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Genetic interplay between HLA-C and MIR148A in HIV control and Crohn disease
- 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
- et al.
Published Web Location
https://doi.org/10.1073/pnas.1312237110Abstract
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.
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