Building Collaborative Research to Drive Improvement of West Virginia Health Outcomes

Mortality rates in Appalachia have not declined in recent years as they have for the remainder of the US. Appalachian mortality rates have actually increased. Most counties of southern West Virginia have mortality rates well in excess of the US average. West Virginia ranks at or near the bottom in most U.S. chronic disease categories, with the highest rate of drug overdose deaths and near the highest rates of cancer and cardiovascular mortality. And yet, West Virginia has many dedicated heath care providers, committed to the care of their patients. The West Virginia Clinical and Translational Science Institute (WVCTSI) seeks to facilitate finding solutions for vexing health problems in West Virginia, working with the many committed healthcare providers to collaboratively improve health outcomes in our state

Fatal methadone toxicity: potential role of CYP3A4 genetic polymorphism

Methadone is difficult to administer as a therapeutic agent because of a wide range of interindividual pharmacokinetics, likely due to genetic variability of theCYP450 enzymes responsible for metabolism to its principal metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). CYP3A4 is one of the primary CYP450 isoforms responsible for the metabolism of methadone to EDDP in humans. The purpose of this study was to evaluate the role of CYP3A4 genetic polymorphisms in accidental methadone fatalities. A study cohort consisting of 136 methadone-only and 92 combined methadone/benzodiazepine fatalities was selected from cases investigated at the West Virginia and Kentucky Offices of the Chief Medical Examiner. Seven single nucleotide polymorphisms (SNPs) were genotyped within the CYP3A4 gene. Observed allelic and genotypic frequencies were compared with expected frequencies obtained from The National Center for Biotechnology Information dbSNP database. SNPs rs2242480 and rs2740574 demonstrated an apparent enrichment within the methadone-only overdose fatalities compared with the control group and the general population. This enrichment was not apparent in the methadone/benzodiazepine cases for these two SNPs. Our findings indicate that there may be two or more SNPs on the CYP3A4 gene that cause or contribute to the methadone poor metabolizer phenotype