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Meta-Analysis
. 2020 Oct 28;20(1):462.
doi: 10.1186/s12872-020-01744-2.

The impact of growth differentiation factor 15 on the risk of cardiovascular diseases: two-sample Mendelian randomization study

Zhuo Wang  1 , Fangkun Yang  1 , Menghuai Ma  1 , Qinyi Bao  1 , Jinlian Shen  1 , Feiming Ye  1 , Xiaojie Xie  2
Affiliations
Meta-Analysis

The impact of growth differentiation factor 15 on the risk of cardiovascular diseases: two-sample Mendelian randomization study

Zhuo Wang et al. BMC Cardiovasc Disord. .

Abstract

Background: Growth differentiation factor 15 (GDF-15), a stress responsive cytokine, belongs to transforming growth factor β cytokine superfamily. Some evidence support that it's involved in inflammation, coagulation, oxidative stress, endothelial dysfunction, and hemostasis. However, it's still controversial whether GDF-15 directly contributes to the morbidity and mortality of patients suffered with cardiovascular disease (CVD). Besides prospective cohort study and randomized controlled trial, Mendelian randomization (MR) is a genetic epidemiological method that exploits genetic variants as unbiased proxies for modifiable to determine the causal relationships between exposures and health outcomes. Herein, we introduced a two-sample MR approach to evaluate the causal relationships of circulating GDF-15 levels with major CVDs incidence.

Methods: Genetic instruments and summary statistics for two-sample MR analysis were obtained from 5 independent large genome-wide association studies (GWAS) to investigate the causal correlation between circulating GDF-15 levels and 9 CVDs, respectively. Conventional inverse variance weighted method was adopted to evaluate the causality of GDF-15 with different outcomes; weighted median and MR egger were used for sensitivity analyses.

Results: Among 9 SNPs identified from 5 GWASs in 2.6 million individuals, 5 SNPs (rs1227731, rs3195944, rs17725099, rs888663, rs749451) coming from chromosome 19 and containing the PGPEP1 and GDF-15 genes were employed. Based on the instruments, circulating GDF-15 levels significantly linked to the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction. However, no significant causal association was observed for circulating GDF-15 levels with the incidence of any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy.

Conclusions: The MR study provides with genetic evidence for the causal relationship of circulating GDF-15 levels with the increased risk of cardioembolic stroke, atrial fibrillation, coronary artery disease and myocardial infarction, but not any ischemic stroke, large-artery atherosclerotic stroke, small vessel stroke, heart failure and nonischemic cardiomyopathy. It indicates that GDF-15 might be a promising biomarker or potential therapeutic target for some CVDs.

Keywords: Atrial fibrillation; Cardioembolic stroke; Cardiovascular diseases; Coronary artery disease; Growth differentiation factor 15; Mendelian randomization; Myocardial infarction.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Forest plot of the relationship between GDF-15 and 9 CVDs. Data are reported as OR (odd ratio) and 95% CI ( confidence interval). AIS any ischemic stroke, CES cardioembolic stroke, LAS large-artery atherosclerotic stroke, SVS small vessel stroke, AF atrial fibrillation, HF heart failure, NICM nonischemic cardiomyopathy, CAD coronary artery disease, MI myocardial infarction
See this image and copyright information in PMC

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