Multiple Genetic Regions Are Associated with Cigarette Smoking Behavior
The Bottom Line
Results of genomic analyses support previous findings that a region of human chromosome 15 contains one or more genes that are associated with smoking intensity (the number of cigarettes smoked per day) and the closely related trait of nicotine dependency.
The Whole Story
Tobacco smoking is the leading cause of preventable deaths worldwide. It is a risk factor for more than two dozen diseases, including lung cancer and several other types of cancer. Dependence on the nicotine in tobacco leads most people who start smoking to continue despite their desire to quit. Although environmental factors are known to play a role in tobacco dependence, hereditary factors are also likely to influence a range of smoking behaviors, such as the age at which a person starts smoking, the number of years they smoke, and whether or not someone quits.
As part of the NCI Cancer Genetic Markers of Susceptibility project, researchers looked for genetic variations that are associated with smoking behaviors in a combined analysis of data from two previous genome-wide association studies. Information on smoking behaviors, obtained from questionnaires, was available for 2,060 men participating in the NCI's Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and 2,282 postmenopausal women participating in the Nurses' Health Study (NHS). Of these men and women, 2,617 had smoked regularly at some time during their lives.
To identify regions of DNA that are associated with various smoking behaviors, the researchers looked for differences in common genetic variants known as SNPs (single-nucleotide polymorphisms) between people who had ever smoked versus those who never smoked, smokers who had quit versus those who had not, and people who smoked 10 or more cigarettes per day versus those who smoked fewer than 10 cigarettes per day. The researchers also looked for SNPs associated with the number of cigarettes smoked per day, the age at starting smoking, the number of years of smoking, and the number of pack-years smoked. In a parallel analysis, called a candidate gene association study, the researchers examined associations between smoking behaviors and SNPs in 359 genes that had previously been hypothesized to have a relationship with these behaviors.
In the genome-wide association analysis, the researchers found that no DNA region met the strongest evidence for an association with smoking behaviors. However, they did find evidence of an association between a section of DNA on chromosome 15 (known as 15q25.1) and the number of cigarettes smoked per day. This DNA region contains a number of genes that code for nicotinic receptors—proteins that mediate the nervous system's response to nicotine. Previous studies had also indicated that this genetic region is associated with smoking intensity.
In their parallel analysis of SNPs in the 359 candidate genes, the researchers found an association between genetic variation in the MAOA gene, which codes for the enzyme monoamine oxidase A, and smoking intensity. Previous studies have shown that smoking reduces the activity of MAO enzymes, which help regulate chemical messengers in the brain that play a role in addiction. When MAO enzyme activity is reduced, the addictive effects of nicotine are reinforced.
Although this study did not provide definitive evidence for the role of individual genes on smoking behaviors, it independently confirmed the association between the 15q25.1 region of chromosome 15 and smoking intensity and also provided evidence that other genetic regions are associated with smoking behavior. Identifying genes that influence smoking behavior could lead to insights about the causes of these behaviors and make possible the development of interventions to reduce smoking-related deaths and disease.
More summaries of selected scientific advances from NCI-supported research are available at http://www.cancer.gov/aboutnci/servingpeople/advances.
