No abstract

Pharmacogenetic studies investigating the 40-bp VNTR polymorphism at SLC6A3 and methylphenidate response have shown conflicting results and large differences in study design and efficacy endpoints. Our objective was to investigate the relation between the 3'-VNTR at SLC6A3 and variability in methylphenidate response in a sample of 141 ADHD children and adolescents, assessed before and after methylphenidate treatment with both clinical and neuropsychological outcome measures. 10-R homozygotes were significantly overrepresented in the low response group, but no genotype effect was shown in cognitive variables improvement. A meta-analysis of pharmacogenetic studies with comparable data (responders vs. non-responders) on a total of 475 subjects showed a significant association between the 10-10 genotype and low rates of methylphenidate response (mean Odds Ratio = 0.46; 95% CI [0.28-0.76]). Heterogeneity between these studies did not reach a significant level but, as publications with different endpoints were excluded from this meta-analysis, our results do not rule out a possible influence of study design.

Discrepancies in the role of the 40 bp VNTR polymorphism of the dopamine transporter gene (DAT1) in attention-deficit hyperactivity disorder (ADHD) could be due to various sources of genetic or phenotypical heterogeneity. We therefore analyzed a sample of 146 ADHD children and their parents, with a transmission disequilibrium test (TDT) design, assessing age, inattention, and hyperactivity dimensions and total score of the ADHD Rating Scale, the number of errors and the total score at Stroop Color-Word test, and the total score at the Trail Making Test. The TDT for 10-repeat (10-R) allele shows a perfect lack of transmission bias (Mc Nemar chi(2) = 0) and PBAT analyses showed no role of this polymorphism for any of the studied endophenotypes. Lack of statistical power is always a possibility, but with a sample size above the average of the majority of previous studies, and an odds ratio (number of transmitted versus untransmitted 10-R allele) of 1.00 exactly, this possibility may be considered as not very likely.