Nav: Home

Scientists find a likely genetic driver of smoking-related heart disease

May 01, 2017

PHILADELPHIA -- Cigarette smoking accounts for about one fifth of cases of coronary heart disease (CHD), one of the leading causes of death worldwide, but precisely how smoking leads to CHD has long been unclear. Now, a team co-led by researchers from the Perelman School of Medicine at the University of Pennsylvania and Columbia University has uncovered a molecule that may at least partly explain the smoking-CHD connection. Their findings are published this week in the journal Circulation.

The molecule is an enzyme called ADAMTS7 that is normally produced in the linings of blood vessels. Studies in recent years have suggested that when ADAMTS7 is produced in excess, it promotes the buildup of fatty plaque in coronary arteries, leading to CHD. In the team's new study, they discovered that many people have a DNA variation that reduces their production of ADAMTS7 and also apparently lowers their CHD risk. However, carriers of this DNA variation who are smokers loose this natural protection. The study identified the likely reason: smoking appears to boost ADAMTS7 production.

"Findings from this study will hopefully encourage the development of novel therapeutic and preventive programs for CHD, specifically targeting those who smoke," said lead author Danish Saleheen, PhD, an assistant professor of Biostatistics and Epidemiology at Penn. The study is part of a large, ongoing effort by scientists to determine how genetic variants influence CHD risk, either directly or through interactions with behavioral and environmental factors, in this case smoking.

Saleheen and his colleagues pooled DNA data from 29 prior studies, involving more than 140,000 people, making this study the largest ever to study the interaction of genetic variation and smoking. To find clues to smoking's effect on CHD, the scientists examined 45 small regions of the genome--known as loci--that had already been associated with an abnormal risk of CHD.

"Our hypothesis was that for some of these loci, the associated CHD risk would be different in smokers versus non-smokers," Saleheen said. "By identifying the genes involved, we could hopefully discover clues to how smoking promotes CHD."

The analysis revealed that at a certain spot on chromosome 15, very close to the gene for ADAMTS7, a change in a single DNA "letter" -- found in about 40 percent of people of European heritage, for example -- was associated with a 12 percent lower CHD risk in non-smokers. By contrast, smokers with this same DNA variation had only a five percent lower CHD risk, representing a loss of most of the apparent protective effect.

DNA variations that lie just outside of a gene often inhibit the gene's transcription, leading to lower-than-normal levels of the associated protein. In follow-up laboratory experiments, the researchers confirmed that this was the case for the variation they discovered: In cells that line arteries of the human heart, ADAMTS7 production dropped significantly when the cells contained this single-letter DNA variant.

How does smoking modify this effect? In another laboratory experiment, the researchers applied a liquid extract of cigarette smoke to coronary artery-lining cells, and found that the cells' production of ADAMTS7 more than doubled.

ADAMTS7 has been implicated not only in CHD but also in arthritis and some cancers, making it a potential target for treatments for these disorders. The new findings suggest that reducing the activity of this enzyme could be particularly beneficial for smokers. "This has been one of the first big steps towards solving the complex puzzle of gene-environment interactions that lead to CHD," Saleheen said.

Saleheen and colleagues are now planning larger studies to uncover genetic variants that interact with lifestyle factors such as smoking to influence CHD risk.

"We hope that these studies will lead to more cost-effective targeting of existing interventions, identification of new therapeutic targets, and a better understanding of the biology of CHD," he said.
-end-
The study was co-led by Muredach P. Reilly, MD, a former professor of Medicine at Penn and the Herbert and Florence Irving Professor of Medicine in the Department of Cardiology at Columbia University's College of Physicians and Surgeons.

Funding was provided by the National Institutes of Health (R01-HL-111694, K24-HL-107643), the Wellcome Trust, and Pfizer. Saleheen has received support from Genentech, Regeneron and Eli Lilly and Pfizer.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.

University of Pennsylvania School of Medicine

Related Smoking Articles:

Smoking rates falling in adults, but stroke survivors' smoking rates remain steady
While the rate of Americans who smoke tobacco has fallen steadily over the last two decades, the rate of stroke survivors who smoke has not changed significantly.
What is your risk from smoking? Your network knows!
A new study from researchers at Penn's Annenberg School for Communication found that most people, smokers and non-smokers alike, were nowhere near accurate in their answers to questions about smoking's health effects.
Want to quit smoking? Partner up
Kicking the habit works best in pairs. That's the main message of a study presented today at EuroPrevent 2019, a scientific congress of the European Society of Cardiology (ESC).
Smoking and mortality in Asia
In this analysis of data from 20 studies conducted in China, Japan, South Korea, Singapore, Taiwan and India with more than 1 million participants, deaths associated with smoking continued to increase among men in Asia grouped by the years in which they were born.
Predictors of successfully quitting smoking among smokers registered at the quit smoking clinic at a public hospital in northeastern Malaysia
In the current issue of Family Medicine and Community Health, Nur Izzati Mohammad et al. consider how cigarette smoking is one of the risk factors leading to noncommunicable diseases such as cardiovascular and respiratory system diseases and cancer.
Restaurant and bar smoking bans do reduce smoking, especially among the highly educated
Smoking risk drops significantly in college graduates when they live near areas that have completely banned smoking in bars and restaurants, according to a new study in the American Journal of Epidemiology.
How the UK smoking ban increased wellbeing
Married women with children reported the largest increase in well-being following the smoking bans in the UK in 2006 and 2007 but there was no comparable increase for married men with children.
Smoking study personalizes treatment
A simple blood test is allowing Vanderbilt University Medical Center (VUMC) researchers to determine which patients should be prescribed varenicline (Chantix) to stop smoking and which patients could do just as well, and avoid side effects, by using a nicotine patch.
A biophysical smoking gun
While much about Alzheimer's disease remains a mystery, scientists do know that part of the disease's progression involves a normal protein called tau, aggregating to form ropelike inclusions within brain cells that eventually strangle the neurons.
A case where smoking helped
A mutation in the hemoglobin of a young woman in Germany was found to cause her mild anemia.
More Smoking News and Smoking Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Climate Mindset
In the past few months, human beings have come together to fight a global threat. This hour, TED speakers explore how our response can be the catalyst to fight another global crisis: climate change. Guests include political strategist Tom Rivett-Carnac, diplomat Christiana Figueres, climate justice activist Xiye Bastida, and writer, illustrator, and artist Oliver Jeffers.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Speedy Beet
There are few musical moments more well-worn than the first four notes of Beethoven's Fifth Symphony. But in this short, we find out that Beethoven might have made a last-ditch effort to keep his music from ever feeling familiar, to keep pushing his listeners to a kind of psychological limit. Big thanks to our Brooklyn Philharmonic musicians: Deborah Buck and Suzy Perelman on violin, Arash Amini on cello, and Ah Ling Neu on viola. And check out The First Four Notes, Matthew Guerrieri's book on Beethoven's Fifth. Support Radiolab today at Radiolab.org/donate.