Pharmacogenetics of lethal opioid overdose: Study protocol and preliminary findings

Abstract There has been a worldwide substantial increase in accidental lethal opioid-overdose (ALOO). In this project, we will examine the role of genetic variation in opioid metabolism, transport, or opioid receptors, in contributing to opioid-related overdose deaths by 1) comparing the frequency of those variants to a corresponding reference population and exploring sex differences; 2) investigating the association between the metabolizer type (i.e., CYP2D6 poor metabolizers) and plasma concentrations; and 3) generating a series of polygenic risk scores (PRS) for predicting ALOO by using summary statistics from several large-scale genome-wide association studies (GWAS) of phenotypes relevant to opioid use disorder. This sample is currently being collected; however, we have analyzed the frequency of CYP2B6*4, CYP2B6*9 and OPRM1 A118G variants in methadone-only fatalities (n = 41). Findings showed a higher frequency of impaired CYP2B6 metabolism in males compared to females (p = 0.009, chi sq = 9.455), which suggests a potential genetic risk factor for lethal overdose in males.