Norepinephrine Transporter Gene Polymorphisms Research Articles

The T-182C Polymorphism Enhances Promoter Activity of the Norepinephrine Transporter Gene, but may not be Associated with Antidepressant Response.

Background: Previous evidence has suggested that norepinephrine transporter (NET) gene (solute carrier family 6, member 2 [SLC6A2]) polymorphisms are involved in antidepressant response. Specifically, the polymorphism T-182C (rs2242446) located in the promoter region of SLC6A2 has been found to be associated with antidepressant response in multiple ethnic backgrounds. However, the results are inconsistent. Moreover, few studies have focused on how this T-182C polymorphism might regulate SLC6A2 promoter function. Methods: In this study, luciferase reporter assays were performed to examine the functional significance of the T-182C polymorphism. In addition, we performed a meta-analysis to explore whether this genetic variant is significantly involved in the antidepressant response. Results: We found that the -182(T) allele significantly increased promoter function compared to the C allele based on luciferase reporter assays. For the meta-analysis, six articles were identified that explored the relationship between the NET T-182C polymorphisms and antidepressant response. This study revealed no significant association between these polymorphisms and response to antidepressants (OR = 1.23, 95% CI = 0.77 - 1.97, p = 0.38 for T-182C). Conclusions: The T-182C polymorphism enhances promoter activity, but may not be associated with antidepressant response.

Meta-analysis on the Association Between Norepinephrine Transporter Gene rs2242446, rs5569 Polymorphisms and Risk of Major Depressive Disorder

The association between norepinephrine transporter (NET) gene polymorphisms and the risk of major depressive disorder (MDD) has been investigated extensively, but with contradictory findings. To clarify such contradiction, a comprehensive meta-analysis was conducted by searching PubMed, EMBASE, Web of Science and China Knowledge Resource Integrated Database. Odd ratios (ORs) and 95% confidence intervals (Cis) were used to evaluate the strength of the association. Totally 23 case-control studies regarding rs2242446 and rs5569 polymorphisms were included. Overall analysis and subgroup analysis indicated no significant association between NET gene rs2242446 polymorphism and MDD risk. However, recessive and homozygous models revealed a significant association between NET rs5569 polymorphism and increased risk of MDD. The stratified analysis further indicated significant associations in Asians, hospital-based studies and studies with other genotyping methods. In conclusion, NET gene rs5569 polymorphism could increase the risk of MDD, especially among Asians.

Association between T-182C, G1287A polymorphism in NET gene and suicidality in major depressive disorder in Chinese patients

Objective: Previous studies have implicated norepinephrine transporter gene (NET) polymorphisms in the etiology of major depressive disorder (MDD). A functional NET T-182C polymorphism (rs2242446) in the promoter region and a synonymous polymorphisms G1287A in the exon 9 (rs5569) were associated with MDD in different populations. However, few studies have focused on the relationship between these polymorphisms and MDD patients with suicidality. The objective of the present study was to examine whether the two polymorphisms are associated with MDD patients with suicidality in the Han Chinese population.Methods: Two hundred and sixty-three suicidal depressed patients and 241 non-suicidal depressed patients who met DSM-IV criteria for MDD were recruited from our hospital. Three hundred and three unrelated, age- and sex-matched healthy control subjects participated in this case-control study. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton rating scale for depression (HAMD). Genotypes of T-182C polymorphism (rs2242446) and G1287A (rs5569) were screened by polymerase chain reaction.Results: No statistical significant differences between patients and controls were found for any of the analysed polymorphisms, either in the genotype or allele distribution.Conclusions: Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of MDD with suicidality. However, the results must be verified in larger samples and different ethnicities.

