Most of the 44.5 million American adults who smoke cigarettes would prefer not to. Why do so many would-be quitters fail, even with the help of stop-smoking interventions like nicotine replacement? Why, for that matter, do people become addicted to smoking in the first place? The answers lie partly in our genes.
NIDA researchers in collaboration with Perlegen Sciences, Inc., a private company, recently completed a search of the entire human genome for differences between individuals who are nicotine-dependent and those who smoked but never became dependent. Their target: single nucleotide polymorphisms (SNPs), locations on the genome where individuals differ by just one chemical unit in the makeup of their DNA. From 2.2 million known SNPs, researchers have identified roughly 40 to 80 that are highly correlated with nicotine addiction.
Once researchers link an SNP statistically to drug abuse, the question becomes: Does the gene do anything that might explain why people with one of its forms are more vulnerable to drugs than people with another? Some of the genes researchers have implicated in addiction affect the dopamine reward circuit. Others involve neurotransmitter systems and neural pathways not previously known to figure in smoking's effects. Researchers will use techniques such as brain imaging to correlate genetic differences with differences in brain structure or function and psychological tests to match them to behavior. Findings from the genome exploration may ultimately yield novel, more effective interventions.
Genetic variations can only partly explain why people become addicted to nicotine: A person's genetic makeup, experiences, and surroundings all combine to determine whether he or she will smoke and, if so, how difficult quitting will be. NIDA-funded epidemiologists and behaviorial scientists are conducting a large longitudinal study to elucidate these interactions. They have been following pairs of twins, now 17 years old, collecting information about participants' smoking and environmental factors like stressors and peer relationships that can increase the risk of substance abuse or protect against it. The next step will be to analyze these data, together with information on the twins' genetic and biological traits.
NIDA-supported researchers are also working to discover why interventions like nicotine replacement therapy (NRT) work for some people and not others. By comparing smokers who have successfully used pharmacotherapy with those whose efforts to quit have failed, the researchers hope to identify groups of genes that predict who will do well with NRT, with bupropion, or with varenicline, the newest smoking cessation drug. The ultimate goal is to tailor the treatment to the smoker. Ultimately, we hope genetic studies will lead to strategies that protect vulnerable young people from addiction.