Causal role of circulating inflammatory proteins in Angina pectoris: a bidirectional Mendelian randomization study with mediator insights

Abstract

Background: Angina pectoris (AP), characterized by retrosternal chest pain, pressure, or discomfort, serves as a prognostic indicator for significant cardiac adverse events and has been associated with numerous inflammatory mechanisms in prior research. Nevertheless, the precise causal connection between AP and diverse circulating inflammatory proteins remains inadequately elucidated. Methods: This study used a thorough two-sample Mendelian randomization analysis to determine the causal link between inflammatory proteins in the blood and AP. We used public genetic data to study the link between 91 inflammatory cytokine signatures and susceptibility to AP. Furthermore, we employed a two-step MR approach, incorporating data from 1400 metabolites, to explore potential mediators in the relationship between circulating inflammatory proteins and AP. A comprehensive sensitivity analysis was conducted to ascertain the validity of the findings, considering factors such as robustness, pleiotropy, and heterogeneity. Results: Following the application of the false discovery rate (FDR) correction (P < 0.05), it was determined that circulating inflammatory proteins exhibited a significant impact on AP. In our study, one circulating inflammatory protein was identified as negatively associated with AP risk significance: interleukin-10. In addition, we examined 5 circulating inflammatory proteins with no statistically significant effect of AP, but it is worth mentioning that they had an unadjusted low P-value phenotype. Two of them, respectively, leukemia inhibitory factor, interleukin−4 have a negative effect on the incidence of AP, whereas the remaining three, interleukin−20 ，interleukin−22 receptor subunit alpha−1, neurotrophin−3 have a positive effect on the incidence of AP. At the same time, we also detected the effects of AP on three circulating inflammatory proteins after multiple FDR correction adjustments. They are t−cell surface glycoprotein CD5, interleukin−10 receptor subunit beta, and interleukin−18 receptor 1. We also examined the effect of a circulating inflammatory proteins called hepatocyte growth factor on AP without statistical significance, but its P FDR <0.2. They all showed a downward trend after the onset of AP. Conclusions: As a result of our study, it was demonstrated that circulating inflammatory proteins are closely associated with AP via genetic means, which provides guidance for future clinical studies. This finding provides evidence for the prevention and treatment of AP with drug therapy targeting circulating inflammatory proteins. Further exploration is needed to verify the clinical significance of the association of circulating inflammatory proteins with the risk of AP development.