Biomedical subjects

Tatiana Roman

Publications and source records attributed to Tatiana Roman.

13 recordsLinked to original sources

PubMed2007

No significant association between response to methylphenidate and genes of the dopaminergic and serotonergic systems in a sample of Brazilian children with attention-deficit/hyperactivity disorder.

Few studies on pharmacogenetics of Attention-Deficit/Hyperactivity Disorder (ADHD) have been conducted. Most of them evaluated dopaminergic genes resulting in positive and negative findings. We assessed effects of polymorphisms in candidate dopaminergic (DRD4, DAT1) and serotonergic genes (HTR1B, HTR2A, and 5-HTT) on the response to treatment in 111 patients for whom methylphenidate (MPH) was prescribed. Outcome measures (Swanson, Nolan, and Pelham scale-version IV, Children Global Assessment Scale, Barkley's Stimulants Side Effects Rating Scale) were assessed at baseline and 1 month after the intervention. No significant association was detected between polymorphisms assessed and both response and side effects to MPH. Prospective multi-site controlled studies with larger sample sizes are needed in order to disentangle the role of candidate genes in response to ADHD treatment.

Adolescent↗

PubMed2007

A promoter polymorphism (-839 C > T) at the dopamine transporter gene is associated with attention deficit/hyperactivity disorder in Brazilian children.

The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission and is also the major site of action for methylphenidate which is one of the main drugs used to treat attention deficit hyperactivity disorder (ADHD). Most association studies with ADHD have concentrated on the 3'-untranslated region of the gene (3'-UTR) mainly in a variable number of tandem repeat (VNTR) polymorphism, but these investigations have reported discordant results. In this study, we tested this VNTR polymorphism and an additional promoter polymorphism -839 C>T (Rs: 2652511) using family-based association analyses in a sample of 243 Brazilian ADHD children and adolescents and their parents. No significant linkage disequilibrium between the two polymorphisms was detected in this sample (D' = 0.56; P = 0.22). No evidence of association with the VNTR polymorphism was found. A significant association (P = 0.03) for biased transmission of the C allele at the -839 C>T polymorphism to ADHD children in the total sample was observed, which was strengthened when the analyses were restricted to the ADHD combined type (P = 0.004). Our results suggest a role for the promoter region of DAT1 gene in ADHD susceptibility in this Brazilian sample.

Attention Deficit Disorder with Hyperactivity↗

PubMed2007

Serotonin genes and attention deficit/hyperactivity disorder in a Brazilian sample: preferential transmission of the HTR2A 452His allele to affected boys.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Low serotonin activity has been associated in both animal and human studies with measures of impulsivity, aggression, and disinhibited behaviors, which make genes from the serotonin system reasonable candidates for ADHD susceptibility. In the present study, we investigated a polymorphism in the promoter region of the serotonin transporter (SLC6A4) and two polymorphisms (-1438 A > G and His452Tyr) in the serotonin 5-HTR2A receptor gene using family based association analyses in a sample of 243 Brazilian ADHD children and adolescents and their parents. No linkage disequilibrium between the two HTR2A polymorphisms was detected in this sample (P = 0.76). Considering several evidences from animal models for sexual dimorphism in serotonin genes expression, analyses were performed separately for the whole sample and for male probands. No evidences for biased transmissions of both HTR2A -1438 A > G and SLC6A4 polymorphisms to ADHD youths were observed. Preferential transmission of the HTR2A His452 allele was observed only in families with affected boys (P = 0.04). Our results suggest that findings from ADHD association studies for serotonin genes might be understood in the context of a gender effect, which may help to explain conflicting results in these association studies.

Adolescent↗

PubMed2006

Association between alpha-2a-adrenergic receptor gene and ADHD inattentive type.

