title: A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical response to atomoxetine in attention-deficit hyperactivity disorder (ADHD).
abstract: Atomoxetine is a specific inhibitor of the norepinephrine transporter (NET) that has demonstrated efficacy in the treatment of children with attention-deficit hyperactivity disorder (ADHD). We investigated whether polymorphisms in the NET/SLC6A2 gene may influence atomoxetine response in ADHD. Two independent cohorts of 160 and 105 ADHD children treated for 6 weeks with atomoxetine (0.5-1.8 mg/kg per day) were genotyped on CYP2D6, which metabolizes atomoxetine, and 108 single nucleotide polymorphisms in the NET/SLC6A2 gene. Response was defined as a minimum decrease of 25% in ADHD Rating Scale IV-Parent Version and a Clinical Global Impression-Severity (CGI-S) score less than or equal to 2 at week 6. Interindividual response was independent of the genetic variants of CYP2D6. Significant (p<0.05) associations between 20 NET/SLC6A2 single nucleotide polymorphisms (SNPs) and clinical efficacy in atomoxetine responders, compared with non-responders, were observed. The genomic region across exons 4 to 9 of NET/SLC6A2, where 36 SNPs have been genotyped, was associated with treatment response in both cohorts (p<0.01, odds ratio=2.2 and p=0.026, odds ratio=6.3, respectively), in the combined cohort (p<0.01, odds ratio=1.83), and in the subgroup of Caucasians only (p=0.02, odds ratio=1.8). Clinical efficacy of atomoxetine treatment in ADHD shows potential dependence upon a series of genetic polymorphisms of its mechanistic target, the norepinephrine transporter. Taking into account the high heritability of ADHD, the significance of the present finding and replication of a similar haplotype allele sequence result in an independent cohort, it is suggested that further assessment of this region could be useful in determining response to atomoxetine in ADHD.
authors.affiliation: INSERM U675, IFR02, Faculty Xavier Bichat, University of Paris, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ramoz
authors.forename: Claudette
authors.initials: C
authors.lastname: Boni
authors.forename: Anncatherine M
authors.initials: AM
authors.lastname: Downing
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Close
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Peters
authors.forename: Angela M
authors.initials: AM
authors.lastname: Prokop
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Allen
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: Diane
authors.initials: D
authors.lastname: Purper-Ouakil
authors.forename: Philip
authors.initials: P
authors.lastname: Gorwood
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011437:Propylamines / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D018759:Adrenergic Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; C493227:SLC6A2 protein, human; D000069445:Atomoxetine Hydrochloride; D019389:Cytochrome P-450 CYP2D6