Novel genetic locus implicated for HIV-1 acquisition with putative regulatory links to HIV replication and infectivity

A genome-wide association study

Eric O. Johnson, Dana B. Hancock, Nathan C. Gaddis, Joshua L. Levy, Grier Page, Scott P. Novak, Cristie Glasheen, Nancy L. Saccone, John P. Rice, Michael P. Moreau, Kimberly F. Doheny, Jane M. Romm, Andrew I. Brooks, Bradley E. Aouizerat, Laura J. Bierut, Alex H. Kral

Research output: Contribution to journalArticle

Abstract

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=1.38×10-4), although the UHS-WIHS meta-analysis p-value did not reach genome-wide significance (P=4.47×10-7 vs. P-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=6.9×10-5); (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=8×10-5); (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.

Original languageEnglish (US)
Article numbere0118149
JournalPLoS One
Volume10
Issue number3
DOIs
StatePublished - Mar 18 2015

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Genetic Loci
Genome-Wide Association Study
Human immunodeficiency virus 1
HIV-1
pathogenicity
Genes
Health
HIV
Gene expression
loci
Urban Health
F-Box Proteins
drug injection
Value engineering
Ubiquitin-Protein Ligases
Testing
Pharmaceutical Preparations
Drug Users
Animals
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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.

In: PLoS One, Vol. 10, No. 3, e0118149, 18.03.2015.

Research output: Contribution to journalArticle

Johnson, EO, Hancock, DB, Gaddis, NC, Levy, JL, Page, G, Novak, SP, Glasheen, C, Saccone, NL, Rice, JP, Moreau, MP, Doheny, KF, Romm, JM, Brooks, AI, Aouizerat, BE, Bierut, LJ & Kral, AH 2015, 'Novel genetic locus implicated for HIV-1 acquisition with putative regulatory links to HIV replication and infectivity: A genome-wide association study', PLoS One, vol. 10, no. 3, e0118149. https://doi.org/10.1371/journal.pone.0118149
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. In: PLoS One. 2015 ; Vol. 10, No. 3.
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