Genes may determine response to nicotine patch

Researchers and experts say study findings are far too preliminary to alter current smoking-cessation strategies, but could lead to more personalized treatment of tobacco addiction.

By Victoria Stagg Elliott — Posted April 12, 2004

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Variations of a gene believed to be a significant player in the brain's reward system and frequently implicated in addiction can impact the effectiveness of nicotine replacement therapy in women, according to a study published online in the British Medical Journal last month.

The same gene variants were found in men, although they did not seem to have the same effect.

Researchers at Oxford University in England genotyped more than 750 people in 1999 and 2000. All had tried to quit smoking as participants in a 1991-1992 nicotine patch trial. Those who claimed to have maintained their nonsmoking status were tested for cotinine levels for confirmation.

At the eight-year mark, 12% of women with the CT or TT allele of the dopamine D2 receptor gene who had received the patch had remained abstinent. Only 5% of women with the CC allele had maintained their nonsmoking status. No difference based on genetics was noted in men.

"If it's replicated, and it's a genuine finding, then doctors will be able to genotype patients before recommending smoking cessation, and that would be very helpful and save people time, money, upset and disappointment," said Patricia Yudkin, PhD, lead author and a professor in medical statistics at Oxford.

Researchers suggested that this finding may mean that nicotine replacement works differently on women than on men or that smoking itself may have less to do with nicotine in women. "It could be, at least for some women, that there's much more of behavioral and social aspects involved in smoking than for men," said Dr. Yudkin.

This study may also explain the long-suspected, although never definitively proven, reduced effectiveness of the patch and other smoking cessation strategies for women.

"Women might not do as well in quitting, especially on the patch," said Paul Cinciripini, PhD, professor of behavioral science and director of the tobacco research and treatment program at M.D. Anderson Cancer Center in Houston.

"When you consider genotype, you find that there's one particular genotype that is able to do better. It makes biological sense, but there's no easy answer to why this didn't happen in the men," said Dr. Cinciripini.

But while many experts noted that this was an intriguing finding, they and the researchers agreed that it was not time to stop recommending the patch to women. Both suggested that the findings are far too preliminary to alter anything about current treatments for smoking cessation. And, even if genetic profiling was desired by a patient, they wouldn't be able to access it out of a research setting.

"It's tantalizing, but I certainly don't think we should jump to a pharmacogenomic approach at this point," said Reed E. Pyeritz, MD, PhD, chief of medical genetics at the University of Pennsylvania in Philadelphia.

But many said that this study and future ones could lead to more tailored smoking cessation approaches.

"We're getting closer to having this be a part of the treatment landscape, but we're not there yet," said Dr. Cinciripini. "We like to think of one-size-fits-all, but that's not necessarily true. Is a smoker, a smoker, a smoker? Probably not."

Critics as well as the researchers said, however, that this study could well be a statistical aberration rather than a biological reality, particularly because the same effect was not noted in men, and that the study needed to be replicated before it could be applied to clinical practice.

"This needs to be confirmed by other people before anybody gets excited about it," said Dr. Yudkin. "It's possible that this may just be a fluke."

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Nicotine genes

Objective: Determine if variations of the dopamine D2 receptor determine the efficacy of nicotine replacement therapy.

Participants: More than 750 current and former smokers from a 1991 nicotine patch trial.

Method: In 1999, subjects were contacted again and, if they consented, their blood was taken and genotyped. If they claimed abstinence, this was confirmed with a plasma cotinine concentration test. Treatment effectiveness was analyzed by sex and genotype.

Results: For women, 12% of those with the CT or TT genotype who received the patch were abstinent after 8 years. Only 5% of those with the CC genotype were. This was a statistically significant difference. For men, 10% of those with the CT or TT allele were abstinent, although 13% of those with the CC variant were still no longer smoking. This did not achieve statistical significance.

Conclusion: For women, but not for men, the effectiveness of the patch is related to genotype.

Source: British Medical Journal, online March 19

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External links

"Effectiveness of nicotine patches in relation to genotype in women versus men: randomized controlled trial," British Medical Journal, online March 19 (link)

"Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch," abstract, Pharmacogenetics, February (link)

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