Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad 44000, Pakistan.
Department of Biomedical Engineering and Sciences, School of Mechanical and Manufacturing Engineering (SMME), National University of Sciences and Technology (NUST), H-12, Islamabad 44000, Pakistan.
Infect Genet Evol. 2020 Nov;85:104514. doi: 10.1016/j.meegid.2020.104514. Epub 2020 Aug 27.
Host genetic variability interplays with the environment and variegating viral factors to determine the outcome in HIV-1/AIDS. Several GWAS studies have reported that genetic heterogeneity of individuals leads to differential HIV susceptibility. Proxy SNPs that are in Linkage Disequilibrium to the GWAS SNPs could be important targets in HIV pathogenesis and need to be analyzed further for their potential regulatory role. Current study thus aimed to identify novel proxy SNPs that may play a critical role in HIV susceptibility and disease progression. 372 SNPs, associated with HIV-1/AIDS pathogenesis, were retrieved via GWAS catalogue. 1854 proxy SNPs, in Linkage Disequilibrium (r = 0.8) to the GWAS reported SNPs, were identified using the SNAP web tool. Regulatory functions of aforementioned 1854 polymorphic sites (GWAS SNPs and their proxy SNPs) were acquired from RegulomeDB. 178 of the proxy SNPs showed evidence of strong regulatory potential returning a score of ≤3. Among these regulatory SNPs, 22 had already been reported for their association with HIV/AIDS while 156 SNPs showed novel association. Three of these novel SNPs (g.rs6457282T>C, g.rs17064977C>T and g.rs3130350G>T) were validated using sequence specific PCR (SSP-PCR) on HIV-infected patients. For g.rs6457282T>C and rs17064977C>T, CT genotype was determined to be significantly associated with increased risk of HIV-1 infection (rs6457282T>C: OR = 9.5, 95% CI = 3.0792-29.3099, p = 0.0001; rs17064977C>T: OR = 8.1077, 95% CI = 3.1125-21.119, p = 0.0001). Moreover, the association of interacting protein partners of affected genes with HIV-1 elucidates the significance of corresponding SNPs in HIV disease outcome that further needs to be functionally deciphered.
宿主遗传变异性与环境和多样化的病毒因素相互作用，决定了 HIV-1/AIDS 的结局。几项全基因组关联研究报告称，个体的遗传异质性导致 HIV 易感性的差异。与全基因组关联研究 SNP 处于连锁不平衡的替代 SNP 可能是 HIV 发病机制中的重要靶点，需要进一步分析其潜在的调节作用。因此，本研究旨在确定可能在 HIV 易感性和疾病进展中起关键作用的新型替代 SNP。通过全基因组关联研究目录，共检索到与 HIV-1/AIDS 发病机制相关的 372 个 SNP。使用 SNAP 网络工具，确定了 1854 个与全基因组关联研究报告的 SNP 处于连锁不平衡（r=0.8）的替代 SNP。上述 1854 个多态性位点（全基因组关联研究 SNP 及其替代 SNP）的调节功能从 RegulomeDB 获得。178 个替代 SNP 显示出较强的调节潜力，得分≤3。在这些调节 SNP 中，有 22 个已经被报道与 HIV/AIDS 相关，而 156 个 SNP 显示出了新的相关性。其中三个新的 SNP（g.rs6457282T>C、g.rs17064977C>T 和 g.rs3130350G>T）通过对 HIV 感染患者进行序列特异性 PCR（SSP-PCR）进行了验证。对于 g.rs6457282T>C 和 rs17064977C>T，CT 基因型被确定与 HIV-1 感染的风险增加显著相关（rs6457282T>C：OR=9.5，95%CI=3.0792-29.3099，p=0.0001；rs17064977C>T：OR=8.1077，95%CI=3.1125-21.119，p=0.0001）。此外，受影响基因的相互作用蛋白伴侣与 HIV-1 的关联阐明了相应 SNP 在 HIV 疾病结局中的重要性，这需要进一步从功能上进行破译。
