Catechol-O-methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children.
Methylphenidate is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD) but it is not effective in every case. Therefore, identifying genetic and/or biological markers predicting drug-response is increasingly important. Here we present a case-control study and pharmacogenetic association analyses in ADHD investigating three dopaminergic polymorphisms. Previous studies suggested variable number of tandem repeats (VNTR) in the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1) genes as genetic risk factors for ADHD and as possible markers of methylphenidate response. Our results did not indicate substantial involvement of these two VNTRs in ADHD, however, both the case-control and the pharmacogenetic analyses showed significant role of the high activity Val-allele of cathecol-O-methyltransferase (COMT) Val158Met polymorphism in our ADHD population. The Val-allele was more frequent in the ADHD group (n = 173) compared to the healthy population (P = 0.016). The categorical analysis of 90 responders versus 32 non-responders showed an association between the Val-allele or Val/Val genotype and good methylphenidate response (P = 0.009 and P = 0.034, respectively). Analyzing symptom severity as a continuous trait, significant interaction of COMT genotype and methylphenidate was found on the Hyperactivity-Impulsivity scale (P = 0.044). Symptom severity scores of all three genotype groups decreased following methylphenidate administration (P < 0.001), however Val/Val homozygote children had significantly less severe symptoms than those with Met/Met genotype after treatment (P = 0.015). This interaction might reflect the regulatory effect of COMT dominated prefrontal dopamine transmission on subcortical dopamine systems, which are the actual site of methylphenidate action.
Kereszturi
Eva
E
Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
Tarnok
Zsanett
Z
Bognar
Emese
E
Lakatos
Krisztina
K
Farkas
Luca
L
Gadoros
Julia
J
Sasvari-Szekely
Maria
M
Nemoda
Zsofia
Z
D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D002648:Child; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D018598:Minisatellite Repeats; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D050638:Receptors, Dopamine D4 / Q000235:genetics; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4; D008774:Methylphenidate; D002394:Catechol O-Methyltransferase