Causal effects between circulating immune cells and heart failure: evidence from a bidirectional Mendelian randomization study

Abstract

Background: Heart failure (HF) is a prevalent cardiac condition characterized by high mortality and morbidity rates. Immune cells play a pivotal role as crucial biomarkers in assessing the overall immune status of individuals. However, the causal relationship between circulating immune cells and the pathogenesis of HF remains an area requiring further investigation.

Objectives: The aim of this study was to investigate the genetic interactions between circulating immune cells and HF, and to further elucidate the genetic associations between different lymphocyte subsets and HF.

Methods: We obtained genetic variants associated with circulating immune cells as instrumental variables (IVs) from the Blood Cell Consortium and publicly available HF summary data. We conducted additional subsets analyses on lymphocyte counts. Our study utilized two-sample and multivariate Mendelian randomization (MVMR) analysis to investigate the causal effect of immune cells on HF. The primary analysis employed inverse variance weighting (IVW) and was complemented by a series of sensitivity analyses.

Results: The findings of the study showed that the IVW model demonstrated a significant correlation between an elevation in lymphocyte count and a decreased risk of HF (OR = 0.97, 95% CI, 0.94 - 1.00, P = 0.032). However, no such correlation was evident in the MVMR analysis for lymphocytes and HF. Furthermore, the examination of the lymphocyte subsets indicated that an increase in CD39⁺ CD4⁺ T-cell counts was notably linked to a reduced risk of HF (OR = 0.96, 95% CI, 0.95 - 0.98, P = 0.0002). The MVMR results confirmed that the association between CD39⁺ CD4⁺ T-cell counts and HF remained significant. There was no substantial evidence of reverse causality observed between circulating immune cells and HF.

Conclusion: Our MR research provided evidence for a causal relationship between lymphocyte cell and HF. Subsets analyses revealed a causal relationship between CD39⁺ CD4⁺ T lymphocytes and HF. These findings will facilitate a future understanding of the mechanisms underlying HF.

Keywords: Heart failure; Immune cell; Inflammation; Lymphocytes; Mendelian randomization.