Genetic Variation Assessment of genetic variations as a predictor for smoking cessation and health risks.

Genetic polymorphisms and smoking cessation success

Tobacco smoking remains the major preventable cause of premature morbidity and mortality throughout the world. Research on tobacco use and smoking cessation has contributed to reductions in smoking prevalence. However there are currently still more than 1.2 billion smokers world-wide, resulting in 3-4 million deaths per year and the development of many smoking-related diseases, typical examples being respiratory and cardiovascular disorders (CVDs) and many types of cancer, but also many other diseases such as parodontitis, dementia, diabetes mellilitus and kidney failure. Because smoking is a modifiable risk factor, a large part of these smoking-related deaths and diseases could be prevented. However, both smokers and healthcare practitioners are confronted with high relapse rates after initial successful smoking cessation attempts. Despite progress made in the pharmacological treatment of nicotine dependence, the efficacy of available treatments is limited; even with a combination of pharmacotherapeutic and behavioural therapy only 5-30% of the smokers are actually successful with continuous abstinence.
Recently accumulating evidence has become available that links genetic predisposition to smoking. Twin studies have shown that genetic factors account for 64-84% of the variance in the susceptibility to develop nicotine dependence. Variations in several genes have been suggested to contribute to smoking addiction and cessation. The search for specific genetic effects on smoking behaviour have focused on two broad classes of genes: (1) genes that may predispose to addictive behaviour via their effects on key neurotransmitter pathways (especially dopamine) and (2) genes that are involved in the metabolism of nicotine (especially determining the half-life of nicotine). Associations between smoking and variations in genes for the cytochrome P450 enzymes CYP2A6, CYP2B6 and CYP2D6, and genes from the dopamine and serotonin pathway have been found.
Therefore, it is a logic following step to assess whether SNPs in these genes are also associated with successful quit attempts. This approach opens avenues for individually tailored approaches to quit smoking based on a genetic background. This will probably improve efficacy of the treatment and possibly the same will account for toxicity and for side effects of these treatments. Recent research has shown that this approach may be very promising.
So far most studies investigated only single genes. Regarding the number of genes that are implicated in smoking-addiction, and the large number of polymorphisms present, approaches analysing single genes will probably fail to fully determine the role of genetic variation in the individual susceptibility towards smoking-addiction. Also, the effect of genetics on only a couple of smoking cessation therapies has been investigated. Therefore, in this project we will investigate the effect of multiple susceptibility genes as well as their mutual interactions on several smoking cessation therapies in this study.

Genetic polymorphisms and DNA damage endpoints

Genetic polymorphisms in genes involved in processes that affect DNA damage may explain part of the large interindividual variation in DNA adduct levels. We indeed showed that analysis of multiple genetic polymorphisms simultaneously may predict at least part of the interindividual variation in DNA adduct levels upon exposure to cigarette smoke. Because of the complexity of processes involved in formation of DNA adducts, it is very unlikely that one single polymorphism accounts for interindividual differences in DNA adduct levels in smokers. Thus, studies investigating single polymorphisms in relation to DNA adduct levels may either overestimate or underestimate the involvement of such polymorphisms. To identify the most relevant genetic polymorphisms and to quantitate possible interactions between them, studies are required that analyze many polymorphisms simultaneously in a single exposed population.

Associated Staff

Frederik-Jan van Schooten
Professor, Head of the department

Prof. dr. Frederik-Jan van Schooten Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, more ...

Roger Godschalk
Associate Professor

Dr. Roger Godschalk graduated in Biological Health Sciences in 1995 at the Maastricht University (The Netherlands). He specialised in genetic toxicolo more ...

Daniëlle Pachen

Daniëlle Pachen studied at the technical school for chemistry in Heerlen, and she is specialised in analytical an instrumental techniques. From 1991 s more ...