Abstract
The “Genetics and Pharmacogenetics of Substance Use Disorder” session was chaired by Dr. Pao-Luh Tao and had three speakers. The speakers and their topics were: Dr. Li-Shiun Chen presented on Genomics and Personalized Medicine for Smoking Cessation Treatments, Dr. Chih-Ken Chen presented on the Genetics of Methamphetamine Abuse and Methamphetamine Psychosis, and Dr. Yu-Li Liu presented on a Pharmacogenomics Study in a Taiwan Methadone Maintenance Cohort.
Keywords: genetics, pharmacogenetics, substance use disorders, smoking cessation, methamphetamine, methadone
1. Introduction
Cigarettes, methamphetamine, and heroin are addictive substances that are used worldwide. In this symposium, three topics related to these substances were presented.
2. Presentations
Dr. Li-Shiun Chen, of the Washington University School of Medicine, stated that there is evidence that genetic variants in the nicotinic receptor genes on chromosome 15 (CHRNA5) and the Cytochrome P450 2A6 (CYP2A6) gene can influence smoking behaviors and cessation success. Dr. Li-Shiun Chen's group examined the influence of these genetic variants on smoking cessation success and response to cessation pharmacotherapy. Survival analyses were used to model the relationship between smoking cessation (relapse likelihood over 90 days) and nicotine metabolism in subjects from a randomized smoking cessation trial (N = 1,073, European ancestry). Individuals with high risk CHRNA5 haplotypes were more likely to relapse and benefit from cessation pharmacotherapy. Similarly, individuals with faster CYP2A6 nicotine metabolic activity were more likely to relapse than were individuals with slower metabolism when both are given placebo. Further, pharmacotherapy condition (active vs. placebo) interacted with the genotypes: the number needed to treat (NNT) varied by genotype. The genetic risks of CYP2A6 and the previously reported genetic marker (CHRNA5) on smoking cessation are independent and additive. Details of this presentation can be found in the article by Dr. Chen [1] included in this special issue.
Dr. Chih-Ken Chen, of Chang Gung Memorial Hospital, and his group found that the COMT gene (rs4680) and a COMT haplotype (rs4680/rs165599) were associated with methamphetamine abuse [2]. They found that variants in “methamphetamine abuse/dependence” genes are likely to alter cell adhesion, enzymatic functions, transcription, cell structure, DNA, RNA, and/or protein handling or modification. Cell adhesion genes CSMD1 and CDH13 displayed the largest numbers of clustered nominally positive SNPs. Methamphetamine associated psychosis (MAP) is likely a complex genetic disease in which environmental factors interact with multiple polymorphic genes to influence susceptibility. Dr. Chih-Ken Chen's group reported superoxide dismutase 2 (SOD2) to be associated with MAP [3]. Future genetic research on methamphetamine abuse and MAP should include replicating genetic associations within and across ethnically diverse populations, adjusting for multiple comparisons to minimize false-positive associations, and increasing statistical power by using larger population cohorts to minimize false-negative associations.
Dr. Yu -Li Liu's group found that the pharmacokinetic genes of CYP2B6 and 2C19 were significantly associated with plasma methadone concentrations [4]. The CYP3A4 was associated with withdrawal symptom scores. Interactions among CYP2B6, 3A4, and 2C19 could allow for the subgrouping of the patients into different methadone dosage groups and were associated with methadone tolerance. Pharmacodynamic genetic variants (e.g., OPRM1) were demonstrated to have associations with the methadone side effects of insomnia and severity of cigarette smoking [5]. More studies should be performed to decipher the potential mechanism for methadone dosage requirements.
3. Conclusions
In conclusion, genotypes are useful in predicting individuals' smoking cessation outcomes and response to pharmacotherapy. The wide variation in NNT between smokers with different genetic backgrounds may guide the development of a personalized smoking cessation intervention based upon genotype. Pharmacogenomics also seems promising for future individualized medicine for methadone maintenance treatment.
References
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