Novel genetic locus implicated for HIV-1 acquisition with putative regulatory links to HIV replication and infectivity: a genome-wide association study.
paper
Cited
Public
- 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
- Year
- 2015
- Journal
- PloS one
- PMID
- 25786224
- DOI
- 10.1371/journal.pone.0118149
- PMCID
- PMC4364715
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.
Overview of Study Design.AA represents African Americans, EA represents European Americans, and UofC represents University of Chicago.
Manhattan plot showing the meta-analysis results of approximately 8 million SNPs and indels tested for association with HIV-1 acquisition in 2,004 African Americans and 1,132 European Americans from the Urban Health Study.The–log10 (P value) is plotted by chromosomal position of SNPs (shown as circles) and indels (shown as triangles). The SNPs and indels selected for replication testing from 8 gene regions are highlighted in red. The gene region above the solid grey line (P<5x10-8) exceeded the threshold for genome-wide statistical significance. In addition, the 6 gene regions above the dashed black line (P<1x10-6) and the region around the top genotyped SNP (P = 1x10-5 on chromosome 9) were selected for replication testing.
Correlation between FBXO10 and BCL2 gene expression.Individual data points for 60 HapMap CEU samples are presented as blue dots, and the linear trend line is shown in black. Microarray data generated and made publically available by Montgomery et al. [34].
Putative pathway between FRMPD1 SNP rs4878712 and reduced risk of HIV acquisition through FBXO10 and BCL2/Bcl-2.
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| Associations of common variants in the BST2 region with HIV-1 acquisition in African American and European American people who inject drugs. | Hancock DB et al. | — | 2015 | → |
| Correction: Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study. | Johnson EO et al. | — | 2015 | → |
| Replication of ZNF804A gene variant associations with risk of heroin addiction. | Hancock DB et al. | — | 2015 | → |