Genetic Liability to Smoking Linked to Atherosclerotic Cardiovascular Disease

Michael G. Levin, MD

While smoking is linked to atherosclerotic cardiovascular disease (ASCVD), the relative contribution to each subtype is not entirely understood.

A team, led by Michael G. Levin, MD, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, determined the link between genetic liability to smoking and the risk of coronary artery disease (CAD), peripheral artery disease (PAD), and large-artery stroke.

In the mendelian randomization study, the investigators used summary statistics from genome-wide associations of smoking from the UK Biobank (n = 462,690), Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium (n = 60,801 cases, n = 123,504 controls), VA Million Veteran Program (n = 24,009 cases, n = 150,983 controls), and MEGASTROKE (n = 4373 cases, n = 406,111 controls).

The investigators sought main outcomes of risk, defined as odds ratios (OR) of CAD, PAD, and large-artery stroke.

The researchers used 2 measures for smoking throughout the study—lifetime smoking index and smoking initiation. The primary measure of smoking was lifetime smoking index, which was previously validated continuous measure that accounts for self-reported smoking status, age at initiation, age at cessation, number of cigarettes smoked per day, and a simulated half-life constant that captures the decreasing effect of smoking on health outcomes following a given exposure.

Link Between ASCV and Smoking

The investigators found genetic liability to smoking was linked to an 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).

The team also found the genetic liability to smoking was associated with a greater risk of PAD than risk of large-artery stroke (ratio of OR, 1.52; 95% CI, 1.05-2.19; P = 0 .02) or CAD (ratio of OR, 1.44; 95% CI, 1.12-1.84; P = 0 .004).

The link between genetic liability to smoking and atherosclerotic cardiovascular diseases was independent from the effects of smoking on traditional cardiovascular risk factors.

“In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD,” the authors wrote. “The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.”

The Dangers of Smoking

Atherosclerotic cardiovascular disease impacts a number of vascular beds throughout the body, with clinical manifestations. Smoking tobacco is consistently among the leading risk factors for atherosclerotic cardiovascular disease.

Smoking also had independent effects on inflammation, endothelial function, and platelet aggregation, but it is unknown whether the effect of smoking on atherosclerotic cardiovascular disease is primarily mediated through correlated alterations of traditional cardiovascular risk factors or operates through independent mechanisms.

While the detrimental effects of smoking could persist for decades, clarifying the basis of the smoking-atherosclerosis relationship might enable more targeted risk-reduction strategies among both current and former smokers.

The study, “Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases,” was published online in JAMA Network Open.