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

TitleEvaluating the Impact of Functional Genetic Variation on HIV-1 Control.
Publication TypeJournal Article
Year of Publication2017
AuthorsMcLaren PJ, Pulit SL, Gurdasani D, Bartha I, Shea PR, Pomilla C, Gupta N, Gkrania-Klotsas E, Young EH, Bannert N, Del Amo J, M Gill J, Gilmour J, Kellam P, Kelleher AD, Sönnerborg A, Zangerle R, Post FA, Fisher M, Haas DW, Walker BD, Porter K, Goldstein DB, Sandhu MS, DE Bakker PIW, Fellay J
JournalJ Infect Dis
Volume216
Issue9
Pagination1063-1069
Date Published2017 11 27
ISSN1537-6613
KeywordsAdult, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, HIV Infections, HIV-1, Host-Pathogen Interactions, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Viral Load, Whole Exome Sequencing
Abstract

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.

DOI10.1093/infdis/jix470
Alternate JournalJ. Infect. Dis.
PubMed ID28968755
PubMed Central IDPMC5853944
Grant ListMC_UU_12023/15 / / Medical Research Council / United Kingdom
UM1 AI068634 / AI / NIAID NIH HHS / United States
G0901213 / / Medical Research Council / United Kingdom
UM1 AI106701 / AI / NIAID NIH HHS / United States
MR/K013491/1 / / Medical Research Council / United Kingdom
U01 AI035039 / AI / NIAID NIH HHS / United States
U01 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States