Circulating levels of cytokines and risk of cardiovascular disease: a Mendelian randomization study

Front Immunol. 2023 May 25:14:1175421. doi: 10.3389/fimmu.2023.1175421. eCollection 2023.

Abstract

Background: Epidemiological studies have linked various circulating cytokines to cardiovascular disease (CVD), which however remains uncertain whether these relationships represent causality or are due to bias. To address this question, we conducted a Mendelian randomization (MR) analysis to systematically investigate the causal effects of circulating cytokine levels on CVD development.

Methods: This study leveraged the summary statistic from respective genome-wide association study (GWAS) of 47 cytokines and four types of CVD. The cis-quantitative trait locus (cis-QTL) definition, derived from a GWAS meta-analysis comprising 31,112 participants of European descent, served as instruments for cytokines. A two-sample MR design was employed, followed by comprehensive sensitivity analyses to validate the robustness of results.

Results: The results of inverse-variance weighted method using cis-protein QTL (cis-pQTL) instruments, showed the causal effects of four cytokines (i.e., IL-1ra, MCSF, SeSelectin, SCF) on the risk of coronary artery disease (CAD). We also identified causal relationships between two cytokines (i.e., IL-2ra, IP-10) and heart failure (HF), as well as two cytokines (i.e., MCP-3, SeSelectin) and atrial fibrillation (AF), after controlling for false discovery rate (FDR). The use of cis-expression QTL (cis-eQTL) revealed additional causal associations between IL-1a, MIF and CAD, between IL-6, MIF, and HF, as well as between FGFBasic and AF. No significant sign was survived for stroke with FDR applied. Results were largely consistent across sensitivity analyses.

Conclusion: The present study provides supportive evidence that genetic predisposition to levels of certain cytokines causally affects the development of specific type of CVD. These findings have important implications for the creation of novel therapeutic strategies targeting these cytokines as a means of preventing and treating CVD.

Keywords: European; Mendelian randomization; cardiovascular disease; circulating cytokines; cis-quantitative trait locus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atrial Fibrillation*
  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / genetics
  • Coronary Artery Disease*
  • Genome-Wide Association Study
  • Heart Failure*
  • Humans
  • Mendelian Randomization Analysis

Grants and funding

This study was supported by the Qin Chuangyuan Traditional Chinese Medicine Innovation Research and Development Transformation Project (No.2022-QCYZH-022), Key Program for the Traditional Chinese Medicine Inheritance and Innovation and “Qin Medicine” Development [No. 2021-03-22-001], the Key Basic Natural Science Foundation of Shaanxi Province [No. 2022JZ-47], the Key Industrial Innovation Chain Project in Shaanxi Province of China [No. 2021ZDLSF02-03 and 2020ZDLSF01-08], the Shaanxi Provincial Health and Health Research Fund Project [No. 2022D024], and the Natural Science Foundation of Shaanxi Province [No.2023-YBSF-086 and No.2021JQ-911].