NEW YORK – Researchers at Vanderbilt University Medical Center are investigating whether a phenotype reflecting CYP2A6 activity can serve as a biomarker for informing smoking cessation treatment strategies.
Variations in the CYP2A6 gene are associated with faster nicotine metabolism in some smokers, predisposing them to smoke more frequently and making it harder for them to quit. Some researchers are now exploring how knowledge of these pharmacogenetic variations can be best utilized to distinguish fast and slow nicotine metabolizers and identify those who need more support to quit cigarettes.
"It's not widely appreciated that smoking actually has a very strong genetic basis," said Scott Lee, an assistant professor at Vanderbilt University Medical Center (VUMC) who studies health behavior change. In fact, based on studies of twins, researchers suspect that the decision to start smoking is linked to both genetic and environmental factors, Lee said.
He noted that smoking remains the primary cause of preventable deaths in the US. While smoking rates among US adults have declined — in 2005, 20.9 percent of adults smoked, compared to 11.5 percent in 2021 — that still leaves millions of smokers, many of whom want to quit, according to data from the US Centers for Disease Control and Prevention.
Nicotine replacement therapy, in which patients use long-acting and short-acting pharmacotherapy to manage withdrawal, is one of the most common smoking cessation approaches. However, it tends to be treated as a one-size-fits-all strategy, without considering genetic factors as part of care management.
Investigators at VUMC believe that a personalized treatment approach may be able to improve smoking cessation rates by targeting support to those who would benefit most from it, such as those with CYP2A6 variations. CYP2A6 encodes an eponymous enzyme responsible for metabolizing nicotine in the liver, variants in which influence how quickly that process occurs.
Early evidence on a personalized smoking cessation strategy derived from this underlying pharmacogenetic association was published in Nicotine & Tobacco Research this spring by investigators at the Vanderbilt Center for Tobacco, Addiction and Lifestyle (ViTAL). Within this program, VUMC conducts clinical trials on smoking cessation, pharmacogenetics, and epidemiology and spearheads clinical and quality improvement initiatives and education programs for staff and patients.
Lee was the first author on that Nicotine & Tobacco Research study, in which researchers retrospectively analyzed data from a randomized clinical trial called Helping HAND 4 that compared smoking cessation support interventions among patients. Lee and colleagues used a nicotine metabolite ratio (NMR) — which captures how fast nicotine breakdown occurs and, thus, a person's CYP2A6 status — to categorize adults who smoked daily and were hospitalized at VUMC as fast or slow nicotine metabolizers. NMR represents the proportion of 3-hydroxycotinine to cotinine, two nicotine metabolites, in the blood.
"It's easier to measure metabolites in blood than to genotype," Lee said of the decision to use the NMR, rather than directly genotyping patients to determine if they carried nicotine metabolism-linked CYP2A6 variations. The NMR also reflects environmental, as well as genetic, influences on nicotine metabolism from factors like estrogen, alcohol, and certain medications, he added.
The team classified 241 participants of the Helping HAND 4 trial who opted to receive NMR measurements as fast metabolizers and 80 as slow metabolizers. Patients, upon being discharged from the hospital, were randomly referred to either the usual smoking cessation pharmacotherapy program in which they were connected with a state quit-line that offered smoking cessation counseling and either free nicotine patches or lozenges by mail, or to a pharmacotherapy program paired with enhanced treatment support in which patients were given free nicotine patches and lozenges at discharge and had access to tobacco treatment counselors at VUMC who could coach them on proper use of the nicotine replacement therapy.
Investigators found that providing fast nicotine metabolizers with additional treatment support doubled their chances of quitting smoking and narrowed the disparity in quit rates between fast and slow metabolizers.
For fast nicotine metabolizers who were offered additional treatment support, 16.8 percent had quit smoking six months after hospital discharge, compared to 25 percent of slow metabolizers and 9.8 percent of fast metabolizers in the usual care arm. In other words, additional support cut the abstinence gap between fast and slow metabolizers in half.
However, the study authors cautioned their results were still too exploratory to influence clinical practice. "We would like to see confirmation of the research in a larger and more diverse sample," Hilary Tindle, an associate professor at VUMC and founding director of ViTAL, as well as a senior author on the Nicotine & Tobacco Research paper, wrote in an email. "The larger issue is that smoking cessation is still, to some extent, practiced without precision."
Tindle is leading another trial at ViTAL that is currently enrolling patients and investigating whether NMR results can be used to target smoking cessation aids. In that trial, dubbed the Metabolism Informed Smoking Treatment (MIST) study, researchers are aiming to recruit 1,000 hospitalized smokers and randomize them, at discharge, to either precision care or usual care.
In the precision care arm, fast metabolizers will be prescribed Pfizer's Chantix (varenicline), a smoking cessation aid that's designed to reduce nicotine cravings, while slow metabolizers are prescribed nicotine replacement therapy. Those assigned to the usual care arm will receive a prescription for either Chantix or nicotine replacement therapy, irrespective of NMR results.
Findings from that study, researchers hope, will continue to inform how variations in nicotine metabolism can inform tailored management strategies for smokers trying to quit.
"We know, with a high level of certainty now, that fast metabolizers both biologically and behaviorally are different from slow metabolizers in ways that make it harder for them to quit smoking," Lee said. "They certainly warrant more support or attention when it comes to clinical interventions — what form that should take is an active area of research."