Association of norepinephrine transporter gene polymorphisms in attention-deficit/hyperactivity disorder in Korean population

We investigated the association of three single nucleotide polymorphisms(SNP) of the norepinephrine transporter (NET) gene SLC6A2, T-182C (rs2242446), A-3081T (rs28386840), and G-1287A (rs5569) with the prevalence of attention-deficit/hyperactivity disorder (ADHD), its clinical severity, and other disease-related characteristics in a Korean population. The genotype, allele frequency and haplotype of 103 ADHD patients and 173 controls were analyzed for these three SNPs. All participants completed the Korean version of the ADHD Rating Scale (K-ARS). The ADHD group also completed the Korean Educational Development Institute-Wechsler Intelligence Scale for Children (KEDI-WISC) and the Continuous Performance Test (CPT) in a drug-naive state.The χ2 test and logistic regression analysis revealed no significant differences in the genotype distribution or allele frequencies of each SNP between the ADHD group and the control. In the haplotype analysis, the most common T-A-G haplotype was related to an increased risk of ADHD in females (P=0.002). There was no statistical significance between clinical features of ADHD and any specific allele of each SNP after multiple test correction except lower omission error in non-A girl carriers (GG type) of G-1287A (carrier 76.75±18.74, non-carrier 55.00±9.26, t=3.026, P=0.007, Bonferroni-corrected P=0.042). Some values related A-3081 and G-1287A showed a trend approaching the significance level when analyzed separately by gender. Even though it was not statistically meaningful after multiple test correction, G allele might have some protective effect against development of ADHD symptoms and this finding was consistent with previous studies.

P.3.b.028 - Gene polymorphism of neurotransmitter transporters in schizophrenic patients with drug-induced hyperprolactinemia

The regular therapy of schizophrenia includes a maintenance antipsychotic treatment, which improves the long-term prognosis of the disease [2]. Unfortunately antipsychotics also have a spectrum of side effects, including metabolic, endocrine and movement disorders [3,4]. One of the common side effects of these drugs is hyperprolactinemia (HP) [1]. The results of pharmacogenetic studies aimed at prognostic evaluation of the safe use of antipsychotics are the most persuasive. The components of dopamine, serotonin and norepinephrine neurotransmission in schizophrenia are considered as the main target for the action of antipsychotics. The present study aims to elucidate the role of 12 SNPs of dopamine transporter gene SLC6A3, 9 SNPs of norepinephrine transporter gene SLC6A2 and polymorphism of vesicular monoamine transporter gene SLC6A2 in the pathogenesis of antipsychotic-induced hyperprolactinemia in patients with schizophrenia. A total of 445 ethnic Russian patients from Siberia regions were studied, including 224 women and 221 men with a diagnosis of paranoid schizophrenia (the mean age - 42.1±1.4 years). Prolactin level was analyzed using the AccuBind ELISA Microwells kit (Monobind Inc., USA). Genotyping of SNPs was done with The MassARRAY® Analyzer 4 by Agena Bioscience™, using SEQUENOM. Statistical analysis was performed using the SPSS program. The Hardy-Weinberg equilibrium and differences in genotype frequencies were tested using a chi-square test. Differences were considered significant at p

Relationship between G1287A of the NET Gene Polymorphisms and Brain Volume in Major Depressive Disorder: A Voxel-Based MRI Study.

BackgroundEarlier studies implicated norepinephrine transporter (NET) gene (SLC6A2) polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide SLC6A2 polymorphisms, G1287A in exon 9 and T-182C in the promoter region, were found to be associated with MDD in different populations. We investigated the relationship between the brain volume and these two polymorphisms of the SLC6A2 in MDD patients.MethodsWe obtained 3D high-resolution T1-weighted images of 30 first-episode MDD patients and 48 age- and sex-matched healthy subjects (HS). All were divided into 4 groups based on polymorphism of either the G1287A or the T-182C genotype. VBM analysis examined the effects of diagnosis, genotype, and genotype-diagnosis interactions.ResultsDiagnosis effects on the brain morphology were found in the left superior temporal cortex. No significant genotype effects were found in the T-182C and the G1287A. A significant genotype (G1287A)–diagnosis interaction was found in the left dorsolateral prefrontal cortex. No significant genotype (T-182C)–diagnosis interaction effects were observed in any brain region.ConclusionsIn MDD patients there seems to be a relationship between the volume of the dorsolateral prefrontal cortex and polymorphism of the SLC6A2 G1287A gene.

