Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study

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-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.人类免疫缺陷病毒1型（HIV-1）易感性的变异中有50%可归因于宿主遗传学因素。因此，鉴定遗传关联对于解析HIV-1的发病机制以及指导靶向药物开发均具有重要意义。然而截至目前，趋化因子受体5（CCR5）仍是唯一被证实与HIV感染相关的基因。 为鉴定HIV-1感染的新型宿主遗传决定因素，本研究依托城市健康研究（UHS）队列，纳入3136名注射吸毒者（IDUs）组成的高风险样本开展了全基因组关联研究（genome-wide association study）。本研究中，HIV阴性对照除需为注射吸毒者外，还在环境暴露因素上与病例进行频数匹配，以提升遗传效应的检测效能。 我们在妇女间HIV研究（WIHS，N=2533）中开展了独立验证实验。此外，本研究还分析了公开可用的基因表达数据，以将与HIV感染相关的单核苷酸多态性（Single Nucleotide Polymorphism, SNP）与已知的影响HIV复制/感染性的机制关联起来。 对UHS队列的分析筛选出8个遗传区域用于后续验证实验。位于FRMPD1基因内的SNP rs4878712在独立验证中通过了多重检验校正（P=1.38×10⁻⁴）；尽管UHS与WIHS的荟萃分析P值（P=4.47×10⁻⁷）未达到全基因组显著性水平（阈值为P<1×10⁻⁸）。 基因表达分析为rs4878712位点的保护性G等位基因降低HIV感染风险提供了有力的生物学佐证：(1) G等位基因与FBXO10基因的低表达呈显著相关（相关系数r=-0.49，P=6.9×10⁻⁵）；(2) FBXO10是Skp1-Cul1-F-box（SCF）型E3泛素连接酶复合物的组成成分，该复合物可靶向B细胞淋巴瘤因子2（Bcl-2）蛋白使其降解；(3) FBXO10的低表达与BCL2基因的高表达呈显著相关（r=-0.49，P=8×10⁻⁵）；(4) 已有体外细胞实验证实，较高的基础Bcl-2表达水平可降低HIV在人类及动物细胞中的复制能力与感染性。 本研究结果揭示了宿主遗传学通过潜在新生物学通路影响HIV暴露后易感性的机制，可为后续相关研究提供参考方向。