New study identifies genetic link between smoking and coronary heart disease

By Paul Basilio, MDLinx
Published May 15, 2017

Key Takeaways

Researchers at the Columbia University Medical Center (CUMC) and University of Pennsylvania recently described a genetic link between smoking and coronary heart disease (CHD). Smoking counteracts the protective effect of a common gene type that reduces levels of an enzyme connected to plaque and CHD, according to the study published in the journal Circulation.

“Our findings suggest that interventions to inhibit this enzyme would be particularly beneficial for smokers, and they may also prove useful for anyone at heightened risk of coronary heart disease,” said study leader Muredach P. Reilly, MBBCH, MSCE, the Herbert and Florence Irving Professor of Medicine (in Cardiology) and director of the Irving Institute for Clinical and Translational Research at CUMC.

Cigarette smoking is linked with approximately 1 in 5 CHD cases, but the exact mechanism has not been fully understood.

In this study, investigators pooled genetic data for more than 140,000 people from almost 30 previous studies. They focused on 45 small regions of the genome that was previously associated with an increased risk of CHD. Their hypothesis was that the associated heart risk would be different in smokers and nonsmokers in some of these regions.

Results showed that a single DNA “letter” was changed on chromosome 15, which is near the gene that expresses the enzyme ADAMTS7. ADAMTS7 is produced in blood vessels and is associated with a 12% reduction in heart risk in nonsmokers. However, smokers with this same variation had only a 5% lower risk of CHD, which indicates a reduction of the protective effect of this genetic variation by more than half.

DNA variations located near a gene can occasionally inhibit the gene’s activity, which can lead to below-normal levels of the protein it produces. In this case, the team found that the single-letter DNA variation that protected patients from CHD resulted in a significant decline in the production of ADAMTS7.

In a separate mouse study, Dr. Reilly’s lab recently demonstrated that genetic deletion of ADAMTS7 decreased the buildup of fatty plaques in the arteries, which suggests that blocking the production of production of this enzyme may offer a treatment target to reduce the risk of CHD.

In the current study, ADAMTS7 production nearly doubled when a liquid extract of cigarette smoke was applied to coronary artery cells. This supports the conclusion that smoking could counteract the genetic protection from CHD by increasing the level of ADAMTS7 in the artery wall.

“This has been one of the first big steps towards solving the complex puzzle of gene-environment interactions that lead to CHD,” said lead author Danish Saleheen, PhD, assistant professor of biostatistics and epidemiology at the Perelman School of Medicine at the University of Pennsylvania.

In the future, the research team hopes to describe exactly how the ADAMTS7 protects against CHD, how smoking affects the genetic activity that produces the enzyme, and whether reducing or inhibiting ADAMTS7 can slow the progression of atherosclerosis due to cigarette smoking.

“This study is an important example of the emerging field of precision medicine and precision public health,” said Dr. Reilly. “Through these large-scale genetic studies, we’re beginning to understand the genetic variations that drive risk in response to certain environmental exposures or lifestyle behaviors. Not everyone reacts the same to the same exposures or behaviors. For example, some people who don’t exercise develop diabetes while others do not. So, instead of saying there are rules for everybody, we can specify which interventions will be especially beneficial for specific populations or individuals and focus our health resources more efficiently.”

The study was funded by grants from the National Institutes of Health to Dr. Reilly, the Wellcome Trust, and Pfizer. Dr. Saleheen has received support from Genentech, Regeneron, and Eli Lilly, and Pfizer.

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