Association between norepinephrine transporter gene polymorphism and decision-making processing in patients with cerebral infarction

Objective To investigate the association between norepinephrine transporter (NET) gene polymorphism and decision-making processing in patients with cerebral infarction. Methods A total of 145 patients with cerebral infarction and 188 normal controls were enrolled in our study. In all subjects, the polymerase chain reaction (PCR) for NET-T182C/G1287A polymorphism assay, gel electrophoresis, image analysis and enzymatic reaction, gene sequencing methods were used. The relationships of NET-T182C/G1287A genotypes and alleles with decision-making processing were analyzed in patients with cerebral infarction.All participants completed six kinds of choice situational problems. Results There were significant differences in genotype and allele frequencies of T182C and G1287A polymorphism in NET between the patients with cerebral infarction and control group(for NET-T182C: genotype, χ2=4.437, P=0.049, allele frequency, χ2=4.363, P=0.037, OR=0.625, 95%CI: 0.436-0.895; for NET-G1287A: genotype, χ2=8.435, P=0.038, allele frequency, χ2=2.765, P=0.036, OR=1.520, 95%CI: 1.053-2.193). The cerebral infarction patients with three NET-T182C genotypes and T/C alleles all completed six choice scenarios, and the scheme selection probability had no significant difference (all P>0.05). In high-risk and no-risk loss situation (scenario 4), the scheme selection probability had significant difference in cerebral infarction patients with NET-G1287A genotypes and G/A alleles (P 0.05). Conclusions NET-G1287A polymorphism may be associated with decision-making processing in patients with cerebral infarction. In the high-risk and no-risk loss condition, patients with GG genotype and G allele have more loss risk aversion. Key words: Brain infarction; Choice behavior; Norepinephrine plasma membrane transport proteins; Polymorphism, single nucleotide

Serotonin transporter (5-HTTLPR) and norepinephrine transporter (NET) gene polymorphisms: Susceptibility and treatment response of electroconvulsive therapy in treatment resistant depression

Serotonin transporter (5-HTTLPR) and norepinephrine transporter (NET182C) polymorphisms are associated with susceptibility and treatment response in major depressive disorder (MDD). Thus, we examined association between these polymorphisms and susceptibility to treatment resistant depression, and treatment response in severe MDD patients treated with electroconvulsive therapy (ECT).In total, 119 Finnish patients with treatment resistant depression and 395 healthy volunteer blood donors were genotyped. Depression severity was assessed using the Montgomery–Åsberg Depression Scale (MADRS), with MADRS score change during ECT the treatment response indicator.Underrepresentation of the 5-HTTLPR l/l genotype in the NET TT subgroup was observed in patients compared with controls. There were no genotype or allele frequency differences between patients and control groups separately. Patients with combined 5-HTTLPR l/l and NET TT genotypes also had poorer treatment responses than other patients. No differences in ECT response were observed when the polymorphisms were examined separately.Our results suggest that a NET 182C and 5-HTTLPR polymorphism interaction is associated with susceptibility to treatment resistant depression and ECT treatment response in antidepressant resistant depression patients.

Analysis of Association between Norepinephrine Transporter Gene Polymorphisms and Personality Traits of NEO-FFI in a Japanese Population

ObjectiveNorepinephrine is an important chemical messenger that is involved in mood and stress in humans, and is reabsorbed by the norepinephrine transporter (NET). According to Cloninger's theory, the noradrenergic system mediates the personality trait of reward dependence. Thus far, although association studies on NET gene polymorphisms and Cloninger's personality traits have been reported, they yielded inconsistent results. Therefore, in the present study we investigated whether or not the 1287G/A, -182T/C and -3081A/T polymorphisms of the NET gene (SLC6A2) are associated with reward dependence-related traits, as assessed by the five-factor model.MethodsAfter written informed consent was obtained from participants, the three NET gene polymorphisms were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and personality was assessed by the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) in 270 Japanese university students.ResultsA significant relation was found between the -3081A/T functional promoter polymorphism and NEO-FFI scores: those with the T allele exhibited a lower extraversion (E) score than those without the T allele (Mann-Whitney U-test: z=-3.861, p<0.001). However, there was no correlation between the other NET gene polymorphisms and E score, and no association with other dimensions and these three polymorphisms.ConclusionWe conclude that the -3081A/T functional polymorphism in the NET gene may affect the extraversion of reward dependence-related traits, as measured by NEO-FFI. However, we used only the shortened version of NEO-PI-R in this study. Further investigations are necessary using the full version of self-rating personality questionnaires.

