Wednesday, April 11, 2007

Smoking, Genes and Public Health

According to the World Health Organization tobacco is a public health priority and is responsible for killing approximately 1 in 10 adults worldwide (5 000 000 deaths each year). Tobacco is the fourth most common risk factor for disease worldwide and the harmful effects of smoking impact not only the lives of the smokers who develop disease, but also their families and society-at-large (e.g. economic costs).

The Pharmacogenomics Journal has an interesting (free online) piece entitled “Overview of the Pharmacogenomics of Cigarette Smoking” which examines how a better understanding of the genetic influences on different smoking stages and phenotypes can help us better tackle the problem of tobacco smoking. Here is a sample:

Cigarette smoking is a complex behavior that includes a number of stages such as initiation, experimentation, regular use, dependence, cessation and relapse. Although environmental factors such as the influence of family members, peers and culture undoubtedly affects one's smoking behaviors at these stages, genetics also has a substantial role. Numerous twin, adoption and family studies have been performed and large variations in the estimation of heritability of 'ever' smoking have been reported in ranges of 11–78%. This may be due, at least in part, to the broadness of this phenotype which encompasses those who have only tried cigarettes once to regular heavy smokers. Once smoking is initiated, the heritability for persistence to regular smoking has been estimated at 28–84%, for number of cigarettes smoked at 45–86% and for diagnosed ND at 31–75%. A genetic influence on nicotine withdrawal symptoms and smoking cessation has also been identified with heritability estimated at 26–48 and 50–58%, respectively. Taken together, these studies suggest a substantial genetic contribution to most aspects of smoking. It should be noted that genetic risk factors for different aspects of smoking (such as initiation and persistence) only partially overlap, suggesting some genes will be specific to one smoking phenotype whereas others may influence multiple aspects of smoking. Further, the proportion of genetic versus environmental influences on the different smoking stages vary by gender, with genetics appearing to have a larger role on initiation compared to persistence in women, whereas the opposite is observed in men.

While heritability studies can demonstrate a genetic influence in smoking behaviors, advances in our understanding of the human genome have allowed for the localization of specific genes involved. Genome-wide linkage analysis is used to locate areas in the genome with high linkage disequilibrium for a specific phenotype such as ND. The impact of variation in genes found in these loci can then be examined in candidate gene association studies. Candidate gene association studies have focused primarily on targets identified in linkage studies and on genes selected for their biological relevance. Current research has focused mainly on genes involved in neurotransmitter pathways of the brain reward system and nicotine metabolism. It should be noted that like other complex disorders, it is likely that multiple interacting genetic factors underlie ND with each gene contributing a small effect. This review will provide a brief overview of the data from linkage scans and candidate gene association studies, and discuss some of the observed discrepancies in the literature. An examination of how genetic variation may be associated with differential outcomes to nicotine cessation pharmacotherapies will also be described. A better understanding of the genetic influences on the different smoking stages and phenotypes can provide a rationale for prevention strategies, can be used to optimize current treatments and provide novel targets for the development of new treatments.