Genetics might determine which smokers get hooked

Dr. Dan Belsky

Dan Belsky, PhD, alumnus of the Gillings School of Global Public Health at The University of North Carolina in Chapel Hill, is co-author of the study, published online March 27 in JAMA Psychiatry.

Belsky completed his dissertation at the Gillings School in 2012 and is now a postdoctoral fellow at Duke University’s Center for the Study of Aging and Human Development and the Duke Institute for Genome Sciences and Policy. The study was part of his dissertation research.

The authors examined earlier studies by other research teams to develop a genetic risk profile for heavy smoking. They also reviewed their own long-term study of 1,000 New Zealanders from birth to age 38 to identify whether individuals at high genetic risk became frequent users of cigarettes more quickly as teens and whether, as adults, they had a harder time quitting.

Study participants who had the high-risk genetic profile were found to be more likely to smoke daily as teenagers and then progress more rapidly to heavy smoking (one pack or more per day). When assessed at age 38, the higher-risk individuals had smoked heavily for more years, had more often developed nicotine dependence and were more likely to have failed in attempts to quit smoking.

“Genetic risk accelerated the development of smoking behavior,” Belsky said. “Teens at a high genetic risk transitioned quickly from trying cigarettes to becoming regular, heavy smokers.”

A person’s genetic risk profile did not predict whether he or she would try cigarettes. However, for those who did try cigarettes, having a high-risk genetic profile predicted increased likelihood of heavy smoking and nicotine dependence.

Researchers developed a new “genetic risk score” for the study by examining prior genome-wide associations of adult smokers. These studies scanned the entire genomes of tens of thousands of smokers to identify variants that were more common in the heaviest smokers. The variants they identified were located in and around genes that affect how the brain responds to nicotine and how nicotine is metabolized, but it is not yet known how the specific variants affect gene function.

After determining the genetic risk score was able to predict heavy smoking among individuals in two large databases created by other researchers, the authors turned to their New Zealand sample of 880 individuals of European descent to determine whether the genetic risk score predicted who initiated smoking, who progressed to heavy smoking, and who developed nicotine dependence and experienced relapse after quitting.

Genetic risk was not related to whether a person tried smoking, which 70 percent of the sample had done. One reason for this was that smokers who consume cigarettes only on weekends or smoke only one or two per day had even lower genetic risk than did nonsmokers.

Genetic risk was related to the development of smoking problems. Among teens who tried cigarettes, those with a high-risk genetic profile were 24 percent more likely to become daily smokers by age 15 and 43 percent more likely to become pack-a-day smokers by age 18.

As adults, those with high-risk genetic profiles were 27 percent more likely to become nicotine-dependent and 22 percent more likely to fail in their attempts at quitting. By age 38, a study participant with high-risk genetic profile had smoked about 7,300 more cigarettes (one “pack-year”) than the average smoker.

Study participants who did not become regular, heavy smokers during their teens appeared to be “immune” to genetic risk for adult smoking problems.

“The effects of genetic risk seem to be limited to people who start smoking as teens,” Belsky said. “This suggests there may be something special about nicotine exposure in the adolescent brain, with respect to these genetic variants. Public health policies that make in harder for teens to become regular smokers should continue to be a focus in antismoking efforts.”

The research was supported by multiple grants from the U.S. National Institutes of Health (National Institute on Aging and National Institute of Mental Health), the U.K. Medical Research Council, the New Zealand Health Research Council, and the U.S. Agency for Health Care Research and Quality.

Gillings School of Global Public Health contact: David Pesci, director of communications, (919) 962-2600 or dpesci@unc.edu.