Association Study between Norepinephrine Transporter Gene Polymorphism and Schizophrenia in a Korean Population.

ObjectiveWe aimed to investigate possible associations between three norepinephrine transporter gene (SLC6A2) single nucleotide polymorphisms (T182C, A3081T, and G1287A) and schizophrenia. Also, we investigated the relationships of those polymorphisms with clinical severity and characteristics of schizophrenia.MethodsParticipants were 220 schizophrenia patients in the acute phase and 167 healthy controls. The genotype, allele frequency, and haplotype of each group were analyzed for T182C, A3081T, and G1287A polymorphisms. Of the 220 schizophrenia patients, 163 patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Korean version of the Calgary depression scale for schizophrenia (K-CDSS) at baseline.ResultsWe found no significant differences between the schizophrenia patient group and the control group in genotype distribution or allele frequency of the three tested polymorphisms. Likewise, we could not find any significant differences in genotype or allele frequency by analyzing according to gender. In the haplotype study, no significant association emerged between specific haplotype combinations and schizophrenia. We also found no association between clinical scales (PANSS and K-CDSS) and the studied polymorphisms.ConclusionOur results suggest that the investigated polymorphisms of the NET gene are not associated with susceptibility to schizophrenia or its clinical features in a Korean population. However, this study remains significant because it is the first haplotype study to investigate associations between NET gene (SLC6A2) single nucleotide polymorphisms and schizophrenia in a Korean population. Future research with a larger sample size and more genetic markers is needed to replicate our results.

Association between norepinephrine transporter gene (SLC6A2) polymorphisms and suicide in patients with major depressive disorder

BackgroundAlthough several studies have investigated possible associations between norepinephrine neurotransmitter transporter gene (SLC6A2) polymorphisms and depression, few studies have examined associations between SLC6A2 polymorphisms and suicide. MethodsThree single-nucleotide polymorphisms (rs2242446, rs28386840, and rs5569) were measured in 550 patients: 201 with major depressive disorder (MDD) and suicide attempt/s, 160 with MDD without suicide attempts, and 189 healthy controls. Analysis of single-nucleotide polymorphisms (SNPs) and haplotype was conducted for the three groups. Subsequently, multivariate logistic regression analysis adjusting for age and gender was conducted to identify independent influences of each SNP. A possible association between suicide lethality and SLC6A2 polymorphisms was also investigated. ResultsIn the genotype and allele frequency analysis, there were significant differences in rs28386840 between suicidal MDD patients and healthy controls. In the haplotype analysis, TAA (rs2242446–rs28386840–rs5569, from left to right) was associated with suicide attempts in MDD, although the significance (p=0.043) disappeared after Bonferroni correction. There were no relationships between lethality scores and SLC6A2 polymorphisms in suicidal MDD. LimitationsModest sample size and a single type of neurotransmitter analyzed (norepinephrine) are the primary limitations. ConclusionOur results suggest that SLC6A2 polymorphisms were associated with suicide risk in patients with MDD. Future studies are warranted to elucidate possible mechanisms by which SLC6A2 polymorphisms influence suicide risk.

The relationship of violent behavior with polymorphism of norepinephrine transporter gene, childhood abuse and their interaction effect in male adolescents

Objective To explore the relationship between the rs3785143 polymorphism of norepinephrine transporter gene, and investigate the influence of interaction effect between NET gene polymorphism and childhood abuse in adolescents with violent behavior. Methods Adolescent male offenders were divided into violent group (124 samples) and nonviolent group (120 samples). The rs3785143 polymorphisms of NET gene were measured by used SNaPshot SNP technology in 244 samples. Chi-square test was used to compare the distribution difference between three groups of each gene type and the allele frequency distribution. Results ①There was no statistically significant difference among violent group and nonviolent group in the genotype and allele frequencies of rs3785143 polymorphism (χ2=0.753, 0.022; all P>0.05). ②64.5% violent adolescents have experience of childhood abuse, and 35.5% had no history of abuse; 48.3% nonviolent adolescents have experience of childhood abuse, and 51.7% had no history of abuse(χ2=6.50, P 0.05) 95%CI(0.457-4.739)). Conclusions The NET gene polymorphism is not associated with violent behavior in male adolescents, and there was not interaction between NET gene polymorphism and childhood abuse. Key words: Adolescents; Violent behavior; Norepinephrine transporter

