Causal relationship between aspirin consumption and heart failure: a Mendelian randomization study

Abstract

Aims: This study aimed to investigate the causal association of aspirin consumption with the risk of heart failure.

Methods: Our study included a total of 218 208 individuals, with 23 397 cases of heart failure. Genetic summary data on the association between single-nucleotide polymorphisms (SNPs) and aspirin consumption were obtained from a large-scale genome-wide association study involving 462 933 individuals, of which 61 702 people were taking aspirin. After the exclusion of critical confounding factors, we assessed the final and independent association between the aspirin consumption and the risk of heart failure using 3 two-sample Mendelian randomization (MR) methods-inverse variance weighted (IVW), weighted-median, and MR-Egger regression. Sensitivity analyses and directionality test were employed to further validate the stability of the results.

Results: After excluding the SNPs that exhibited associations with potential confounders and harmonizing the data, a total of 32 SNPs were finally selected for MR analysis from the initially identified 60 SNPs that displayed strong associations with the exposure. The results of the main method (IVW) showed a significant positive association between aspirin use and the occurrence of heart failure (OR [odds ratio]: 1.085; 95% CI [confidence interval]: 1.015-1.161; P = 0.017), although other methods did not showed statistically significant results (MR-Egger, OR: 1.211, 95% CI: 0.842-1.21, P = 0.896; weighted-median, OR: 1.087, 95% CI: 0.983-1.202, P = 0.105). Heterogeneity test, the MR-Egger intercept, and the funnel plot did not reveal any evidence of heterogeneity (Cochran's Q statistic = 29.263; P = 0.556) or horizontal pleiotropy (intercept = 0.007; P = 0.319). The 'leave-one-out' analysis indicated that no individual SNP exerted a dominant influence on the main estimate. Directionality test confirmed the accuracy of the causal relationship between exposure and outcome direction in our data.

Conclusions: Our results support a potential positive causal relationship between aspirin consumption and the occurrence of heart failure.

Keywords: Aspirin; Heart failure; Mendelian randomization; Primary prevention.

Figure 1

Schematic overview of MR (Mendelian randomization) study design. The standard MR framework. MR hinges upon three fundamental assumptions to enable causal inference: (1) the relevance assumption, which posits an association between genetic variants and aspirin consumption; (2) the independence assumption, which asserts that the genetic variants are independent of confounders; (3) the exclusion restriction assumption, also known as the ‘no pleiotropy’ assumption, which states that the genetic variants affect the outcome solely through the exposure of interest. BMI, body mass index; MI, myocardial infarction; CAD, coronary artery disease; IHD, ischaemic heart disease; IVs, instrumental variables; IVW, inverse‐variance weighted; LD, linkage disequilibrium; SNP, single nucleotide polymorphism.

Figure 2

Forest plot of the causal effects of SNPs associated with aspirin consumption on heart failure. The significance of red lines below are the results of MR‐Egger test and IVW method.

Figure 3

Scatter plots of genetic associations with aspirin consumption against the genetic associations with heart failure. The slopes of each line depict the causal association estimated by different methods. The blue line represents the estimate derived from the IVW method, the dark blue line represents the MR‐Egger method and the green line means the weighted‐median method.