Adrenergic neurotransmitter system transporter and receptor genes associated with atomoxetine response in attention-deficit hyperactivity disorder children

Abstract

Atomoxetine, a selective inhibitor of the norepinephrine transporter, exerts its therapeutic effect for attention-deficit hyperactivity disorder (ADHD) by increasing the concentration of synaptic norepinephrine. The objective of this study was to evaluate the association of the genetic variants of multiple genes of the noradrenergic neurotransmitter system with atomoxetine response. One hundred and eleven ADHD children and adolescents were enrolled in a prospective, open-label study of atomoxetine for 8-12weeks. The dose was titrated to 1.2-1.4mg/kg per day and maintained for at least 4weeks. The primary efficacy measure was the investigator-rated ADHD Rating Scale-IV. Two categorical evaluations of treatment effects (defined as response and remission) were used. Twelve SNPs in SLC6A2, ADRA2A, and ADRA1A were genotyped to analyze their association with response or remission status. rs3785143 in SLC6A2 was associated with responder status (nominal P=0.0048; corrected by multiple test, P=0.0416; OR 2.66, 95% confidence interval (CI) 1.35-5.26). rs2279805 of SLC6A2 was nominally significantly associated with the remission status. (P=0.0221, OR 2.32, 95% CI 1.13-4.75, multiple test P=0.2130). The GG haplotype of rs1800544 and rs553668 in ADRA2A achieved nominal significance for association with non-remission (P=0.0219, OR 2.82, 95% CI 1.16-6.85, multiple test, P=0.2076). The results of this study suggest that DNA variants of both SLC6A2 and ADRA2A in the adrenergic neurotransmitter system might alter the response to atomoxetine, though further replication study in larger sample for validation of these findings is still needed.