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WIREs Forensic Sci

Pharmacogenetics and the postmortem molecular autopsy

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Abstract There are three possible outcomes from drug therapy: the drug performs as intended; the drug has no effect; or the drug causes an adverse reaction. Variation in drug and endogenous toxin metabolism among individuals in part can be due to genetic makeup. The goal of pharmacogenetics is to elucidate the genetic variation contributing to absorption, distribution, metabolism, excretion, and response (ADME‐R) so that adverse drug reactions can be avoided, and to characterize differential enzyme activity informing appropriate drug dosage on the individual and population levels. The postmortem molecular autopsy may use pharmacogenetic information from a decedent to make conclusions about cause (CoD) and/or manner of death (MoD) when traditional medico‐legal autopsies are negative. The cytochrome p450 family is a group of pharmacogenetically relevant targets with demonstrable utility in the postmortem setting and several key historical applications. ATP‐binding cassettes and opioid receptors are additional critical drug response proteins with essential rolls in additive and suicidal behaviors and drug overdose. Historically, the discipline relied on genetic variation with large effects on a broad spectrum of endogenous and foreign compounds. However, recent advances in pharmacogenomics highlight rare variants and noncoding variation as strong contributing factors to the accuracy of drug response prediction. Furthermore, there is a push to develop more comprehensive predictive models incorporating both rare and common variants contributing to drug response. These advanced genetic capabilities will enable more accurate predictions of drug‐related CoD and/or MoD determinations and contribute to the growing overlap between medical and forensic genetics. This article is categorized under: Forensic Biology > Forensic DNA Technologies Toxicology > Opioids Forensic Medicine > Methods for Certification of Cause and Manner of Death
Example CYP2D6 star (*) alleles. Blue rectangles and horizontal lines represent CYP2D6 exons and introns, respectively; single nucleotide polymorphism (SNP) rs numbers are provided for select * allele defining loci; designated SNP alleles are relative to the hg19 reference genome. CYP2D6*1A is the wild type * allele; CYP2D6*7 and CYP2D6*10A demonstrate how a single SNP, or a collection of SNPs along the length of the gene, confer different * alleles
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Flowchart of typical time course after drug is administered. Postmortem molecular autopsy focuses on how genetic features influence pharmacokinetics on the individual and population levels and can be used to predict pharmacodynamic outcomes related to cause and/or manner of death. Gene families discussed in the text are show in green with dashed arrows pointing to the processes in which they are involved
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Toxicology > Opioids
Forensic Biology > Forensic DNA Technologies
Forensic Medicine > Methods for Certification of Cause and Manner of Death

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