BACKGROUND: Previous investigations have demonstrated that an MspI polymorphism at the adrenergic alpha2A receptor gene (ADRA2A) is associated with severity of attention-deficit/hyperactivity disorder (ADHD) inattentive symptoms in clinical samples composed mainly of subjects with ADHD, combined type. This study aimed to investigate the association between this ADRA2A polymorphism and attention-deficit/hyperactivity disorder-inattentive type (ADHD-I) in a nonreferred sample. METHODS: In a case-control study, we assessed a sample of 100 children and adolescents with ADHD-I and 100 non-ADHD controls. Cases and controls were matched by gender and age and were screened by using teacher reports in a revised version of the Swanson, Nolan, and Pelham rating scale at 12 schools. Psychiatric diagnoses were derived through structured diagnostic interviews. RESULTS: Homozygous subjects for the G allele at the ADRA2A had significantly higher odds ratio (OR) for ADHD-I than did those with other genotypes (CC + CG genotypes), even after adjusting for potential confounders (p = .02; OR = 3.78; 95% confidence interval = 1.23-11.62). In family-based analyses, no significant associations were detected. CONCLUSIONS: Our results suggest that the ADRA2A may be associated with ADHD-I, replicating previous findings from clinical samples that have suggested the importance of this gene for the dimension of inattention. In addition, these results support the role of the noradrenergic system in ADHD.

Adolescent↗

PubMed2006

Association between DRD4 gene and performance of children with ADHD in a test of sustained attention.

BACKGROUND: The adoption of neuropsychological tests as endophenotypic measures can provide an increased sensitivity to specific dimensions of attention-deficit/hyperactivity disorder (ADHD). METHODS: The association between a variable number of tandem repeats polymorphism at the dopamine D4 receptor gene (DRD4) and the performance of children and adolescents with ADHD in a continuous performance test (CPT) was evaluated. The sample comprised 90 clinically referred children and adolescents with ADHD. Errors of omission and commission in the CPT were computed and the number of 48-base pairs tandem repeats in the exon III of DRD4 was assessed. RESULTS: The presence of a 7-repeat allele was associated with more errors of commission and the homozygosity of the 4-repeat allele was related to fewer errors of commission and omission even after adjusting for age. CONCLUSIONS: These findings bring further evidence on the role of DRD4 polymorphisms on the performance in sustained attention tasks among children and adolescents with ADHD diagnosis.

Adolescent↗

PubMed2005

Brain perfusion and dopaminergic genes in boys with attention-deficit/hyperactivity disorder.

Neuroimaging studies have suggested the involvement of several brain areas in attention-deficit/hyperactivity disorder (ADHD). Genetic investigations have supported the role of both dopamine D4 receptor gene (DRD4) and dopamine transporter gene (DAT1) in the vulnerability to the disorder. This study evaluates whether the presence of risk alleles at DRD4 and/or DAT1 genes is associated with differences in regional cerebral blood flow (rCBF) in a sample of ADHD boys. The rCBF was compared between ADHD patients with and without risk alleles at DRD4 (7-repeat allele) and/or at DAT1 (homozygosis for the 10-repeat allele) genes by single photon emission computed tomography (SPECT) during continuous performance test. Images were analyzed using statistical parametric mapping (SPM-99). No significant differences in rCBF were found both between ADHD boys with and without the 7-repeat allele at DRD4 locus, as well as between ADHD boys homozygous for the 10-repeat allele and ADHD subjects with other genotypes at the DAT1 locus. However, a significantly higher perfusion in the right middle temporal gyrus was found in the group with risk alleles at both DRD4 and DAT1 loci (n = 6) compared to ADHD boys without risk alleles at both loci (n = 28) (P < 0.05). Our findings suggest that a higher recruitment in middle temporal gyrus, an area associated to working memory and selective attention, should exist to compensate a putative effect of the interaction between these dopaminergic genes.

