title: The ABCB1, rs9282564, AG and TT Genotypes and the COMT, rs4680, AA Genotype are Less Frequent in Deceased Patients with Opioid Addiction than in Living Patients with Opioid Addiction.
abstract: Sudden death due to acute intoxication occurs frequently in patients with opioid addiction (OA). To examine whether certain genotypes were associated with this, we examined the frequencies of 29 SNPs located in candidate genes related to opioid pharmacology: ABCB1, OPRM1, UGT2B7, CYP3A5, CYP2B6, CYP2C19, CYP2D6, COMT, KCNJ6 and SCN9A in 274 deceased patients with OA (DOA), 309 living patients with OA (LOA) and in 394 healthy volunteers (HV). The main hypothesis of the study was that subjects homozygous for the variant 3435T in ABCB1 (rs1045642) occur more frequently in DOA than in LOA and HV because morphine and methadone more readily cross the blood barrier in these subjects due to a lower efflux transporter activity of the ABCB1 (p-glycoprotein) transporter. Our results did not support this hypothesis, because no statistically significant difference (p = 0.506) in the frequency of the TT genotype of rs1045642 was observed between the DOA, LOA and HV cohorts. However, for another ABCB1 variant, rs9282564, we found that the frequencies of the AG and TT genotypes were 13, 21 and 25% in DOA, LOA and HV, respectively, and after correcting for age, sex and multiple testing, the differences between DOA and LOA were statistically significantly different (p = 0.027). The COMT rs4680 AA genotype frequencies were 25%, 35% and 31% in DOA, LOA and HV, respectively, and the difference between DOA and LOA was also statistically significant (p = 0.0028). In conclusion, this study generated two hypotheses suggesting possible associations of a reduced risk of death and carrying, respectively, the ABCB1 rs9282564 AG and TT genotypes and the COMT rs4680 AA genotype among patients with OA. These findings should be confirmed in independent cohorts, and if a causal relationship between these variants and fatal poisoning in OA is confirmed, then it may be possible at least in theory to personalize prevention of sudden death in this patient group.
authors.affiliation: Institute of Forensic Medicine, University of Southern Denmark, Odense C, Denmark. dchristoffersen@health.sdu.dk.
authors.forename: Dorte J
authors.initials: DJ
authors.lastname: Christoffersen
authors.affiliation: Department of Public Health, Clinical Pharmacology, University of Southern Denmark, Odense, Denmark.|Department of Clinical Chemistry & Pharmacology, Odense University Hospital, Odense C, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
authors.affiliation: Department of Clinical Chemistry & Pharmacology, Odense University Hospital, Odense C, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Feddersen
authors.affiliation: OPEN - Odense Patient data Explorative Network, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense C, Denmark.
authors.forename: Sören
authors.initials: S
authors.lastname: Möller
authors.affiliation: Institute of Forensic Medicine, University of Southern Denmark, Odense C, Denmark.
authors.forename: Jørgen L
authors.initials: JL
authors.lastname: Thomsen
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brasch-Andersen
authors.affiliation: Department of Public Health, Clinical Pharmacology, University of Southern Denmark, Odense, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Brøsen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D003645:Death, Sudden / Q000209:etiology*; D003718:Denmark; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008691:Methadone / Q000097:blood / Q000633:toxicity; D008875:Middle Aged; D009020:Morphine / Q000097:blood / Q000633:toxicity; D009021:Morphine Dependence / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D009294:Narcotics / Q000097:blood / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D009294:Narcotics; D009020:Morphine; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D008691:Methadone