Smoking and heart failure: a Mendelian randomization and mediation analysis

Area of Science:

• Cardiovascular Genetics
• Epidemiology
• Public Health

Background:

• Smoking is a major modifiable risk factor for cardiovascular diseases.
• The causal relationship between various smoking behaviors and heart failure (HF) risk requires further elucidation.
• Understanding genetic predispositions to smoking can provide insights into HF etiology.

Purpose of the Study:

• To investigate the associations between genetic liability to different smoking phenotypes and the risk of heart failure (HF).
• To assess the causal impact of ever smoking, smoking duration, and smoking cessation on HF incidence using Mendelian randomization.
• To explore potential mediation effects of coronary artery disease and atrial fibrillation in the smoking-HF relationship.

Main Methods:

• Mendelian randomization (MR) study design utilizing large-scale genome-wide association studies.
• Genetic variants for smoking initiation, intensity (cigarettes per day), and cessation were sourced from the GWAS and Sequencing Consortium of Alcohol and Nicotine Use (1.2 million individuals) and UK Biobank (462,690 individuals).
• HF associations were analyzed in the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium (47,309 cases; 930,014 controls) using inverse variance-weighted meta-analysis and multivariable MR, with mediation analyses performed.

Main Results:

• Genetic liability to ever smoking was strongly associated with an increased risk of HF (OR, 1.28; P < 1.5 × 10^-18).
• Higher genetic predisposition for smoking more cigarettes per day (OR, 1.37; P = 6.4 × 10^-6) and a greater lifetime smoking burden (OR, 1.49; P = 2.5 × 10^-9) were linked to elevated HF risk.
• Current smokers showed a higher HF risk compared to former smokers (OR, 1.25; P = 1.6 × 10^-3), and these associations remained robust after adjusting for HF risk factors and were independent of coronary artery disease and atrial fibrillation.

Conclusions:

• Genetic predisposition to ever smoking and a higher lifetime smoking burden are significantly associated with an increased risk of heart failure.
• The findings support a causal role for smoking in the development of HF.
• These results underscore the importance of smoking cessation for cardiovascular health and HF prevention.