Variants of Dopamine Beta Hydroxylase Gene Moderate Atomoxetine Response in Children with Attention-Deficit/Hyperactivity Disorder

Abstract

Objective: Atomoxetine is the most widely used nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). It selectively acts on the norepinephrine (NE) system. Dopamine beta hydroxylase (DBH) regulates the synthesis of NE. This study aimed to investigate whether variants in the DBH gene have an effect on the differential response to atomoxetine. Methods: Children and adolescents with ADHD were enrolled in a prospective, open-label study of atomoxetine for 8-12 weeks. The dose was titrated to 1.2-1.4 mg/kg per day and maintained for at least 4 weeks. The primary efficacy measure was the investigator-rated ADHD Rating Scale-IV (ADHD-RS-IV). Three categorical evaluations of treatment effects (defined as response, robust response, and remission) were used. We used a candidate gene approach. Eight single nucleotide polymorphisms (SNPs) in DBH were selected and genotyped based on the functional annotation in literature. Their association with response or remission status was analyzed. Results: Four SNPs were found nominally associated with response status (rs1076150, p = 0.0484; rs2873804, p = 0.0348; rs1548364, p = 0.0383; and rs2519154, p = 0.0097), two were associated with robust response (rs1076150, p = 0.0349; and rs2519154, p = 0.0047), and one was associated with remission (rs2519154, p = 0.0479). The association between rs2519154 and robust response was significant after correction of multiple comparison ( p = 0.0384). Two haplotypes of linkage disequilibrium (LD) block1 (constituted by rs1108580, rs2873804, rs1548364, and rs2519154) were nominally associated with response and robust response status (CTAC: p = 0.0301 for response, p = 0.0374 for robust response; TCGT: p = 0.0317 for response, p = 0.021 for robust response), whereas one haplotype (GC) of LD block2 (constituted by rs2073837 and rs129882) was associated with robust response and remission status ( p = 0.0377 for robust response; p = 0.0321 for remission), although none achieved significant threshold after multiple comparison. Conclusions: Variants in DBH genes were associated with atomoxetine response in the treatment of ADHD. Further replication in larger samples would be warranted.

Dopamine beta‐hydroxylase and its genetic variants in human health and disease

“…This finding was also observed in a meta‐analysis by Catalá‐López, that found a significant adverse health and longevity effect in both autism spectrum disorder and ADHD (Catala‐Lopez et al ). DβH has been widely implicated in ADHD with increased risk, reduced life, and altered pharmacological efficacy (Fang et al ; Tong et al ; Barkley et al ). A longitudinal study performed by Barkley et al () found that the DβH Taq1 A1 and A2 gene polymorphisms contribute to lower estimated life expectancy in ADHD patients.…”

“…Their in vitro gene expression studies showed that cells that are homozygous for the rs129882 variant produce a 2‐fold decrease in luciferase activity. Another study in ADHD reports that rs2519154 (located in intron five) is highly correlated with altered pharmacological intervention in children and adolescents (Fang et al ). Patients carrying either the heterozygous or homozygous rs2519154 polymorphism had a better response to atomoxetine, a mainline medication for ADHD treatment, compared to wild‐type (Fang et al ).…”

“…Another study in ADHD reports that rs2519154 (located in intron five) is highly correlated with altered pharmacological intervention in children and adolescents (Fang et al ). Patients carrying either the heterozygous or homozygous rs2519154 polymorphism had a better response to atomoxetine, a mainline medication for ADHD treatment, compared to wild‐type (Fang et al ). Similarly, in an eastern Indian population, rs1611115 is believed to be involved in a similar drug response as well as more impulsive personality styles, but not directly with ADHD (Hess et al ; Bhaduri et al ).…”

Genetic risk factors and gene–environment interactions in adult and childhood attention-deficit/hyperactivity disorder

“…Four SNPs in the dopamine β-hydroxylase gene (DBH) were found nominally associated with atomoxetine response status in a Chinese sample of 153 children and adolescents with ADHD (rs1076150, rs2873804, rs1548364, and rs2519154). The association between rs2519154 and atomoxetine response remained significant after correction for multiple comparisons (Fang et al, 2015). Ramoz et al (2009) also investigated atomoxetine response in association with SLC6A2 and CYP2D6 gene SNPs.…”

Pharmacogenetics of Dopamine β‐Hydroxylase in cocaine dependence therapy with doxazosin

“…The DBH gene polymorphism (C-1021T) has been reported to moderate treatment outcome with several medications in patients with various medical and psychiatric conditions including CUD (Fang et al, 2015;Kosten et al, 2013;Liu et al, 2014;Schottenfeld et al, 2014). Here, we report greater efficacy of doxazosin (8 mg/day) in reducing cocaine use in individuals with the DBH C-1021T CT or TT genotype (low DβH and NE levels) than those with the CC genotype.…”