What is ADRA2A?
ADRA2A, located on chromosome 10, encodes the α-2A adrenergic receptor, a norepinephrine receptor that is the primary site of action for α-2A agonists. The α-2A adrenergic receptor is predominantly found in the brain and is concentrated in the prefrontal cortex (PFC). This receptor is thought to mediate the effects of norepinephrine in the PFC and regulate symptoms of attention-deficit/hyperactivity disorder (ADHD).1
A few polymorphisms have been identified in this gene. The best studied is a single G>C substitution at position 1291 (rs1800544) in the promotor region of ADRA2A.2 This polymorphism is associated with a reduced response to certain ADHD medications, which is likely due to reduced binding affinity.3 Since this would lead to reduced receptor stimulation, treatment may fail to improve inattentive and hyperactive-impulsive symptoms in ADHD patients who carry this polymorphism.
Is there a connection between ADRA2A genotype and the efficacy of methylphenidate?
Eight studies have reviewed the effect of the rs1800544 SNP on methylphenidate (MPH) efficacy.4–11 Five of these studies showed that subjects with the -1291G>C polymorphism exhibited a reduced response to MPH treatment.4–8 Of these five studies, two (n=165) found that the presence of the G allele improved inattentive symptoms for patients taking MPH.4,5 Similarly, Cheon et al. (n=114) found that subjects taking MPH with the G/G genotype had greater improvement of inattentive and total ADHD symptoms.6 Two additional studies (n=216) showed that MPH-treated patients with the G/G genotype exhibited a greater improvement in mean response time variability.7,8 In contrast, Froehlich et al. (n=89) found that subjects with the G/G genotype had increased hyperactive-impulsive symptoms. However, this conclusion did not stay significant after Bonferroni corrections. Furthermore, this study administered varying doses of MPH to the subjects, while the other studies used a fixed dose to fairly evaluate response.9 Although two other studies (n=268) failed to find an association between ADRA2A variants and reduction in ADHD symptoms, these studies presented with key limitations.10,11 Hong et al. (n=103) acknowledged that it was not clear whether the poor responders had insufficient treatment response to MPH or insufficient dosing because of lack of tolerability10, while Contini et al. (n=165) evaluated adult subjects with ADHD rather than children, who were evaluated in all other studies11. Furthermore, Contini et al. used the Swanson, Nolan, and Pelham (SNAP) Questionnaire to evaluate ADHD symptoms for their adult subjects, but this scale is only intended for children and young adults.12
Is there a connection between ADRA2A genotype and the efficacy of non-stimulant ADHD medicatons?
ADRA2A is the primary site of action for α-2A agonists, such as clonidine and guanfacine. Treatment with either medication can increase norepinephrine signaling through stimulation of postsynaptic receptors, resulting in decreased hyperactive-impulsive and inattentive symptoms.1 Therefore, variation in ADRA2A may also affect response to these medications by reducing receptor binding affinity. While no studies have evaluated the effect of ADRA2A genotype on clonidine and guanfacine in ADHD patients, two studies have analyzed the effect of ADRA2A genotype on clonidine efficacy in other disease states.14,15 Camilleri et al. (n=120) evaluated subjects with irritable bowel syndrome and found that those with the C/C genotype may have a decreased response to clonidine.16 While this finding is in a different field, it demonstrates how the mechanism of action of clonidine is affected by variation in ADRA2A. Since guanfacine is a more selective α-2A agonist, it is likely that the mechanism of action of this medication is also affected by ADRA2A genotype. Another study (n=270) failed to find an association between ADRA2A genotype and clonidine response in patients having cirrhosis with refractory ascites.17 However, the authors suggest that this may be due to the low dose of clonidine used in the study.
One study (n=111) investigated the effect of the rs1800544 SNP on the efficacy of atomoxetine, a norepinephrine reuptake inhibitor, in children with ADHD, but no associations were found.13 This current lack of evidence, in addition to the fact that atomoxetine is not believed to directly target ADRA2A, leads to the reasonable conclusion that the rs1800544 SNP likely does not affect response to atomoxetine.
The rs1800544 SNP displays a consistent association with MPH efficacy in subjects with ADHD. Multiple clinical studies have demonstrated that individuals with the -1291G>C polymorphism in ADRA2A exhibited reduced response to MPH.7-11 Furthermore, since this variation may also reduce the binding affinity of α-2A agonists, individuals may also experience a reduced response to clonidine and guanfacine. Therefore, identifying patients with variation in ADRA2A may be beneficial to healthcare providers when selecting medications to treat ADHD.
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4. Polanczyk, G. et al. Association of the adrenergic alpha2A receptor gene with methylphenidate improvement of inattentive symptoms in children and adolescents with attention-deficit/hyperactivity disorder. Arch. Gen. Psychiatry 64, 218–224 (2007).
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14. Camilleri, M. et al. Pharmacogenetics of low dose clonidine in irritable bowel syndrome. Neurogastroenterol. Motil. 21, 399–410 (2009).
15. Yang, Y. Y. et al. Association of the G-protein and α2-adrenergic receptor gene and plasma norepinephrine level with clonidine improvement of the effects of diuretics in patients with cirrhosis with refractory ascites: a randomised clinical trial. Gut 59, 1545–1553 (2010).