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Meta-Analysis
. 2021 Jun;8(3):1954-1965.
doi: 10.1002/ehf2.13248. Epub 2021 Mar 3.

Smoking and heart failure: a Mendelian randomization and mediation analysis

Yunlong Lu  1 , Zhouming Xu  2 , Marios K Georgakis  3 , Zhen Wang  1 , Hefeng Lin  4 , Liangrong Zheng  1
Affiliations
Meta-Analysis

Smoking and heart failure: a Mendelian randomization and mediation analysis

Yunlong Lu et al. ESC Heart Fail. 2021 Jun.

Abstract

Aims: We performed a Mendelian randomization (MR) study to elucidate the associations of ever smoking, lifelong smoking duration, and smoking cessation with heart failure (HF) risk.

Methods and results: We extracted genetic variants associated with smoking initiation, age at initiation of regular smoking, cigarettes per day, and smoking cessation from the genome-wide association study and Sequencing Consortium of Alcohol and Nicotine use (1.2 million individuals), as well as a composite lifetime smoking index from the UK Biobank (462 690 individuals). The associations between smoking phenotypes and HF were explored in the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium (47 309 cases; 930 014 controls) employing inverse variance-weighted meta-analysis and multivariable MR. The mediation effects of coronary artery disease and atrial fibrillation on smoking-HF risk were explored using mediation analysis. The odds ratios (ORs) for HF were 1.28 [95% confidence interval (CI), 1.22-1.36; P = 1.5 × 10-18 ] for ever regular smokers compared with never smokers and 1.25 (95% CI, 1.09-1.44; P = 1.6 × 10-3 ) for current smokers vs. former smokers. Genetic liability to smoking more cigarettes per day (OR, 1.37; 95% CI, 1.20-1.58; P = 6.4 × 10-6 ) and a higher composite lifetime smoking index (OR, 1.49; 95% CI, 1.31-1.70; P = 2.5 × 10-9 ) were associated with a higher risk of HF. The results were robust and consistent in all sensitivity analyses and multivariable MR after adjusting for HF risk factors, and their associations were independent of coronary artery disease and atrial fibrillation.

Conclusions: Genetic liability to ever smoking and a higher lifetime smoking burden are associated with a higher risk of HF.

Keywords: Heart failure; Mediation analysis; Mendelian randomization; Smoking.

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Conflict of interest statement

None declared.

Figures

Figure 1
Figure 1
Directed acyclic graph model of the causal effect between smoking and heart failure. AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; DBP, diastolic blood pressure; HDL, high‐density lipoprotein; HTN, hypertension; LDL, low‐density lipoprotein; SBP, systolic blood pressure; T2D, type 2 diabetes mellitus; SNPs, single‐nucleotide polymorphisms; TG, triglyceride.
Figure 2
Figure 2
Mendelian randomization (MR) association of genetically predicted smoking initiation, age at initiation of regular smoking, cigarettes per day, and smoking cessation with heart failure. Odds ratios (ORs) are scaled to per genetically predicted per 2.72‐fold (1 log‐odds unit) increase in the genetic liability to be a regular smoker and current smoker and per 1‐SD increase in the genetic liability of the age at initiation of regular smoking and cigarettes per day. *MR pleiotropy residual sum and outlier (MR‐PRESSO) instrumental variable outlier detected: rs12244388. †No outlier detected. ‡MR‐PRESSO instrumental variable outlier detected: rs10204824 and rs10742683. §MR‐PRESSO instrumental variable outlier detected: rs1611124. CI, confidence interval; IVW, inverse variance weighted; MR‐RAPS, MR robust adjusted profile score.
Figure 3
Figure 3
Mendelian randomization (MR) association between genetically predicted lifetime smoking index and heart failure. Odds ratios (ORs) are scaled to per genetically predicted per 1‐SD increase in the lifetime smoking index. *No outlier detected. CI, confidence interval; IVW, inverse variance weighted; MR‐PRESSO, MR pleiotropy residual sum and outlier; MR‐RAPS, MR robust adjusted profile score.
See this image and copyright information in PMC

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