Molecular Genetics Program: Current Projects

Salivary Biomarkers (DNA, RNA and Cortisol), Life Stress, and Nicotine Dependence

Funded by the National Institute on Drug Abuse, 2009-2012

Principal Investigators: Judy A. Andrews, Ph.D., Senior Scientist, Oregon Research Institute and Andrew W. Bergen, Ph.D., SRI International

The broad goal of this project is to lay the foundation for research identifying salivary biomarkers that are predictive of the vulnerability of individuals to (a) progress toward nicotine dependence and (b) ultimately to become dependent on nicotine by emerging adulthood, given their exposure to life stress. Features of the proposed research is the use of an interview-based life stress assessment to provide a precise and reliable measurement of chronic and episodic stress, and initial steps in the identification of easily obtained salivary biomarkers that identify individuals who are exposed to greater levels of chronic stress. This project has the potential to advance drug abuse prevention and intervention research through identifying Genetic x Environment (GxE) interactions, which may help to explain the success or failure of interventions designed to prevent the initiation of tobacco use and the progression to nicotine dependence, or to maintain cessation. The proposed assessment with two cohorts at age 20/21 (n = 390) includes saliva collection for DNA extraction to assess polymorphisms of candidate genes known to be related to the stress-reward pathway, saliva collection for RNA extraction for candidate gene and genome wide gene expression, and a systematic contextual based assessment of chronic and episodic stress, using state-of-the-art assessment tools, at age 20/21. The data from this assessment will be integrated with other multi-source/multi-respondent data from two cohorts from an ongoing eleven-year longitudinal study examining the etiology of substance use, including nicotine dependence, combined with data assessing cortisol reactivity in response to laboratory induced stress, at age 20/21. To accomplish this broad goal, we propose to address the following aims:

(1) Identify GxE interactions which predict change in nicotine dependence across from adolescence to emerging adulthood and across youth from the occurrence of polymorphisms of specified candidate gene known to be related to the stress reward pathway in the context of the experience of chronic and episodic stress;

(2) Assess the association between specific genetic polymorphisms and cortisol reactivity in response to a laboratory induced stressor and assess the effect of GxE interactions on cortisol dysregulation through examining the effect of the interaction of genetic polymorphisms and life stress in emerging adulthood on cortisol dysregulation; and

(3) Evaluate whether the salivary transcriptome contains RNA biomarkers for the identification of individuals with the gene expression signature of chronic stress using RNA samples from 24 individuals who experience the most life stress and 24 individuals with the least stress. We plan to validate an existing functional genomic signature of chronic stress previously identified in lymphocytes by performing gene expression analysis of individual candidate genes, and we will discover, confirm and validate novel candidate genes by performing genome-wide and candidate gene expression analysis.

Pharmacogenetics of Nicotine Addiction Treatment

Funded by the National Institute on Drug Abuse, National Cancer Institute, National Human Genome Research Institute and National Institute of General Medical Sciences, 2010-2015

Principal Investigators: Caryn Lerman, Ph.D., Mary W. Calkins Professor and Director, Tobacco Use Research Center, Department of Psychiatry, Scientific Director, Abramson Cancer Center, University of Pennsylvania; and Rachel Tyndale, Canada Research Chair in Pharmacogenetics, Section Head Pharmacogenetics, Centre for Addiction and Mental Health, Professor of Pharmacology, University of Toronto

Smoking is a significant public health problem, and there is a great need for research to improve smoking cessation treatment outcomes. The goal of the Pharmacogenetics of Nicotine Addiction Treatment (PNAT) research program is to generate the evidence base to optimize treatment decisions for Individuals who want to quit smoking. During the past 4 years of PNAT1, we have characterized genetic variants altering nicotine pharmacokinetics as well as pharmacodynamic genetic variants influencing response to pharmacotherapies for smoking cessation treatment. We have shown that the CYP2A6 enzyme is critical in the metabolic inactivation of nicotine, and inherited variation in nicotine clearance influences smoking behavior and cessation. With a vision toward translation of our research to practice, we have characterized a genetically-informed biomarker of CYP2A6 activity, specifically the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine), which reflects both genetic and environmental influences on CYP2A6 activity and nicotine clearance. The NMR is measured noninvasively in smokers with established reliability, stability, analytic validity, and efficacy as a predictor of therapeutic response in multiple independent (retrospective) clinical trials. Translation of these findings to clinical practice, the ultimate goal of the PGRN, requires validation In a prospective stratified clinical trial comparing alternative therapies for smoking cessation. 

In this competing renewal, we propose to conduct a prospective placebo-controlled multi-center pharmacogenetic (PGx) clinical trial of alternative therapies for smoking cessation treatment in 1,350 smokers. Randomization to placebo, transdermal nicotine, or varenicline will be stratified prospectively based on the NMR, the most robust genetically-informed biomarker for smoking cessation identified to date. Further, to facilitate translation to practice, we will determine the cost-effectiveness of our proposed PGx approach using both primary data and simulation models. In addition to these goals, we propose within this U01 to: identify additional sources of genetic variation in nicotine clearance and the NMR; investigate additional pharmacokinetic and pharmacodynamic gene associations with therapeutic response biomarker; and elucidate the mechanisms involved in identified PGx effects on smoking cessation. 

The proposed research provides the next critical step to validate a genetically-informed diagnostic tool, the NMR, which clinicians can use in the future to optimize treatment decisions for their patients who wish to quit smoking. As outlined recently by NIDA, due to the devastating health consequences of smoking and the urgent demand for better treatments, the validation of biomarker strategies to improve the outcomes of treatments a major public health priority.

Contact Us

For more information about SRI International's Molecular Genetics Research Program, email andrew.bergen@sri.com.