Assessing the Association Between Age at First Sexual Intercourse and HIV Infection Risk Using A Two-sample Mendelian Randomization Framework.

This study applied a two-sample Mendelian randomization framework to investigate the potential association between age at first sexual intercourse (AFS) and the risk of Human Immunodeficiency Virus (HIV) infection. Summary-level Genome-Wide Association Study (GWAS) data from European populations were analyzed, including 214,547 individuals for AFS and 357 HIV cases with 218,435 controls from the FinnGen R5 dataset. Independent single-nucleotide polymorphisms significantly associated with AFS were selected as instrumental variables following linkage disequilibrium clumping and instrument-strength assessment. Causal estimates were evaluated using inverse-variance weighting (IVW), MR-Egger regression, weighted median, weighted mode, and simple mode. Cochran's Q test, MR-Egger intercept analysis, MR-PRESSO assessment, and leave-one-out sensitivity analyses were performed to evaluate heterogeneity, pleiotropy, and robustness. The IVW analysis suggested that genetically predicted later AFS was associated with reduced HIV infection risk (OR = 0.192, 95% CI = 0.062-0.592, P = 0.004), whereas earlier sexual debut corresponded to increased HIV susceptibility. Directionally consistent findings across multiple Mendelian randomization methods supported the stability of the observed association. However, the findings should be interpreted cautiously because the HIV outcome analysis relied on a single dataset with a limited number of HIV cases. These results support a potential association between earlier sexual debut and HIV susceptibility and demonstrate the utility of Mendelian randomization for investigating behavioral risk factors associated with infectious disease outcomes.