Causal Relationship Between Matrix Metalloproteinase with Their Tissue Inhibitors and Human Immunodeficiency Virus...

Studies have shown an association between matrix metalloproteinases (MMPs) along with tissue inhibitors of MMPs (TIMP) and human immunodeficiency virus (HIV) infection and CD4⁺ T cell count, a key clinical indicator for HIV progression, but the causality remains unclear. This study aimed to investigate the bidirectional causal relationship between MMPs/TIMP and HIV. A genome-wide association study-based two-sample bidirectional Mendelian randomization (MR) analysis was conducted to elucidate the potential causal links between MMPs/TIMP and HIV. This approach utilized robust estimators, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. Furthermore, sensitivity analyses including Cochran's Q, MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO) tests were employed to assess heterogeneity and pleiotropic effects. The IVW analysis in the forward MR study indicated that genetically predicted levels of MMP-3 [odds ratio or OR (95% confidence interval or CI) = 0.69 (0.47-1), p = .047], MMP-20 [OR (95% CI) = 0.64 (0.43-0.97), p = .035], and TIMP-2 [OR (95% CI) = 0.68 (0.47-0.97), p = .034] were potentially associated with a lower risk of HIV. MMP-13 exhibited a genetically predicted association with a higher risk of HIV [OR (95% CI) = 2 (1.17-3.41), p = .011]. Additionally, MMP-19 demonstrated a genetic association with CD4⁺ T cell absolute count [OR (95% CI) = 0.90 (0.81-1.00), p = .042). The reverse MR analysis indicated that genetically predicted liability to HIV was associated with a higher level of MMP-1 [OR (95% CI) = 1.04 (1.01-1.08), p = .024]. Heterogeneity and horizontal pleiotropy were found between MMP-9 and HIV by Cochran's Q test and MR-Egger, but MR-PRESSO indicated no outliers. This study revealed a complex MMPs-TIMPs interplay influencing HIV risk. Future research should clarify underlying mechanisms.