Failure to Quit Smoking Attributed to Genetics

By Michael Smith
BALTIMORE, 04 jun 2008-- Smokers who can't seem to quit no matter how hard they try may look to their genomes for 99 reasons, researchers here said.
Ninety-nine autosomal genes are differently expressed in those who successfully quit smoking in clinical trials than in those who couldn't do it, according to George Uhl, M.D., Ph.D., of the NIH's molecular neurobiology branch, and colleagues.
The findings are based on genome-wide association studies of 550 smokers taking part in trials that tested either nicotine replacement therapy or bupropion (Zyban), Dr. Uhl and colleagues reported in the June issue of Archives of General Psychiatry.
The study "helps us understand why some people are able to quit smoking more easily than others," Dr. Uhl said. It may one day allow clinicians to match smokers with particular cessation treatments.
The researchers analyzed blood samples from three cohorts:
Participants in a double-blind placebo-controlled trial of bupropion or an open-label trial of a nicotine nasal spray versus a nicotine patch. The 126 volunteers who were biochemically confirmed to have abstained from smoking for at least seven days before the end of treatment and at a 24-week assessment were contrasted with the 140 smokers who were not abstinent at either time.
Those in a placebo-controlled trial of nicotine skin patches. Fifty-five participants were confirmed by carbon monoxide levels to be abstinent six weeks after the quit date and 79 were not.
Individuals in a second double-blind placebo-controlled trial of bupropion, in which smoking cessation was assessed using point abstinence, defined by self-reporting and saliva cotinine levels. The 60 participants with biochemically confirmed abstinence for at least seven days before the end of treatment and at a 24-week assessment were contrasted with the 90 individuals who were not abstinent at either time.
Dr. Uhl and colleagues looked for clusters of single-nucleotide polymorphisms (SNPs) in more than two independent samples that had significant P-values based on Monte Carlo simulation trials.
The 99 genes they identified are likely to alter cell adhesion, enzymatic, transcriptional, structural, and DNA, RNA, or protein-handling functions, Dr. Uhl and colleagues reported.
Among those, 41 were specific for bupropion and 26 for nicotine replacement therapy, the researchers found. The finding makes sense because the two cessation approaches have different biochemical mechanisms, Dr. Uhl and colleagues said.
"This takes us a big step forward in being able to tailor treatment to individual smokers to provide the therapies that are most likely to benefit them," said co-author Jed Rose, Ph.D., director of Duke's Center for Nicotine and Smoking Cessation Research.
"In a few years, a simple blood test may provide physicians with enough information to recommend one treatment over another," Dr. Rose said.
The genes identified in the study overlapped -- but weren't identical -- with genes found in studies looking at who develops an addiction in the first place, Dr. Uhl and colleagues found. In fact, the authors reported less overlap for smokers than other substances to which dependency develops.
For instance, cadherin 13, a cell adhesion molecule, is expressed in neurons in several brain regions, can inhibit neurite extension, and can activate several signaling pathways, "rendering it a strong candidate for roles in brain mechanisms important for both developing and quitting addictions," the researchers said.
The study may be limited by its relatively small sample size, Dr. Uhl and colleagues said, and by its focus on autosomal genes, which may miss sex-related differences. Also, participants were in "demanding" clinical trials, indicating they may not be representative of all smokers.
The study was supported by the NIH, the Pennsylvania Department of Health, and GlaxoSmithKline, Inc. Dr. Uhl reported that several authors may have proprietary interests in a provisional patent filed (after the study was accepted) by Duke University related to the use of genetic markers to predict smoking cessation success.
Primary source: Archives of General PsychiatrySource reference:Uhl GR, et al "Molecular genetics of successful smoking cessation: convergent genome-wide association study results" Arch Gen Psychiatry 2008; 65(6): 683-693.