Response to methylphenidate is not influenced by DAT1 polymorphisms in a sample of Brazilian adult patients with ADHD
- Authors: Contini, Veronica , Victor, Marcelo , Marques, Francine , Bertuzzi, Guilherme , Salgado, Carlos , Silva, Katiane , Sousa, Nyvia , Grevet, Eugenio , Belmonte-De-Abreu, Paulo , Bau, Claiton
- Date: 2010
- Type: Text , Journal article
- Relation: Journal of Neural Transmission Vol. 117, no. 2 (February 2010 2010), p. 269-276
- Full Text: false
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- Description: Several lines of evidence suggest a relevant role for the dopamine transporter (DAT1) gene not only as a susceptibility factor for attention-deficit hyperactivity disorder (ADHD), but also as a predictor of individual methylphenidate (MPH) response. Pharmacogenetic studies of MPH response in ADHD have mainly focused on the 40-bp variable number of tandem repeats (VNTR) in the 3 untranslated region (3-UTR) of DAT1. Most studies were performed in samples of children and conflicting findings were obtained. Only two studies have assessed 3-VNTR in samples of adults-one with positive and the other with negative findings. In the present study, we investigate three potentially relevant polymorphisms in DAT1 gene (-839 C > T; Int8 VNTR and 3-VNTR), and their possible role in therapeutic response to MPH treatment in a sample of 171 Brazilian adults with ADHD. The diagnostic procedures followed the DSM-IV criteria and the outcome measures were the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at the beginning and after the 30th day of treatment. Drug response was assessed by both categorical and dimensional approaches. There was no effect of any DAT1 polymorphisms or haplotypes on MPH response. This is the second report demonstrating absence of differences in MPH response according to DAT1 genotypes in adults with ADHD. Although DAT protein is crucial for the effect of MPH, genetic variations in DAT1 gene probably do not have a significant clinical role in this sample of adults with ADHD. © 2009 Springer-Verlag.
- Description: C1
Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: Findings from a sample of adults
- Authors: De Azeredo, Luca , Rovaris, Diego , Mota, Nina , Polina, Evelise , Marques, Francine , Contini, Veronica , Vitola, Eduardo , Belmonte-De-Abreu, Paulo , Rohde, Luis , Grevet, Eugenio , Bau, Claiton
- Date: 2014
- Type: Text , Journal article
- Relation: European Archives of Psychiatry and Clinical Neuroscience Vol. 5, no. (2014), p. 401-408
- Full Text: false
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- Description: The dopamine transporter (SLC6A3/DAT1) plays a key role in the regulation of dopaminergic neurotransmission and is the major site of action for methylphenidate, a first-line medication for attention deficit hyperactivity disorder (ADHD). Most genetic association studies with ADHD have investigated a 40-bp variable number of tandem repeats (VNTR) polymorphism in the 3′-untranslated region (UTR) of the DAT1, but these investigations have reported heterogeneous findings. The few studies focused on the 5′ region have reported promising results. Despite rs2652511 not being included, nor having any proxy SNP available in GWAS, the few candidate gene studies that analyzed it suggested an association with ADHD and schizophrenia. Here, we analyzed the -839 C/T (rs2652511) promoter variant and the 3′-UTR and intron 8 (Int8) VNTR polymorphisms in 522 adults with ADHD and 628 blood donor controls. The diagnostic procedures followed the DSM-IV criteria. A significant association was detected (P = 0.002) between the rs2652511 C-allele with ADHD. In addition, the 6-repeat allele of Int8 VNTR was associated with higher inattention scores (P = 0.034). The haplotype analysis including DAT1 3′-UTR and Int8 VNTR polymorphisms did not reveal associations with ADHD susceptibility or severity dimensions. These findings extend to adult samples previous findings from children samples on the role of the rs2652511 polymorphism in the promoter region of DAT1 as a risk factor for ADHD susceptibility. © 2014 Springer-Verlag.
ADRA2A polymorphisms and ADHD in adults : Possible mediating effect of personality
- Authors: de Cerqueira, Caio , Polina, Evelise , Contini, Veronica , Marques, Francine , Grevet, Eugenio , Salgado, Carlos , da Silva, Paula , Picon, Felipe , Belmonte-De-Abreu, Paulo , Bau, Claiton
- Date: 2011
- Type: Text , Journal article
- Relation: Psychiatry Research Vol. 186, no. 2-3 (2011), p. 345-350
- Full Text: false
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- Description: Several studies have tested for the association between polymorphisms in the ADRA2A gene and childhood ADHD. A meta-analysis of these results, however, has pointed towards a significant heterogeneity, raising the need for explanatory studies. As the effect of other relevant clinical characteristics could be a possible source, we studied three polymorphisms in the ADRA2A gene (−1291 C>G–MspI or rs1800544; −262 G>A–HhaI or rs1800544; 1780 C>T–DraI or rs553668) in 403 adult patients with ADHD assessed in relation to comorbidity and personality characteristics, as well as in 232 controls. The diagnosis followed DSM-IV criteria, and personality dimensions were evaluated with the Temperament and Character Inventory (TCI). There were no significant differences in allele and genotype frequencies between cases and controls. Patients carrying the G allele of rs1800544 presented lower scores in harm avoidance, and carriers of the T allele of rs553668 had more novelty seeking and less harm avoidance and persistence. Additionally, the haplotype carrying the G-G-T alleles (rs1800544–rs1800545–rs553668) was associated with lower scores in harm avoidance and persistence, and higher scores in novelty seeking compared to other haplotypes. These findings suggest that the conflicting findings obtained in association studies between ADRA2A polymorphisms and ADHD might be related to temperament profiles, and support additional studies addressing these effects in larger samples.
Is there a role for rare variants in DRD4 gene in the susceptibility for ADHD Searching for an effect of allelic heterogeneity
- Authors: Tovo-Rodrigues, Luciana , Rohde, Luis , Roman, Tatiana , Schmitz, Marcelo , Polanczyk, Guilherme , Zeni, Cristian , Marques, Francine , Contini, Veronica , Grevet, Eugenio , Belmonte-De-Abreu, Paulo , Bau, Claiton , Hutz, Mara
- Date: 2012
- Type: Text , Journal article
- Relation: Molecular Psychiatry Vol. 17, no. 5 (May 2012), p. 520-526
- Full Text: false
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- Description: Although several studies have demonstrated an association between the 7-repeat (7R) allele in the 48-bp variable number of tandem repeats (VNTRs) in the exon 3 at dopamine receptor D4 (DRD4) gene and attention-deficit/ hyperactivity disorder (ADHD), others failed to replicate this finding. In this study, a total of 786 individuals with ADHD were genotyped for DRD4 exon 3 VNTR. All 7R homozygous subjects were selected for VNTR re-sequencing. Subjects homozygous for the 4R allele were selected paired by age, ancestry and disorder subtypes in order to have a sample as homogeneous as possible with 7R/7R individuals. Using these criteria, 103 individuals (66 with ADHD and 37 control individuals) were further investigated. An excess of rare variants were observed in the 7R alleles of ADHD patient when compared with controls (P = 0.031). This difference was not observed in 4R allele. Furthermore, nucleotide changes that predict synonymous and non-synonymous substitutions were more common in the 7R sample (P = 0.008 for total substitutions and P = 0.043 for non-synonymous substitutions). In silico prediction of structural/functional alterations caused by these variants have also been observed. Our findings suggest that not only repeat length but also DNA sequence should be assessed to better understand the role of DRD4 exon 3 VNTR in ADHD genetic susceptibility.
- Description: C1