Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study

Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study

Fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Thus identifying genetic associations is essential to understanding pathogenesis of HIV-1 and important for targeting drug development. To date, however, CCR5 remains the only gene conclusively associated with HIV...

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Main Authors: Johnson, Eric O., Hancock, Dana B., Gaddis, Nathan C., Levy, Joshua L., Page, Grier, Novak, Scott P., Glasheen, Cristie, Saccone, Nancy L., Rice, John P., Moreau, Michael P., Doheny, Kimberly F., Romm, Jane M., Brooks, Andrew I., Aouizerat, Bradley E., Bierut, Laura J., Kral, Alex H.
Format: Online
Language:English
Published: Public Library of Science 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364715/
id pubmed-4364715
recordtype oai_dc
spelling pubmed-43647152015-03-23 Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study Johnson, Eric O. Hancock, Dana B. Gaddis, Nathan C. Levy, Joshua L. Page, Grier Novak, Scott P. Glasheen, Cristie Saccone, Nancy L. Rice, John P. Moreau, Michael P. Doheny, Kimberly F. Romm, Jane M. Brooks, Andrew I. Aouizerat, Bradley E. Bierut, Laura J. Kral, Alex H. Research Article Fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Thus identifying genetic associations is essential to understanding pathogenesis of HIV-1 and important for targeting drug development. To date, however, CCR5 remains the only gene conclusively associated with HIV acquisition. To identify novel host genetic determinants of HIV-1 acquisition, we conducted a genome-wide association study among a high-risk sample of 3,136 injection drug users (IDUs) from the Urban Health Study (UHS). In addition to being IDUs, HIV- controls were frequency-matched to cases on environmental exposures to enhance detection of genetic effects. We tested independent replication in the Women’s Interagency HIV Study (N=2,533). We also examined publicly available gene expression data to link SNPs associated with HIV acquisition to known mechanisms affecting HIV replication/infectivity. Analysis of the UHS nominated eight genetic regions for replication testing. SNP rs4878712 in FRMPD1 met multiple testing correction for independent replication (P=1.38x10-4), although the UHS-WIHS meta-analysis p-value did not reach genome-wide significance (P=4.47x10-7 vs. P<5.0x10-8) Gene expression analyses provided promising biological support for the protective G allele at rs4878712 lowering risk of HIV: (1) the G allele was associated with reduced expression of FBXO10 (r=-0.49, P=6.9x10-5); (2) FBXO10 is a component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase complex that targets Bcl-2 protein for degradation; (3) lower FBXO10 expression was associated with higher BCL2 expression (r=-0.49, P=8x10-5); (4) higher basal levels of Bcl-2 are known to reduce HIV replication and infectivity in human and animal in vitro studies. These results suggest new potential biological pathways by which host genetics affect susceptibility to HIV upon exposure for follow-up in subsequent studies. Public Library of Science 2015-03-18 /pmc/articles/PMC4364715/ /pubmed/25786224 http://dx.doi.org/10.1371/journal.pone.0118149 Text en © 2015 Johnson et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Johnson, Eric O.
Hancock, Dana B.
Gaddis, Nathan C.
Levy, Joshua L.
Page, Grier
Novak, Scott P.
Glasheen, Cristie
Saccone, Nancy L.
Rice, John P.
Moreau, Michael P.
Doheny, Kimberly F.
Romm, Jane M.
Brooks, Andrew I.
Aouizerat, Bradley E.
Bierut, Laura J.
Kral, Alex H.
spellingShingle Johnson, Eric O.
Hancock, Dana B.
Gaddis, Nathan C.
Levy, Joshua L.
Page, Grier
Novak, Scott P.
Glasheen, Cristie
Saccone, Nancy L.
Rice, John P.
Moreau, Michael P.
Doheny, Kimberly F.
Romm, Jane M.
Brooks, Andrew I.
Aouizerat, Bradley E.
Bierut, Laura J.
Kral, Alex H.
Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study
author_facet Johnson, Eric O.
Hancock, Dana B.
Gaddis, Nathan C.
Levy, Joshua L.
Page, Grier
Novak, Scott P.
Glasheen, Cristie
Saccone, Nancy L.
Rice, John P.
Moreau, Michael P.
Doheny, Kimberly F.
Romm, Jane M.
Brooks, Andrew I.
Aouizerat, Bradley E.
Bierut, Laura J.
Kral, Alex H.
author_sort Johnson, Eric O.
title Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study
title_short Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study
title_full Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study
title_fullStr Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study
title_full_unstemmed Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study
title_sort novel genetic locus implicated for hiv-1 acquisition with putative regulatory links to hiv replication and infectivity: a genome-wide association study
description Fifty percent of variability in HIV-1 susceptibility is attributable to host genetics. Thus identifying genetic associations is essential to understanding pathogenesis of HIV-1 and important for targeting drug development. To date, however, CCR5 remains the only gene conclusively associated with HIV acquisition. To identify novel host genetic determinants of HIV-1 acquisition, we conducted a genome-wide association study among a high-risk sample of 3,136 injection drug users (IDUs) from the Urban Health Study (UHS). In addition to being IDUs, HIV- controls were frequency-matched to cases on environmental exposures to enhance detection of genetic effects. We tested independent replication in the Women’s Interagency HIV Study (N=2,533). We also examined publicly available gene expression data to link SNPs associated with HIV acquisition to known mechanisms affecting HIV replication/infectivity. Analysis of the UHS nominated eight genetic regions for replication testing. SNP rs4878712 in FRMPD1 met multiple testing correction for independent replication (P=1.38x10-4), although the UHS-WIHS meta-analysis p-value did not reach genome-wide significance (P=4.47x10-7 vs. P<5.0x10-8) Gene expression analyses provided promising biological support for the protective G allele at rs4878712 lowering risk of HIV: (1) the G allele was associated with reduced expression of FBXO10 (r=-0.49, P=6.9x10-5); (2) FBXO10 is a component of the Skp1-Cul1-F-box protein E3 ubiquitin ligase complex that targets Bcl-2 protein for degradation; (3) lower FBXO10 expression was associated with higher BCL2 expression (r=-0.49, P=8x10-5); (4) higher basal levels of Bcl-2 are known to reduce HIV replication and infectivity in human and animal in vitro studies. These results suggest new potential biological pathways by which host genetics affect susceptibility to HIV upon exposure for follow-up in subsequent studies.
publisher Public Library of Science
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364715/
_version_ 1613200384728236032

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