: P
authors.lastname: Hunt
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.forename: Steven
authors.initials: S
authors.lastname: Wolinsky
authors.forename: Bruce
authors.initials: B
authors.lastname: Walker
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000483:Alleles; D001483:Base Sequence; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D017930:Genes, Reporter / Q000235:genetics; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D015236:HLA-C Antigens / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019562:Viral Load
chemical_list: D020413:3' Untranslated Regions; D015236:HLA-C Antigens; C550570:MIRN148 microRNA, human; D035683:MicroRNAs