title: Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers.
abstract: Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61-4.48; P(trend) = 0.0002) and their mothers (OR 2.74; 95% CI 1.55-4.84; P(trend) = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Sistonen
authors.forename: P
authors.initials: P
authors.lastname: Madadi
authors.forename: C J
authors.initials: CJ
authors.lastname: Ross
authors.forename: M
authors.initials: M
authors.lastname: Yazdanpanah
authors.forename: J W
authors.initials: JW
authors.lastname: Lee
authors.forename: M L A
authors.initials: ML
authors.lastname: Landsmeer
authors.forename: M
authors.initials: M
authors.lastname: Nauta
authors.forename: B C
authors.initials: BC
authors.lastname: Carleton
authors.forename: G
authors.initials: G
authors.lastname: Koren
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D001942:Breast Feeding / Q000009:adverse effects; D002394:Catechol O-Methyltransferase / Q000235:genetics; D002492:Central Nervous System Depressants / Q000009:adverse effects; D003061:Codeine / Q000009:adverse effects*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008957:Models, Genetic; D011237:Predictive Value of Tests; D011247:Pregnancy; D017450:Receptors, Opioid, mu / Q000235:genetics; D012307:Risk Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002492:Central Nervous System Depressants; D005819:Genetic Markers; D017450:Receptors, Opioid, mu; D019389:Cytochrome P-450 CYP2D6; D002394:Catechol O-Methyltransferase; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D003061:Codeine