Psychomotor depressive symptoms may differentially respond to venlafaxine

Predicting differential antidepressant efficacy remains an elusive goal in major depressive disorder (MDD). The aims of this study were three-fold. Firstly, to examine if psychomotor retardation symptoms (item 8 on the 17-item Hamilton Depression Rating Scale) improve preferentially to venlafaxine (VEN) over escitalopram (ESC) treatment. Secondly, whether the 18 item CORE psychomotor signs scale predicted antidepressant remission. Finally, to investigate the role of two norepinephrine transporter gene (NET) polymorphisms (rs2242446 and rs5569) on antidepressant efficacy. Adults with Diagnostic and Statistical Manual of Mental Disorders, 4th ed. MDD (n=113) were treated with ESC or VEN prospectively for 8 weeks and rated serially with the Hamilton Depression Rating Scale. In a subsample (n=51) of patients from one of the three recruitment sites, the CORE psychomotor signs scale was also administered at baseline. Participants treated with VEN had significantly greater reduction in psychomotor retardation symptoms than those treated with ESC. The CORE scale did not predict antidepressant response or remission. Neither NET polymorphism moderated antidepressant efficacy. Findings suggest possible preferential utility of a selective serotonin and noradrenaline reuptake inhibitor in cases of MDD presenting with greater psychomotor retardation. The moderate to small sample size makes a type II error risk possible, and the negative findings need to be interpreted with caution. The positive finding of preferential efficacy of VEN for psychomotor retardation symptoms has potential translational utility.

The association study between the interaction of serotonin and norepinephrine transporter gene polymorphisms and the effects of selective serotonin reuptake inhibitors

Objective To explore the relevance of the interaction of serotonin and norepinephrine transporter gene polymorphisms and the effects of selective serotonin reuptake inhibitors. Methods The subjects comprised 246 patients according to the diagnostic and statistical manual of mental disorders in the fourth edition (DSM-IV) criterion for major depressive disorder(MDD). The clinical efficacy were assessed by using 17 Hamilton depression quantity (HAMD) scale after selective serotonin reuptake inhibitors(SSRIs) citalopram (20 to 60 mg/d) or paroxetine (20 to 60 mg/d) were used randomly for 1, 2, 4, 6 weeks.Polymerase chain reaction(PCR), sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE )and DNA sequencing analysis were used to detect the genotype of 5-HTT gene single nucleotide polymorphisms (SNP) of VNTR and LPR and SNPs at rs2242446 and rs5569 of NET.SPSS13.0 software were used for statistical analysis. Results (1) An association between 5-HTT LPR and the efficacy of SSRIs was found after 6 weeks in these samples (P=0.023). The clinical efficiency of LL genotype was higher than SS+ LS genotype(OR=2.225, OR95%CI=1.118, 4.427). (2) The interaction of 5-HTT LPR and NET rs5569 and the SSRIs antidepressant effects was statistical significance(P=0.01). Conclusion Preliminary study found that the interaction of 5-HTT LPR and NET rs5569 may be related to SSRIs antidepressant effects in China’s patients with MDD. Key words: Major depressive disorders; Serotonin transporter; Norepinephrine transporter; Gene polymorphisms; Interaction

Investigation of the correlation between norepinephrine transporter gene polymorphisms and essential hypertension

