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Environmental Factor, February 2013

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Uncovering the genetic component in nicotine addiction

By Eddy Ball

Laura Bierut, M.D.

The take-it-or-leave-it smokers, or chippers, who make up about 20 percent of daily smokers, were important in forming Bierut’s thinking about nicotine addiction. “They [smoke occasionally] but do not seem to be transitioning to nicotine dependence. … This group is the important [extreme] phenotype to study.” (Photo courtesy of Steve McCaw)

Beirut's audience

Beirut’s audience included scientists from the NIEHS grants program and in-house research groups, as well as two of her colleagues now at RTI — Senior Research Scientist Eric Johnson, Ph.D., and Genetic Epidemiologist Dana Hancock, Ph.D., who completed her postdoctoral fellowship in the NIEHS Epidemiology Branch. (Photo courtesy of Steve McCaw)

Two new studies in the Jan. 24 issue of the New England Journal of Medicine offered good news about living longer, for people who can quit smoking by early middle age or sooner. But that good news is less meaningful for the approximately 44 percent of daily smokers Washington University School of Medicine in St. Louis psychiatrist Laura Bierut, M.D., estimates are truly nicotine dependent and the most resistant to smoking cessation.

Bierut, a National Institute on Drug Abuse (NIDA) grantee and member of the NIDA Genetics Consortium, was at NIEHS Jan. 23 to report on her work uncovering the genetic component in nicotine addiction, with a talk on “The interplay of environment and genes in smoking behaviors,” hosted by NIEHS Health Science Administrator Kimberly McAllister, Ph.D.

The progression of nicotine addiction

Bierut opened the prologue to her narrative by discussing a 2005 study on a gene variant related to macular degeneration, which she said marked the beginning of the new generation of large-scale genome-wide association studies (GWAS). “That really just changed our paradigm of genetic studies,” she explained. “Where we are now, is we are really thinking about how these genetic studies are going to move forward with improving human health and the public health of the population.”

Describing the process of becoming a smoker as a multi-step progression, Bierut said that nearly 60 percent of people in a poll conducted in St. Louis and Detroit, who had smoked that first cigarette, ultimately became smokers. “You become a smoker when you smoke 100 cigarettes in your lifetime. Past this threshold of 100 cigarettes, 85 percent become daily smokers.”

Research by Bierut and others contrasted the genetic profiles of what she described as the extremes of the smoker phenotype — at one end, people who can smoke every so often without becoming nicotine-dependent, or chippers, and, at the other end, nicotine addicts. Their findings led to the chromosome 15 region, where key polymorphisms in nicotinic receptor genes show a very specific association with nicotine dependence, lung cancer, chronic obstructive pulmonary disease, and cardiovascular diseases.

“Across the chromosomes, there are hints of other genetic findings, but you have this really screaming hot association in the chromosome 15 region,” she said. “It appears to change the [nicotinic] receptor functionally. … I call this the Mister Big finding.”

Translating GWAS into primary prevention and treatment

According to Bierut, there is an interplay of variants in the CHRNA5 gene and environmental factors, including parental monitoring, peer smoking, and early-onset smoking, that may help scientists and public health advocates more effectively encourage young people to delay the start of smoking, or completely avoid it, and give nicotine-dependent smokers a better chance at success when they try to quit.

“The environment is really the area that we can change,” Bierut said, pointing to the effects of higher taxes on tobacco and other preventive measures. She cited research findings, indicating that early-onset of smoking amplifies genetic risk. “This [further] supports efforts to keep young people from smoking.”

According to Bierut, studies of participants receiving placebo in smoking cessation groups pointed to another use for the Mister Big finding in the choice of treatment protocols for people who want to quit. The genetic variant that places smokers at the highest risk for nicotine dependence, she explained, is also placing them at highest risk for failed smoking cessation.

Variant status is also predictive of which smokers will benefit the most from pharmacologic treatment. “Depending on your genotype, you are responding very differently to the active pharmacologic treatment for smoking cessation,” Bierut concluded. Patients with the lowest genetic risk can often quit on their own, while those with the high-risk variant should be targeted for pharmacologic intervention to help continue the downward trends of cigarette consumption and deaths from smoking, which still kills some 400,000 people in the U.S. each year.

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