Causal Relationship Between Matrix Metalloproteinase with Their Tissue Inhibitors and Human Immunodeficiency Virus Infection: A Two-Sample Bidirectional Mendelian Randomization Analysis

Abstract

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.