Novel association of genetic variants in non-coding regulatory regions with HIV-1 infection

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 (r² = 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.