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.

Genome-wide association study identifies 17 new loci influencing concentrations of circulating cytokines and growth factors

“…Plasma IL16 levels have previously been associated to HIV progression 34 , but the locus has not been linked to HIV-related traits in GWAS 35 . This might be due to the small allele frequency in Europeans or possible recessive effects.…”

Psoriasis risk SNPs and their association with HIV-1 control

“…For this study, we used the dataset of 366 HIV+ cases of European descent and the 621 HIV+ cases of African American descent that was available through the database of Genotypes and Phenotypes dbGaP. [9]…”

Associations of common variants in the BST2 region with HIV-1 acquisition in African American and European American people who inject drugs

“…A subset of self-reported AA and EA HIV+ cases and HIV- controls with stored serum samples were selected for genotyping [19]. HIV+ cases were frequency-matched to approximately two HIV- controls, based on HIV risk class, self-reported ancestry, sex, age, and year of ascertainment.…”

“…As described elsewhere for this study [19], the Rutgers Cell and DNA Repository extracted gDNA from serum without additional whole genome amplification. The Center for Inherited Disease Research (CIDR) at the Johns Hopkins University, performed restoration of the samples using the Illumina Formalin-Fixed Paraffin-Embedded kit to improve gDNA quality and then performed genotyping using the Illumina HumanOmni1Quad BeadChip with a reagent substitute from Illumina.…”