Genetic interplay between HLA-C and MIR148A in HIV control and Crohn disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-12, Vol.110 (51), p.20705-20710
• Main Authors: Kulkarni, Smita, Qi, Ying, O'hUigin, Colm, Pereyra, Florencia, Ramsuran, Veron, McLaren, Paul, Fellay, Jacques, Nelson, George, Chen, Haoyan, Liao, Wilson, Bass, Sara, Apps, Richard, Gao, Xiaojiang, Yuki, Yuko, Lied, Alexandra, Ganesan, Anuradha, Hunt, Peter W., Deeks, Steven G., Wolinsky, Steven, Walker, Bruce D., Carrington, Mary
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; 3' Untranslated Regions - immunology; Alleles; Base Sequence; Binding sites; Biological Sciences; Crohn Disease - genetics; Crohn Disease - immunology; Crohn Disease - metabolism; Crohn's disease; Disease control; Female; Gene expression; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; Genetic loci; Genetics; Genotypes; HIV; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - metabolism; HLA C antigens; HLA-C Antigens - biosynthesis; HLA-C Antigens - genetics; HLA-C Antigens - immunology; Human immunodeficiency virus; Humans; INDEL Mutation; Linkage Disequilibrium; Male; Messenger RNA; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - immunology; Polymorphism; RNA; Three prime untranslated regions
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1312237110

Variation in the 3′ untranslated region (3′UTR) of the HLA-C locus determines binding of the microRNA Hsa-miR-148a, resulting in lower cell surface expression of alleles that bind miR-148a relative to those alleles that escape its binding. The HLA-C 3′UTR variant was shown to associate with HIV control, but like the vast majority of disease associations in a region dense with causal candidates, a direct effect of HLA-C expression level on HIV control was not proven. We demonstrate that a MIR148A insertion/deletion polymorphism associates with its own expression levels, affecting the extent to which HLA-C is down-regulated, the level of HIV control, and the risk of Crohn disease only among those carrying an intact miR-148a binding site in the HLA-C 3′UTR. These data illustrate a direct effect of HLA-C expression level on HIV control that cannot be attributed to other HLA loci in linkage disequilibrium with HLA-C and highlight the rich complexity of genetic interactions in human disease.