Essential hypertension (EH) is an etiological risk factor that poses a serious threat to human health. The aim of this study therefore was to investigate the correlation between the two SNPs (rs1805067 and rs2397771) of the norepinephrine (NE) transporter gene in the sympathetic nervous system and essential hypertension (EH). A total of 96 hypertensive patients (EH group) and 96 normal subjects (control group) were selected by epidemiological investigation and the sequences at rs1805067 and rs2397771 in the two groups were investigated using polymerase chain reaction (PCR) and Sanger sequencing. In the EH group, systolic and diastolic blood pressure, body mass index (BMI), levels of creatinine, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the percentage of drinkers were found to be higher compared with those of the control group (P<0.05). The results of the analysis of the allele frequencies of rs1805067 (A/G) revealed that there was no difference between the two groups (P>0.05). The analysis results of the allele frequencies of rs2397771 (C/G) in the EH group revealed that G accounted for 48.96% and C for 51.04% of the patients, while in the control group, these values were 64.58 and 35.42%, respectively. These results indicated a significant difference between the two groups (P<0.05). In the population studied, the onset of EH may be correlated with BMI, TG, LDL-C and high-density lipoprotein cholesterol (HDL-C). EH may be related to the rs2397771 (C/G) C allele polymorphism of the NE transporter gene but not to rs1805067 (A/G).

The 1287 G/A polymorphism of the Norepinephrine Transporter gene (NET) is involved in Commission Errors in Korean children with Attention Deficit Hyperactivity Disorder

BackgroundPrevious evidence supports the role of noradrenergic systems in ADHD, and norepinephrine transporter (NET) is critical in regulating the noradrenergic system. The present study aimed to investigate the association between NET gene polymorphism and the performance measures of the Continuous Performance Test (CPT) in Korean ADHD children.MethodsEighty-seven children (mean age = 9.23 ± 1.99 years) with ADHD were recruited from a university hospital. Genotypes of G1287A of the NET gene (SLC6A2) were analyzed. All participants completed the CPT, with performance measures of omission errors, commission errors, reaction time and reaction standardization computed. The relationship between G1287A polymorphisms and CPT performance measures was examined.ResultsThere were 46 subjects with the G/G genotype, 35 subjects with the G/A genotype and 6 subjects with the A/A genotype. Among the three groups, there were no significant differences in the performance of CPTs. When dichotomized according to whether the subjects have the rare allele or not, subjects with the homozygous G/G genotype showed significantly lower commission errors compared to those without G/G genotypes (by independent T-test, t = -2.18, p = 0.026).DiscussionOur study found a significant association between commission errors of the CPT and the G1287A genotype of the NET gene in Korean ADHD children. These findings suggest a protective role of the G/G genotype of the NET polymorphisms in the deficits of response inhibition in ADHD children.

Norepinephrine transporter gene (SLC6A2) is involved with methylphenidate response in Korean children with attention deficit hyperactivity disorder

The purpose of this study was to investigate the association between the methylphenidate (MPH) response and the norepinephrine transporter (NET) gene polymorphisms in Korean children with attention deficit hyperactivity disorder (ADHD). One hundred and fourteen children with ADHD (mean age 9.08 ± 1.94 years) were recruited from a child psychiatric clinic in South Korea. The genomic DNA was extracted from the blood lymphocyte. Patients were administered MPH for 8 weeks. Good response was defined as a decrease of more than 50% from the baseline ADHD rating scale-IV scores or Clinical Global Impression-Severity score was 1 or 2 after treatment. We compared the MPH response according to the genotype of G1287A of the NET gene (SLC6A2). In patients with G/G genotype, 41 patients (71.9%) showed good response and 16 patients (28.1%) showed poor response when it was measured by the ADHD rating scale-IV. In comparison, 23 patients (46.0%) with G/A genotype and four patients (57.1%) with A/A genotype showed good response (P=0.018, by the Fisher's exact test). When we compared the response of MPH between patients with G/G genotype and those without G/G genotype, 41 patients (71.9%) with G/G genotype showed good response, whereas only 27 patients (46.4%) without G/G genotype showed good response. [Pearson χ² = 7.143, degrees of freedom (df)=1, P=0.008]. Our study found a significant association between the G1287A genotype of the NET gene and the MPH response in Korean children with ADHD. These findings support the significant role of the NET gene in ADHD treatment with MPH.

