Clinical Pharmacogenetics in Pediatric Patients

Anwar Husain; Jennifer A. Loehle; David W. Hein


Pharmacogenomics. 2007;8(10):1403-1411. 

In This Article

Attention-deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) is a common childhood disruptive disorder characterized by age inappropriate levels of inattention, hyperactivity and impulsivity. Pharmacogenetic studies in ADHD suggest that interindividual differences in stimulant-response may be related to underlying genetic influences[50,51] Although many studies have examined relationships between methylphenidate response and polymorphisms at the dopamine transporter gene (DAT1), results are inconclusive.[52] Winsberg and Comings reported decreased methylphenidate response in children homozygous for the 10-repeat (480 bp) allele of a VNTR in the 3´-untranslated region of DAT1,[53] later confirmed in a subsequent report.[54] Others have reported increased response with the homozygous ten repeat[50,55] and decreased response with the homozygous nine repeat.[56] Several studies found no effect of DAT1 polymorphism[51,57,58] Other studies have examined the role of dopamine receptor genes (DRD4 and DRD5) in treatment response. Consistent with in vitro studies showing that the seven repeat (48 bp) VNTR polymorphism in the coding region of DRD4 produces blunted responses to dopamine[59,60] one or two copies of the seven repeat necessitated higher methylphenidate doses for optimal symptom reduction.[51] A recent study (111 patients) reported lack of associations between dopaminergic gene polymorphisms with methylphenidate response or adverse effects in ADHD treatment.[61] Clearly, additional studies in larger samples groups will be necessary to confirm or refute a possible role of pharmacogenetic polymorphisms in the efficacy and safety of ADHD treatment.

Another gene with potential effects on medication response is synaptosomal-associated protein (SNAP25), a neuron-specific protein implicated in exocytopic catecholamine release. A significant genotype–dose interaction and small to moderately favorable effects across all ratings for the T1065G SNP suggest that subjects homozygous for the T allele have improved dose responses in comparison with the variant G allele.[62] Patients possessing the T allele of T1069C did worse with methylphenidate. Although neither of these SNPs may be the functional variant underlying these differences and may only be in linkage disequilibrium with the true functional allele, these results provide a strong basis for further investigations of SNAP25. Variation in methylphenidate response also has been shown to be associated with a G1287A polymorphism in the norepinephrine transporter gene.[63] More recently, the adrenergic α-2A receptor gene (ADRA2A) was studied in response to methylphenidate.[64] This study demonstrates the favorable effect of the G allele at the ADRA2A-1291 C>G polymorphism in promoting greater reduction in inattentive symptoms during methylphenidate treatment.[64]

The greatest potential value of ADHD pharmacogenetics may lie in predicting medication tolerability. Side effects influence long-term medication adherence.[65] An awareness of increased risk of particular side effects may lead clinicians to choose medications more likely to be tolerated long term and would avoid exposing patients to drugs with high likelihoods of poor outcomes. For example, SNAP25 variants were associated with tics, buccal-lingual movements, and irritability, while DRD4 variants were associated with picking.[62]


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