Molecular Genetics Program: Current Projects

Pharmacogenetics of Nicotine Addiction and Treatment

Genetic Variants, Personality Traits and Tobacco Use in Chinese Adolescents

1. Pharmacogenetics of Nicotine Addiction and Treatment

Funded by the National Institute on Drug Abuse, National Institute of General Medical Sciences and National Cancer Institute, 2005-2010

Principal Investigator: Neal L. Benowitz, MD, Professor, Medicine, Psychiatry, and Pharmacy, University of California San Francisco

Tobacco use is the most important preventable cause of premature disability and death in the United States and in much of the world. Despite several decades of tobacco control efforts, one-quarter of Americans continue to smoke. Our research for this project aims to elucidate the genetic mechanisms underlying individual variations in nicotine dependence and smoking cessation treatment outcomes. The PNAT program has four goals:

(1) To assess the independent and synergistic role of candidate genes in nicotine metabolism, dependence, and treatment outcome(s) by conducting genetic association analyses involving 5,061 participants in existing and prospectively recruited clinical populations. We will characterize both individual polymorphisms and haplotypes in the candidate genes, as well as gene-gene interactions.

(2) To clinically validate functionally significant genetic polymorphisms by conducting prospective genotype-stratified pharmacokinetic and pharmacodynamic studies.

(3) To comprehensively evaluate the interaction of genetic factors and pharmacological interventions via pathway-based Bayesian hierarchical data modeling. In addition to identifying population-level risk factors, these models may ultimately enable the prediction of individual outcomes for the design of tailored pharmacological interventions within a smoking cessation treatment program.

(4) To contribute informative pharmacogenetic data to the PharmGKB database and to create a shared research resource both for use by other members of the PGRN and by those in the communities focused on the understanding of tobacco dependence and, more broadly, drug addiction.

2.  Genetic Variants, Personality Traits and Tobacco Use in Chinese Adolescents

Funded by the National Cancer Institute, 2004-2009, Project 3 of USC Transdisciplinary Tobacco Use Research Center

Principal Investigator: Anderson C. Johnson, Ph.D, University of Southern California

Genetic variations in components of the brain reward circuits, such as dopamine and serotonin pathways, also play pivotal roles in tobacco dependence and treatment responses. We are conducting a genetic association study of variants in key candidate genes in the serotonin and dopamine systems and of their impacts on tobacco use in 2,661 participants from an existing cohort from Wuhan, China. We hypothesize that the genetic factors responsible for dispositional attributes, such as hostility and depression, act both to influence an individual’s tobacco use progression and to moderate the effectiveness of tobacco control intervention and prevention programs.

In this work, we are using a combination of genomic technologies, including Illumina high-throughput SNP genotyping, GeneScan, Taqman assays, and DNA sequencing to comprehensively profile genetic variations in the candidate genes. We are investigating the relation of these polymorphisms to personality traits and tobacco and alcohol use outcomes.  Additionally, we are examining interaction effects of these polymorphisms combined with the effects from dispositional attributes and from a smoking intervention program. We will also implement hierarchical modeling to include knowledge regarding the biological mechanism for the serotonin and dopamine systems, as well as Bayesian model averaging to comprehensively evaluate the set of risk factors that best represents the underlying complexity of smoking behavior within a multifaceted social context.

The results of the study should enhance our knowledge of genetic predisposition to smoking and allow us to create more effective prevention programs that are specifically tailored to the various subgroups identified in the work. 

Contact Us

For more information about SRI International’s Molecular Genetics Research Program, call 650-859-4618 or email andrew.bergen@sri.com.