주의력결핍 과잉행동장애와 노르에피네프린 수송체 유전자 다형성의 연관성

Objectives：This study aimed to examine the association between norepinephrine transporter gene (SLC6A2) poly-morphisms and attention-deficit hyperactivity disorder (ADHD) and to examine the relationship between the genotypes and allele variants of SLC6A2 and results of the Korean version of the parent ADHD rating scale (K-ARS). Methods：We examined the association between ADHD and norepinephrine transporter gene polymorphism using DNA from 137 Korean children with ADHD and 120 normal controls. We compared the genotype distributions and allele frequencies of SLC6A2 polymorphism between the control group and the ADHD group. Then, we correlated the children’s K-ARS mean totals, inattention scores, and hyperactivity/impulsivity scores with the genotypes and alleles for each SLC6A2 polymorphism. Results：There were no significant differences in genotype and allele distribution for each SLC6A2 polymorphism, as shown by the Chi-square test (p>.01). There was a trend toward a difference in allele frequency in rs 5568, but it was not statistically significant after adjusting for multiple comparisons (p=.048). Also, there were no significant differences in K-ARS scores according to the genotypes and alleles for the SLC6A2 polymorphisms. Conclusion：Our study found no significant evidence of an association between SLC6A2 polymorphisms and ADHD. KEY WORDS：ADHD·SLC6A2·Polymorphism·K-ARS.

Association studies of −3081(A/T) polymorphism of norepinephrine transporter gene with attention deficit/hyperactivity disorder in Korean population

Recent studies showing the improvement of ADHD symptoms obtained with the highly selective noradrenergic reuptake inhibitor, atomoxetine, demonstrate that the noradrenergic system plays the role of pathophysiology in this disorder. It is revealed that the norepinephrine transporter gene (SLC6A2) is a possible candidate gene directly related to ADHD. To determine possible roles of the SLC6A2 as a susceptibility gene for ADHD, we performed the genetic association study for a functional -3081(A/T) polymorphism, located in the promoter region of SLC6A2. For the present study of association between ADHD and the SLC6A2, 103 male patients with ADHD and 103 normal male controls were randomly gathered. Significant differences were found in the allele frequencies (chi(2) = 5.60, P = 0.02) and the odds ratio for the allele T between the ADHD and normal subjects was 1.59 (95% CI: 1.08-2.34) suggesting that T allele is critical to make the group difference. Significant group difference was also found in AA, AT, TT genotypes (chi(2) = 7.1, P = 0.02). The odds ratio for TT and AT genotypes was 4.57 (95% CI: 2.56-8.15) and 1.96 (95% CI: 0.96-3.78), respectively. Findings in the present study provided further evidence of association between ADHD and -3081(A/T) polymorphism of SLC6A2.

P01-188 - Regional brain perfusion differences associated with norepinephrine transporter gene polymorphisms in ADHD

ObjectivesThe aim of this study was to examine whether the presence of risk alleles of the norepinephrine transporter gene (SLC6A2) polymorphisms is associated with differences in regional cerebral blood flow (rCBF) measured by 99mTc-HMPAO single photon emission computerized tomography in a Korean sample of ADHD.MethodsThe present study included 24 children with ADHD (9.5±2.4 years), consisting of 20 boys and 4 girls, aged 6-16 years. We investigated the G1287A and -3081(A/T) polymorphisms of the SLC6A2. The rCBF was compared between the ADHD subjects with and without risk alleles at the G1287A polymorphism and at the -3081(A/T) polymorphism. Image analyses were performed with voxelwise t-statistics using SPM2.Results1)The ADHD subjects with the A allele (risk allele) at the G1287A polymorphism showed reduced perfusion in the left middle frontal gyrus, left inferior parietal lobule, precuneus, right superior frontal gyrus, and right superior parietal lobule as compared with ADHD subjects without the A allele (p&lt; 0.001).2)The ADHD subjects with the A allele at the G1287A polymorphism showed increased perfusion in the right middle frontal gyrus, right middle temporal gyrus, right superior temporal gyrus, right fusiform gyrus, right precentral gyrus, and right anterior lobe of cerebellum as compared with ADHD subjects without the A allele (p&lt; 0.001).3)No significant perfusion differences were found between ADHD subjects with and without the T allele (risk allele) at the -3081(A/T) polymorphism.ConclusionOur findings suggest that the SLC6A2 G1287A polymorphism might exert differential effects on rCBF in children with ADHD.