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Evaluating the Impact of Functional Genetic Variation on HIV-1 Control

BACKGROUND: Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping. METHODS: We sought to systematically assess the full spectrum of functional variation in protein coding ge...

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Autores principales: McLaren, Paul J, Pulit, Sara L, Gurdasani, Deepti, Bartha, Istvan, Shea, Patrick R, Pomilla, Cristina, Gupta, Namrata, Gkrania-Klotsas, Effrossyni, Young, Elizabeth H, Bannert, Norbert, Del Amo, Julia, Gill, M John, Gilmour, Jill, Kellam, Paul, Kelleher, Anthony D, Sönnerborg, Anders, Wolinsky, Steven M, Zangerle, Robert, Post, Frank A, Fisher, Martin, Haas, David W, Walker, Bruce D, Porter, Kholoud, Goldstein, David B, Sandhu, Manjinder S, de Bakker, Paul I W, Fellay, Jacques
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853944/
https://www.ncbi.nlm.nih.gov/pubmed/28968755
http://dx.doi.org/10.1093/infdis/jix470
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author McLaren, Paul J
Pulit, Sara L
Gurdasani, Deepti
Bartha, Istvan
Shea, Patrick R
Pomilla, Cristina
Gupta, Namrata
Gkrania-Klotsas, Effrossyni
Young, Elizabeth H
Bannert, Norbert
Del Amo, Julia
Gill, M John
Gilmour, Jill
Kellam, Paul
Kelleher, Anthony D
Sönnerborg, Anders
Wolinsky, Steven M
Zangerle, Robert
Post, Frank A
Fisher, Martin
Haas, David W
Walker, Bruce D
Porter, Kholoud
Goldstein, David B
Sandhu, Manjinder S
de Bakker, Paul I W
Fellay, Jacques
author_facet McLaren, Paul J
Pulit, Sara L
Gurdasani, Deepti
Bartha, Istvan
Shea, Patrick R
Pomilla, Cristina
Gupta, Namrata
Gkrania-Klotsas, Effrossyni
Young, Elizabeth H
Bannert, Norbert
Del Amo, Julia
Gill, M John
Gilmour, Jill
Kellam, Paul
Kelleher, Anthony D
Sönnerborg, Anders
Wolinsky, Steven M
Zangerle, Robert
Post, Frank A
Fisher, Martin
Haas, David W
Walker, Bruce D
Porter, Kholoud
Goldstein, David B
Sandhu, Manjinder S
de Bakker, Paul I W
Fellay, Jacques
author_sort McLaren, Paul J
collection PubMed
description BACKGROUND: Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping. METHODS: We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load. RESULTS: Multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations. CONCLUSIONS: These results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection.
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spelling pubmed-58539442018-03-23 Evaluating the Impact of Functional Genetic Variation on HIV-1 Control McLaren, Paul J Pulit, Sara L Gurdasani, Deepti Bartha, Istvan Shea, Patrick R Pomilla, Cristina Gupta, Namrata Gkrania-Klotsas, Effrossyni Young, Elizabeth H Bannert, Norbert Del Amo, Julia Gill, M John Gilmour, Jill Kellam, Paul Kelleher, Anthony D Sönnerborg, Anders Wolinsky, Steven M Zangerle, Robert Post, Frank A Fisher, Martin Haas, David W Walker, Bruce D Porter, Kholoud Goldstein, David B Sandhu, Manjinder S de Bakker, Paul I W Fellay, Jacques J Infect Dis Major Articles and Brief Reports BACKGROUND: Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping. METHODS: We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load. RESULTS: Multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations. CONCLUSIONS: These results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection. Oxford University Press 2017-11-01 2017-09-09 /pmc/articles/PMC5853944/ /pubmed/28968755 http://dx.doi.org/10.1093/infdis/jix470 Text en © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Major Articles and Brief Reports
McLaren, Paul J
Pulit, Sara L
Gurdasani, Deepti
Bartha, Istvan
Shea, Patrick R
Pomilla, Cristina
Gupta, Namrata
Gkrania-Klotsas, Effrossyni
Young, Elizabeth H
Bannert, Norbert
Del Amo, Julia
Gill, M John
Gilmour, Jill
Kellam, Paul
Kelleher, Anthony D
Sönnerborg, Anders
Wolinsky, Steven M
Zangerle, Robert
Post, Frank A
Fisher, Martin
Haas, David W
Walker, Bruce D
Porter, Kholoud
Goldstein, David B
Sandhu, Manjinder S
de Bakker, Paul I W
Fellay, Jacques
Evaluating the Impact of Functional Genetic Variation on HIV-1 Control
title Evaluating the Impact of Functional Genetic Variation on HIV-1 Control
title_full Evaluating the Impact of Functional Genetic Variation on HIV-1 Control
title_fullStr Evaluating the Impact of Functional Genetic Variation on HIV-1 Control
title_full_unstemmed Evaluating the Impact of Functional Genetic Variation on HIV-1 Control
title_short Evaluating the Impact of Functional Genetic Variation on HIV-1 Control
title_sort evaluating the impact of functional genetic variation on hiv-1 control
topic Major Articles and Brief Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853944/
https://www.ncbi.nlm.nih.gov/pubmed/28968755
http://dx.doi.org/10.1093/infdis/jix470
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