More than one in four Americans older than 17 regularly smokes cigarettes despite increasing public awareness of tobacco's severe health risks. Some start younger than others and, among those who try to quit, some are more successful than others. NIDA-supported scientists are finding increasing evidence that these differences may be due in part to an inherited vulnerability to nicotine addiction.

A Medical College of Virginia study involving 949 female twin pairs found genetic factors to be more influential than environmental factors in smoking initiation and nicotine dependence. Likewise, a St. Louis University study of 3,356 male twin pairs found genetic factors to be more influential for dependence on nicotine and alcohol.

At the St. Louis University Health Sciences Center, Dr. William True and Dr. Hong Xian interviewed male twin pairs to assess genetic influences on smoking. In twin studies, researchers compare patterns of tobacco use in fraternal and identical twin pairs, who typically are exposed to common environmental influences. If genes play a role in determining tobacco use, identical twins-who share the same genes-will be more similar in their use of tobacco than fraternal twins, who share roughly half of their genes. The St. Louis University researchers found that among the 3,356 twin pairs studied, genetic factors make a stronger contribution to nicotine dependence (61 percent) than do environmental factors (39 percent) and also play a more prominent role (55 percent) than environmental factors (45 percent) in alcohol dependence. In another study, Dr. Kenneth Kendler and his colleagues at the Medical College of Virginia in Richmond interviewed 949 female twin pairs and found that genetic factors play a more important role (78 percent) than do environmental factors (22 percent) in smoking initiation and in nicotine dependence (72 percent vs. 28 percent).

"These studies emphasize the importance of understanding the role of genetic influences in smoking," says Dr. Jaylan Turkkan, chief of NIDA's Behavioral Sciences Research Branch. "The more we understand about vulnerabilities, risks, and possible protective factors, the better able we will be to tailor treatments that help people stop smoking."

Other NIDA-supported scientists are studying genes that are polymorphic-that is, in different individuals the same gene has slight variations called alleles-and have found that individuals with one type of allele are more likely to begin smoking or to have greater success quitting than are individuals with another type. For example, researchers at the University of Toronto have found that different alleles in a gene that helps regulate nicotine metabolism may protect some smokers from becoming dependent on nicotine (see "Study Shows How Genes Can Help Protect from Addiction," NIDA NOTES Vol. 13, No. 6).

Dr. Caryn Lerman, principal investigator of the NIDA-supported Transdisciplinary Tobacco Use Research Center at Georgetown University in Washington, D.C., and her colleagues studied two genes, designated SLC6A3 and DRD2, that may influence smoking behavior by affecting the action of the brain chemical dopamine. In a study involving 289 smokers and 233 nonsmokers (42 percent male, 58 percent female, average age 43), the researchers found that smokers were less likely to have an allele designated SLC6A3-9 (46.7 percent) than were nonsmokers (55.8 percent). The likelihood of smoking was even lower if the individual had both the SLC6A3-9 allele and the DRD2-A2 allele. In addition, Dr. Lerman observed that smokers with the SLC6A3-9 allele were more likely to have started smoking later and to have had longer periods of smoking cessation than those without the allele. These findings imply that the allele may impart a protective effect. Therefore, Dr. Lerman suggests, smokers without the SLC6A3-9 allele may be better able to quit smoking if their treatment incorporates a medication such as bupropion that acts on the brain's dopamine pathway. This hypothesis is currently being tested in a randomized trial.

Dr. Lerman and her colleagues also studied a polymorphism in a gene, designated 5-HTTLPR, that helps regulate the brain chemical serotonin to determine the gene's possible role in smoking. The polymorphism has two alleles, one designated the short, or S, allele, the other the long, or L allele. In previous studies the S allele has been linked to neuroticism-an anxiety-related personality trait. Dr. Lerman and her colleagues studied 185 smokers (46 percent male, 54 percent female, and average age 45) to investigate the possible relationship between genetically influenced neuroticism and smoking behavior. They found that neuroticism was associated with increased nicotine dependence, smoking for stimulation, and smoking to relieve negative mood in the group of smokers who had the S allele. Among smokers with the L allele, neuroticism was not associated with these smoking patterns. "Anxious persons tend to smoke more and have more difficulty quitting," Dr. Lerman says. The new findings suggest that among smokers with neuroticism, determining the 5-HTTLPR genotype may help identify who will be more responsive to a particular type of treatment. "Once validated, these results may lead to targeted pharmacotherapy for smoking cessation," says Dr. Lerman.

"This area of research represents our first small steps along a very complicated path to understanding the role that genes play in drug abuse," notes Dr. Harold Gordon of NIDA's Clinical Neurobiology Branch. "Many genes interact with each other and with other biological and environmental factors. Defining these interactions and understanding their influence on nicotine addiction will be crucial to development of treatments for smoking and for other addictions."

Sources

Kendler, K., et al. A population-based twin study in women of smoking initiation and nicotine dependence. Psychological Medicine 29(2):299-308, 1999. [Abstract]

Lerman, C., et al. Evidence suggesting the role of specific genetic factors in cigarette smoking. Health Psychology 18(1):14-20, 1999. [Abstract]

Lerman, C., et al. Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence. Molecular Psychiatry In press.

True, W.R., et al. Common genetic vulnerability for nicotine and alcohol dependence in men. Archives of General Psychiatry 56(7):655-661, 1999. [Abstract]