title: Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD.
abstract: Methylphenidate (MPH) is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD). Several pharmacogenetic studies suggested that catecholamine candidate genes influence individual MPH-responses, but these results are mostly contradictory. Genetic analyses of MPH metabolizing carboxylesterase 1 enzyme (CES1) have not been carried out, whereas, meta-analysis of CYP2D6 genetic variants has been already indicated significant pharmacogenetic differences in atomoxetine treatment. Here we present an association analysis of the CES1 Gly143Glu functional polymorphism in a Hungarian ADHD group (n = 173). The genotype frequencies were similar to that of the general population (5.8% vs 4.1% of Gly/Glu heterozygote). Pharmacogenetic analysis was conducted among 122 ADHD children treated with MPH. Neither the categorical analysis comparing 90 responders vs 32 non-responders, nor the dimensional analysis of Inattention and Hyperactivity-Impulsivity score reduction showed a significant main genotype effect. However, analyzing the daily dose, we observed an association with the rare 143Glu-variant: 5 patients in the responder group carrying the Glu-allele required lower doses of MPH for symptom reduction (0.410 +/- 0.127 vs 0.572 +/- 0.153 mg/kg, t(1,88) = 2.33, p = 0.022). This result warrants for further investigations of the CES1 gene in larger ADHD samples.
authors.affiliation: Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary. zsofia.nemoda@eok.sote.hu
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Nemoda
authors.forename: Nora
authors.initials: N
authors.lastname: Angyal
authors.forename: Zsanett
authors.initials: Z
authors.lastname: Tarnok
authors.forename: Julia
authors.initials: J
authors.lastname: Gadoros
authors.forename: Maria
authors.initials: M
authors.lastname: Sasvari-Szekely
mesh_terms: D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000201:enzymology; D043182:Carboxylesterase / Q000235:genetics*; D002265:Carboxylic Ester Hydrolases; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D002648:Child; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D011110:Polymorphism, Genetic
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D043182:Carboxylesterase