Sonia Ruiz

Variations in a single DNA nucleotide — the smallest subunit of DNA — could impact how smokers experience nicotine withdrawal, according to a new Yale study.

Researchers at the Yale Department of Psychiatry, in conjunction with the Veterans Affairs Connecticut Healthcare System and the Boston University School of Medicine, have pinpointed genetic factors — three DNA single nucleotide variations, or polymorphisms — that affect the severity of nicotine withdrawal. After conducting a scan of tobacco smokers’ genomes, the team determined that these polymorphisms code for protocadherin, a cellular adhesion protein. Although protocadherin’s exact role in nicotine dependence has yet to be determined, the study offers further insight into the molecular basis for nicotine addiction, which could lead to more effective smoking cessation treatment.

“If [people who are trying to quit smoking] develop withdrawal symptoms, it increases their risk of relapse, so it’s important to know about the biological mechanisms,” said lead study author Kevin Jensen, Yale associate research scientist in psychiatry and VA health-science specialist. “This new information could be used to understand the biological processes involved and potentially be used to build new models of how [nicotine withdrawal] works and develop new treatments.”

According to Jensen, prior studies have shown that individual responses to nicotine withdrawal are a genetically inherited trait. However, he said, the study, which was published on April 12 in the journal Molecular Psychiatry, is one of the first to use a genomewide scan to find cellular evidence that nicotine withdrawal is genetically inherited. Marina Picciotto, a psychiatry professor and researcher at the Center for Nicotine and Tobacco Use Research at Yale who was unaffiliated with the study, lauded the team’s decision to employ a genome scan in their study.

“A genomewide study doesn’t have assumptions ahead of time on what [the researchers] might find, so the things they do find can be completely novel, like the protocadherin cluster,” she said.

After the genome scan, the research team decided to focus their efforts on one of the three polymorphisms, which had already been analyzed extensively in previous genomic studies. They conducted a separate laboratory study, which involved giving smokers an intravenous nicotine infusion after a night of abstaining from smoking. Following the nicotine infusion, smokers with the polymorphism displayed a greater decrease in the urge to smoke than patients without the polymorphism. This greater alleviation in the urge to smoke indicates that the person with the polymorphism is more dependent on nicotine. This can also lead to a higher risk of relapse if they try to quit.

The study’s findings have many implications for research on nicotine dependence, according to the researchers. For example, the DNA polymorphism could predict better responses to nicotine replacement therapies, such as the nicotine patch, said Director of Yale’s Division of Substance Abuse Research Stephanie O’Malley, who was not affiliated with the study.

The researchers also suggested investigating further the relationship between the protocadherin protein and nicotine dependence. Picciotto, whose research focuses on the molecular basis of nicotine addiction, said there are many roles protocadherin could play in nicotine uptake. The altered protocadherin could influence the strength of signaling in existing neurons, or it could affect the development of neurons in embryonic cells, she said, while hypothesizing future avenues of research. According to Department of Psychiatry Chair John Krystal MED ’84, who was not affiliated with the study, the gene variant could be studied in relation to smoking-related cancer, which often involves cadherin proteins. The most intensive studies of nicotine effects on cadherins thus far have been related to cancer, he added.

Jensen said his team hopes to conduct more extensive genetic analyses to expand understanding of these polymorphisms.

“We could potentially discover more variance with larger samples,” he said. “This is just one of probably hundreds of thousands of variances that could potentially have a role and be informative [in assessing nicotine dependence].”

According to the Centers for Disease Control and Prevention, 16.8 percent of American adults were regular cigarette smokers in 2014.