Analysis of Association Between the Effects of Methylphenidate and DRD4 Gene Polymorphisms in Patients with Attention Deficit Hyperactivity Disorder

Background: Drug treatment is one of the most important treatments for attention deficit hyperactivity disorder (ADHD). The DRD4 gene is a transporter and receptor coding gene of dopamine and is one of the most important genes under investigation in the disorder and etiology of ADHD. In this study, the association between rs3758653 C/T and VNTR exon 3 repetition polymorphisms of the DRD4 gene and the effects of methylphenidate were investigated in patients with ADHD disorder consuming methylphenidate. Methods: The descriptive-analytical study was performed on 122 patients (5 - 18 years old) with ADHD who were treated with methylphenidate. DNA was extracted using salting out method. Subsequently, the rs3758653 polymorphism in the 5'UTR region of DRD4 gene was genotyped by PCR-RFLP method, and the VNTR fragment in exon III of DRD4 gene was investigated by electrophoresis gel on acrylamide gel method. After eight weeks from the start of drug treatment with methylphenidate, the intensity of symptoms was evaluated using the Conners scale. Finally, all data from questionnaires and information that were resulted from laboratory findings were analyzed using ANOVA and repeated measure analysis. Results: Of the 122 patients under study, 15 patients (12.3%) were responded to the drug treatment, and 107 patients (87.7%) were not responded. The significant differences were not revealed in genotype, and allele frequencies of between rs3758653 (C/T) and exon III 3'VNTR repeats polymorphisms of the DRD4 gene and responder and non-responder of ADHD groups to the drug treatment. Conclusions: The results showed that the reduction of ADHD symptoms with drug treatment is not related to DRD4 sub-types in patients with ADHD.

Genetically-predicted prefrontal DRD4 gene expression modulates differentiated brain responses to food cues in adolescent girls and boys

The dopamine receptor 4 (DRD4) in the prefrontal cortex (PFC) acts to modulate behaviours including cognitive control and motivation, and has been implicated in behavioral inhibition and responsivity to food cues. Adolescence is a sensitive period for the development of habitual eating behaviors and obesity risk, with potential mediation by development of the PFC. We previously found that genetic variations influencing DRD4 function or expression were associated with measures of laboratory and real-world eating behavior in girls and boys. Here we investigated brain responses to high energy–density (ED) and low-ED food cues using an fMRI task conducted in the satiated state. We used the gene-based association method PrediXcan to estimate tissue-specific DRD4 gene expression in prefrontal brain areas from individual genotypes. Among girls, those with lower vs. higher predicted prefrontal DRD4 expression showed lesser activation to high-ED and low-ED vs. non-food cues in a distributed network of regions implicated in attention and sensorimotor processing including middle frontal gyrus, and lesser activation to low-ED vs non-food cues in key regions implicated in valuation including orbitofrontal cortex and ventromedial PFC. In contrast, males with lower vs. higher predicted prefrontal DRD4 expression showed minimal differences in food cue response, namely relatively greater activation to high-ED and low-ED vs. non-food cues in the inferior parietal lobule. Our data suggest sex-specific effects of prefrontal DRD4 on brain food responsiveness in adolescence, with modulation of distributed regions relevant to cognitive control and motivation observable in female adolescents.

Utilization of Biotechnology, Neurotransmitter and Cytogenetic Indices in Selecting Pigeon Breeds

The DNA polymorphism LDH-A and DRD4 gene, some neurotransmitter and cytogenetic indices of three sexed pigeon breeds; non-racing pigeons (wild rock), racing long and short distances pigeons (e.g: Gan aarden) and (e.g: Gansen) have been performed. The long-distance pigeon demonstrated the highest levels of neurotransmitters in brain tissues. Long distance male pigeons have a unique LDH-A polymorphism, so A changed to G, which means that changes in gene expression resulted in differences in amino acid structure K(lys) was converted to E(glu) in the LDH-A gene only in long distance male pigeons compared to other breeds. In addition to this, the DRD4 polymorphism of long distance male pigeons in which A changed to C and A changed to T indicates the presence of a unique diversity in this breed. This means that changes in gene expression resulted in overall amino acid structure differences only in long distance male pigeons when compared to other breeds, where R(arg) and L(leu) were converted to S(ser) and F(phe). Neurotransmitters are synthesised in the body from these amino acids. It concluded that measurements would be useful indices for the differentiation, genetic characterization, provide a foundation for conservation programs of the breeding and selecting racing pigeon breeders.

Biological Determinants of Hostility

Our aim was to study the association of hostility with the DRD4, DAT, MAOA genes in an open male population of 25–64 years old. A representative sample of men aged 25–64 years (n = 657 men, average age 44.3 ± 0.4 years) was examined in 1994–1995 and 45–64 years old (n = 781 men, average age - 56.48 ± 0.2 years) in 2003–2005 using the methods proposed by the WHO international program “MONICA-psychosocial” and “HAPIEE”. All respondents completed the hostility questionnaire on their own. Genotyping of the DRD4, DAT and MAOA gene polymorphisms was carried out. It was established that the level of hostility in the male population was 76.9% in the group of 25–64 years old and 60.3% in the group of 45–64 years old. Genotypes 4/6, 4/7 of the DRD4 gene are reliably associated with a high level of hostility; the genotype 4/4 of the DRD4 gene is associated with an average and lower level of hostility. There was no association of individual genotypes and VNTR alleles of DAT gene polymorphism with different levels of hostility. It was found that among individuals with low-active alleles of the MAOA-L gene (alleles 2 and 3), a high level of hostility was more common - 50.9%. The results of constructing a logistic regression model showed that the presence of low-active alleles (2; 3) of the MAOA gene increases the likelihood of hostility OR = 2.103 (95% CI 1.137–3.889, p = 0.018). Based on the received data we can assume that the long alleles of the DRD4 gene and the low-level allele of the MAOA-L gene are associated with hostility.

Determining the association between polymorphisms of the DAT1 and DRD4 genes with attention deficit hyperactivity disorder in children from Java Island

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural in the children. Genetic factor is known one of the factors which contributed in ADHD development. VNTR polymorphism in 3’UTR exon 15 of DAT1 gene and exon 3 of DRD4 gene are reported to be associated in ADHD. In this study we examine the association of ADHD with VNTR polymorphism of DAT1 and DRD4 gene in Indonesian children. Sixty-five ADHD children and 70 normal children (6- 13 years of age), were included in the study, we matched by age and gender. ADHD was diagnosed by DSM-IV. We performed a casecontrol study to found the association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes. The 10-repeat allele of DAT1 and 2-repeat allele of DRD4 were higher in Indonesian children. Although the frequency of these allele was higher, but it was similar both in ADHD and control groups. Neither DAT1 nor DRD4 gene showed showed significant difference in genotype distribution and frequency allele between both groups (p > 0.05). No association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes found in Indonesian children. This data suggest that DAT1 and DRD4 do not contribute to etiology of ADHD in Indonesian children. Further studies are needed to clarify association between VNTR polymorphism of DAT1 and DRD4 genetic with ADHD of Indonesian children in larger sample size and family based study.