title: Novel genetic locus implicated for HIV-1 acquisition with putative regulatory links to HIV replication and infectivity: a genome-wide association study.
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=1.38x10(-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.
authors.affiliation: RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA, United States of America.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Johnson
authors.affiliation: RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA, United States of America.
authors.forename: Dana B
authors.initials: DB
authors.lastname: Hancock
authors.affiliation: RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA, United States of America.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Gaddis
authors.affiliation: RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA, United States of America.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Levy
authors.affiliation: RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA, United States of America.
authors.forename: Grier
authors.initials: G
authors.lastname: Page
authors.affiliation: RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA, United States of America.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Novak
authors.affiliation: RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA, United States of America.
authors.forename: Cristie
authors.initials: C
authors.lastname: Glasheen
authors.affiliation: Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Saccone
authors.affiliation: Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Rice
authors.affiliation: Rutgers University Cell and DNA Repository (RUCDR), Piscataway, NJ, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Moreau
authors.affiliation: Center for Inherited Disease Research (CIDR), Johns Hopkins University, Baltimore, MD, United States of America.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.affiliation: Center for Inherited Disease Research (CIDR), Johns Hopkins University, Baltimore, MD, United States of America.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Romm
authors.affiliation: Rutgers University Cell and DNA Repository (RUCDR), Piscataway, NJ, United States of America.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Brooks
authors.affiliation: School of Nursing, University of California San Francisco, San Francisco, CA, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Aouizerat
authors.affiliation: Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.affiliation: RTI International, Research Triangle Park, NC, Atlanta, GA, San Francisco, CA, United States of America.
authors.forename: Alex H
authors.initials: AH
authors.lastname: Kral
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D003430:Cross-Sectional Studies; D044783:F-Box Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015658:HIV Infections / Q000235:genetics* / Q000503:physiopathology; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D014779:Virus Replication
chemical_list: C000595707:BCL2 protein, human; D002352:Carrier Proteins; D044783:F-Box Proteins; C000595863:FBXO10 protein, human; C532305:Frmpd1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D044767:Ubiquitin-Protein Ligases