Evaluating the relationship between alcohol consumption, tobacco use, and cardiovascular disease: A multivariable Mendelian randomization study

Abstract

Background Alcohol consumption and smoking, 2 major risk factors for cardiovascular disease (CVD), often occur together. The objective of this study is to use a wide range of CVD risk factors and outcomes to evaluate potential total and direct causal roles of alcohol and tobacco use on CVD risk factors and events. Methods and findings Using large publicly available genome-wide association studies (GWASs) (results from more than 1.2 million combined study participants) of predominantly European ancestry, we conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of alcohol consumption and smoking on a wide range of CVD risk factors and outcomes. Multiple sensitivity analyses, including complementary Mendelian randomization (MR) methods, and secondary alcohol consumption and smoking datasets were used. SVMR showed genetic predisposition for alcohol consumption to be associated with CVD risk factors, including high-density lipoprotein cholesterol (HDL-C) (beta 0.40, 95% confidence interval (CI), 0.04–0.47, P value = 1.72 × 10−28), triglycerides (TRG) (beta −0.23, 95% CI, −0.30, −0.15, P value = 4.69 × 10−10), automated systolic blood pressure (BP) measurement (beta 0.11, 95% CI, 0.03–0.18, P value = 4.72 × 10−3), and automated diastolic BP measurement (beta 0.09, 95% CI, 0.03–0.16, P value = 5.24 × 10−3). Conversely, genetically predicted smoking was associated with increased TRG (beta 0.097, 95% CI, 0.014–0.027, P value = 6.59 × 10−12). Alcohol consumption was also associated with increased myocardial infarction (MI) and coronary heart disease (CHD) risks (MI odds ratio (OR) = 1.24, 95% CI, 1.03–1.50, P value = 0.02; CHD OR = 1.21, 95% CI, 1.01–1.45, P value = 0.04); however, its impact was attenuated in MVMR adjusting for smoking. Conversely, alcohol maintained an association with coronary atherosclerosis (OR 1.02, 95% CI, 1.01–1.03, P value = 5.56 × 10−4). In comparison, after adjusting for alcohol consumption, smoking retained its association with several CVD outcomes including MI (OR = 1.84, 95% CI, 1.43, 2.37, P value = 2.0 × 10−6), CHD (OR = 1.64, 95% CI, 1.28–2.09, P value = 8.07 × 10−5), heart failure (HF) (OR = 1.61, 95% CI, 1.32–1.95, P value = 1.9 × 10−6), and large artery atherosclerosis (OR = 2.4, 95% CI, 1.41–4.07, P value = 0.003). Notably, using the FinnGen cohort data, we were able to replicate the association between smoking and several CVD outcomes including MI (OR = 1.77, 95% CI, 1.10–2.84, P value = 0.02), HF (OR = 1.67, 95% CI, 1.14–2.46, P value = 0.008), and peripheral artery disease (PAD) (OR = 2.35, 95% CI, 1.38–4.01, P value = 0.002). The main limitations of this study include possible bias from unmeasured confounders, inability of summary-level MR to investigate a potentially nonlinear relationship between alcohol consumption and CVD risk, and the generalizability of the UK Biobank (UKB) to other populations. Conclusions Evaluating the widest range of CVD risk factors and outcomes of any alcohol consumption or smoking MR study to date, we failed to find a cardioprotective impact of genetically predicted alcohol consumption on CVD outcomes. However, alcohol was associated with and increased HDL-C, decreased TRG, and increased BP, which may indicate pathways through impact CVD risk, warranting further study. We found smoking to be a risk factor for many CVDs even after adjusting for alcohol. While future studies incorporating alcohol consumption patterns are necessary, our data suggest causal inference between alcohol, smoking, and CVD risk, further supporting that lifestyle modifications might be able to reduce overall CVD risk.

Consensus and Controversy in the Debate over the Biphasic Impact of Alcohol Consumption on the Cardiovascular System

“…By implementing a 2-sample Mendelian randomization design and analyzing data of genome-wide association studies, including more than 1.2 million participants, Rossof et al failed to prove a genetic basis for a cardioprotective effect of ethanol consumption on CVD risk factors and outcomes. This research supports the increasing evidence that the beneficial impact of low to moderate-alcohol intake previously reported by several studies might be the results of concomitant healthier lifestyles [12].…”

Lifestyle, cardiometabolic disease, and multimorbidity in a prospective Chinese study

“…Fourth, the observational nature of our study precluded causal inference. However, the casual associations of LFs with single CMDs are supported by emerging evidence from prospective cohort studies, 10 , 32 Mendelian randomization studies, 33 , 34 and randomized controlled trials. 35 , 36 Nevertheless, the casual roles of modifiable LFs in the prognosis of CMDs need further research.…”

Cannabis Use and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study

“…In addition, GWAS of cannabis use reported a strong genetic correlation between cannabis use and cigarette smoking ( 17 ). A previous MR study found that smoking is a risk factor for several CVD outcomes, including MI, HF, and large artery atherosclerosis ( 47 ). By analyzing data of 3,117 participants with artery calcium measurements, Auer et al found that cannabis use was associated with subclinical atherosclerosis, but only among ever tobacco users ( 48 ).…”