Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases: A Mendelian Randomization Study

Abstract

Importance: Smoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood. Objective: To determine the effect of smoking on risk of coronary artery disease, peripheral artery disease, and large-artery stroke. Design: Mendelian randomization study using summary statistics from genome-wide associations of smoking (up to 462,690 individuals), coronary artery disease (up to 60,801 cases, 123,504 controls), peripheral artery disease (up to 24,009 cases, 150,983 controls), and large-artery stroke (up to 4,373 cases, 406,111 controls) Setting: Population-based study of primarily European-ancestry individuals Participants: Participants in genome-wide association studies of smoking, coronary artery disease, peripheral artery disease, and stroke. Exposures: Genetic liability to smoking defined by lifetime smoking index: an integrated measure of smoking status, age at initiation, age at cessation, number of cigarettes smoked per day, and declining effect of smoking on health outcomes). Main Outcome Measure: Risk of coronary artery disease, peripheral artery disease, and large-artery stroke. Results: Genetic liability to smoking was associated with increased risk of PAD (OR 2.13; 95% CI 1.78-2.56; P = 3.6 x 10-16), CAD (OR 1.48; 95% CI 1.25-1.75; P = 4.4 x 10-6), and stroke (OR 1.4; 95% CI 1.02-1.92; P = 0.036). Risk of PAD in smokers was greater than risk of large-artery stroke (pdifference = 0.025) or CAD (pdifference = 0.0041). The effect of smoking on ASCVD remained independent from the effects of smoking on traditional cardiovascular risk factors. Conclusions and Relevance: Genetic liability to smoking is a strong, causal risk factor for CAD, PAD, and stroke, although the effect of smoking is strongest for PAD. The effect of smoking is independent of traditional cardiovascular risk factors.

Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association

“…Mendelian randomization analysis has linked genetic liability to smoking to ASCVD, including increased risk of PAD (OR, 2.13 [95% CI, 1.78–2.56]; P =3.6×10 −16 ), CAD (OR, 1.48 [95% CI, 1.25–1.75]; P =4.4×10 −6 ), and stroke (OR, 1.40 [95% CI, 1.02–1.92]; P =0.04). 42…”

Appraising the causal role of smoking in multiple diseases: A systematic review and meta-analysis of Mendelian randomization studies

“…After exclusion of studies using overlapping or same outcome data, 29 articles based on non-overlapping populations were eligible for inclusion in one or more meta-analyses. The number of studies included in each outcome category was seven for circulatory system diseases, 4 , 5 , 6 , 7 , 8 , 9 , 10 six for digestive system diseases, 11 , 12 , 13 , 14 , 15 , 16 six for nervous system diseases, 17 , 18 , 19 , 20 , 21 three for musculoskeletal system outcomes, 22 , 23 , 24 two for endocrine and metabolic diseases, 25 , 26 two for eye diseases, 27 , 28 and four for neoplasms. 29 , 30 , 31 , 32 In addition to the included studies, 123 de novo MR analyses ( n =51 for smoking initiation, n = 72 for lifetime smoking) were conducted.…”

“…During the last few years, the potential causal association between smoking and risk of different diseases has been investigated using the Mendelian randomization (MR) approach. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 MR is a method that utilizes genetic variants associated with a difference in the exposure (e.g., smoking liability) as instrumental variable for the exposure to determine the causal role of the exposure in the development of disease. 33 The MR design mitigates confounding because genetic alleles are randomly allocated when passed from parents to offspring and therefore usually not related to other risk factors.…”

Genetic Variation in Blood Pressure and Lifetime Risk of Peripheral Artery Disease: A Mendelian Randomization Study

“…While broad recommendations for lifestyle modification and treatment of ASCVD risk factors are clearly important at both the population level and individual level, understanding the impact of interventions on specific ASCVD outcomes may further inform treatment and prevention guidelines and discussions with patients. Particularly in light of our recent finding that smoking more strongly increases risk of PAD in comparison to CAD or ischemic stroke (28), this study adds further nuance to the relationship between traditional ASCVD risk factors and specific ASCVD outcomes.…”