Adolescent↗

PubMed2005

Attention-deficit/hyperactivity disorder: advancing on pharmacogenomics.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder. An impressive volume of literature documents both a strong participation of genetics in its etiology and a high rate of response to medication. However, few studies on the pharmacogenomics of ADHD have been conducted to date. This systematic review aims to present a critical discussion of findings from recent investigations. The majority of studies have focused on individual polymorphisms of the dopaminergic genes, with special emphasis on variants of the dopamine transporter gene (DAT1). Almost all studies have assessed the effects of genes in the response to methylphenidate (MPH). Some preliminary results suggest an association between homozygosity for the 10-repeat allele at DAT1 and poor response to MPH. However, other studies have reported contrasting findings. Very few investigations addressed the role of non-dopaminergic genes or gene-gene interactions in ADHD pharmacogenomics. Recent findings suggesting an association between response to MPH and an MspI polymorphism in the promoter region of the alpha2A-adrenoceptor gene (ADRA2A) are discussed. Pharmacogenomic studies of ADHD are in their infancy, and comparability between studies is difficult due to the use of different methodological approaches. As such, multi-site collaborative efforts to obtain larger samples with standardized methodology should be encouraged.

Attention Deficit Disorder with Hyperactivity↗

PubMed2004

Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes.

Attention Deficit Disorder with Hyperactivity↗

PubMed2004

Polymorphisms of the dopamine transporter gene: influence on response to methylphenidate in attention deficit-hyperactivity disorder.

Attention deficit-hyperactivity disorder (ADHD) is a very common and heterogeneous childhood-onset psychiatric disorder, affecting between 3% and 5% of school age children worldwide. Although the neurobiology of ADHD is not completely understood, imbalances in both dopaminergic and noradrenergic systems have been implicated in the origin and persistence of core symptoms, which include inattention, hyperactivity, and impulsivity. The role of a genetic component in its etiology is strongly supported by genetic studies, and several investigations have suggested that the dopamine transporter gene (DAT1; SLC6A3 locus) may be a small-effect susceptibility gene for ADHD. Stimulant medication has a well-documented efficacy in reducing ADHD symptoms. Methylphenidate, the most prescribed stimulant, seems to act mainly by inhibiting the dopamine transporter protein and dopamine reuptake. In fact, its effect is probably related to an increase in extracellular levels of dopamine, especially in brain regions enriched in this protein (i.e. striatum). It is also important to note that dopamine transporter densities seem to be particularly elevated in the brain of ADHD patients, decreasing after treatment with methylphenidate. Altogether, these observations suggest that the dopamine transporter does play a major role in ADHD. Among the several polymorphisms already described in the SLC6A3 locus, a 40 bp variable number of tandem repeats (VNTR) polymorphism has been extensively investigated in association studies with ADHD. Although there are some negative results, the findings from these reports indicate the allele with ten copies of the 40 bp sequence (10-repeat allele) as the risk allele for ADHD. Some investigations have suggested that this polymorphism can be implicated in dopamine transporter gene expression in vitro and dopamine transporter density in vivo, even though it is located in a non-coding region of the SLC6A3 locus. Despite all these data, few studies have addressed the relationship between genetic markers (specifically the VNTR) at the SLC6A3 locus and response to methylphenidate in ADHD patients. A significant effect of the 40 bp VNTR on response to methylphenidate has been detected in most of these reports. However, the findings are inconsistent regarding both the allele (or genotype) involved and the direction of this influence (better or worse response). Thus, further investigations are required to determine if genetic variation due to the VNTR in the dopamine transporter gene is able to predict different levels of clinical response and palatability to methylphenidate in patients with ADHD, and how this information would be useful in clinical practice.

Attention Deficit Disorder with Hyperactivity↗

PubMed2003

Is the alpha-2A adrenergic receptor gene (ADRA2A) associated with attention-deficit/hyperactivity disorder?

Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex childhood-onset psychiatric disorder characterized by marked symptoms of inattention, hyperactivity, and impulsivity. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Although most of the molecular studies have investigated the dopamine D4 receptor gene (DRD4) and the dopamine transporter gene (DAT1) genes in its etiology, pharmacological and brain imaging evidences seem to indicate that genes of the adrenergic system could also be attractive for association studies. We investigated a sample of 96 Brazilian ADHD children and adolescents and their parents for the ADRA2A MspI polymorphism. Although no association with either MspI allele was observed through the haplotype relative risk (HRR) analysis, effects of the ADRA2A gene on inattention and combined (inattention + hyperactivity/impulsivity) symptom scores were detected (U = 222.5, z = 2.19, P = 0.03; and U = 208.5, z = 2.32, P = 0.02, respectively). Our results suggest that the ADRA2A gene might have a small effect on ADHD susceptibility or that this gene might modulate the severity of the disorder. They are also consistent with the noradrenergic theories of ADHD, suggesting a role for the alpha2A adrenergic receptors in the disorder.

Adolescent↗

PubMed2003

Dopamine transporter gene, response to methylphenidate and cerebral blood flow in attention-deficit/hyperactivity disorder: a pilot study.

The homozygosity of the 10-repeat allele at dopamine transporter gene (DAT1) seems to be associated with a poor response to methylphenidate (MPH) in children with attention-deficit/hyperactivity disorder (ADHD). This pilot study aimed to simultaneously assess polymorphisms at DAT1, response to MPH, and neuroimaging. Only ADHD children with at least a moderate response to MPH were included. Significantly higher regional cerebral blood flows assessed by single photon emission computerized tomography (SPECT) were detected in medial frontal and left basal ganglia areas in children with homozygosity for the 10-repeat allele at DAT1 gene (n = 4) than in children without this genotype (n = 4) (P < 0.05). These findings provide a preliminary connection between pharmacogenetics and neurobiological investigations on stimulant treatment of ADHD.

Attention Deficit Disorder with Hyperactivity↗

PubMed2002

Further evidence for the association between attention-deficit/hyperactivity disorder and the dopamine-beta-hydroxylase gene.

Attention-deficit/hyperactivity disorder (ADHD) is a very common and heterogeneous psychiatric disorder of childhood with marked inattentive, hyperactive, and impulsive symptoms. The DBH gene, the locus that encodes the enzyme dopamine-beta-hydroxylase (DbetaH), seems to be an important candidate gene for association studies, since DbetaH catalyzes the conversion of dopamine to norepinephrine. The aim of this study was to test for association between the DBH gene and ADHD in a sample of 88 Brazilian nuclear families. Haplotype relative risk (HRR) analysis of the DBH TaqI restriction site polymorphism showed a preferential transmission of the TaqI A2 allele in our whole ADHD sample (chi(2)=3.61, one-tailed P=0.03). The significant effect of the A2 allele was stronger when only families with no ADHD parental diagnosis were considered (chi(2)=5.42, one-tailed P=0.01). Our results suggest a contribution of this gene to ADHD susceptibility, partially replicating previous findings that have demonstrated an association between the DBH TaqI A2 allele and ADHD.

Alleles↗

PubMed2002

Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity disorder.

This study aims to evaluate whether a previously reported association between homozygosity for the 10-repeat allele of the dopamine transporter gene (10/10) and poor response to methylphenidate (MPH) would be replicated in a sample of Brazilian attention deficit/hyperactivity disorder (ADHD) boys. In a blind naturalistic study, 50 male ADHD youths were treated with MPH. Efficacy of the medication was measured by means of the 10-item Conners Abbreviated Rating Scale (ABRS), and the Children's Global Assessment Scale (CGAS). While 75% (15/20) of the youths without 10/10 genotype demonstrated an improvement higher than 50% in the ABRS scores with MPH, only 47% (14/30) of the subjects with 10/10 genotype achieved the same level of improvement with medication (one-tailed P = 0.04). In addition, the group without this genotype had significantly higher increase in the CGAS scores than the other group (one-tailed P < 0.01). Our findings support an association between homozygosity for the 10-repeat allele at dopamine transporter gene locus and poor response to MPH.

Adolescent↗