The causal effect of matrix metalloproteinase 9 on interstitial lung disease risk mediated by effector memory double negative T cells: A mediation Mendelian randomization study

Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of interstitial lung disease (ILD). However, the causal role of MMPs in ILD pathogenesis remains to be elucidated. This study aimed to investigate the causal effects of circulating MMPs on ILD risk and to evaluate whether immune cell phenotypes mediate this relationship. A comprehensive Mendelian randomization (MR) and mediation analysis was conducted using publicly available data of genome-wide association study (GWAS) summary statistics. Genetic instruments for 6 MMPs (MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-12) and 731 immune cell traits were selected. Inverse-variance weighted (IVW) was the primary analytical method, supplemented by other MR techniques. Sensitivity analyses included MR-Egger regression, Cochran Q test, and MR-PRESSO to assess pleiotropy and heterogeneity. Mediation analysis was performed to quantify the proportion of the effect mediated by significant immune cells. Genetically predicted MMP-9 levels showed a significant positive causal effect on ILD risk (odds ratio [OR] = 1.034, 95% confidence interval [CI]: 1.006-1.064, P = .018). Among 731 immune cell phenotypes, 8 were identified as causal for ILD, including effector memory double negative T cells (EM DNT; OR = 1.170, P = .001). MMP-9 was further found to increase the abundance of EM DNT (OR = 1.041, 95% CI: 1.009-1.074, P = .012). Mediation analysis indicated that EM DNT mediated 18.5% of the total effect of MMP-9 on ILD. Sensitivity analyses revealed no evidence of horizontal pleiotropy or significant heterogeneity. This study provides genetic evidence supporting a causal role of MMP-9 in the development of ILD, partially mediated through EM DNT. These findings suggest that MMP-9 and EM DNT could be potential therapeutic targets for preventing or treating ILD.