A118G Polymorphism Research Articles

Journal-related Activities and Other Special Activities at the 2011 American Society of Anesthesiologists Annual Meeting

Journal-related Activities and Other Special Activities at the 2011 American Society of Anesthesiologists Annual Meeting

Pharmacogenomics of the Human µ-Opioid Receptor

The µ-opioid receptor is a primary target for clinically important opioid analgesics, including morphine, fentanyl and methadone. Many genetic variations have been identified in the human µ-opioid receptor MOP gene (OPRM1), and their implications have been reported in the effects of opioid drugs and susceptibility to drug dependence. Interestingly, agonistic and antagonistic opioid effects are inversely associated with the A118G polymorphism genotype. The A118G polymorphism may also be associated with substance dependence and susceptibility to other disorders, including epilepsy and schizophrenia. The IVS1+A21573G, IVS1-T17286C, and TAA+A5359G polymorphisms in the OPRM1 gene may be associated with alcohol, opioid and tobacco dependence, respectively. However, some studies have failed to confirm the correlations between the polymorphisms and opioid effects and substance dependence. Further studies are needed to elucidate the molecular mechanisms underlying the effects of OPRM1 polymorphisms.

Human Opioid μ-receptor A118G Polymorphism May Protect Against Central Pruritus by Epidural Morphine for Postcesarean Analgesia

Human Opioid μ-receptor A118G Polymorphism May Protect Against Central Pruritus by Epidural Morphine for Postcesarean Analgesia

Human mu‐opioid receptor gene A118G polymorphism predicts the efficacy of tramadol/acetaminophen combination tablets (ultracet) in oxaliplatin‐induced painful neuropathy

The A118G polymorphism of the mu-opioid receptor gene (OPRM1), resulting in the substitution of an amino acid, has been found to be associated with functional effects and response to opioid treatment. The purpose of this study was to assess whether this polymorphism contributes to the variability in response to tramadol/acetaminophen combination tablets (Ultracet) for treating oxaliplatin-induced painful neuropathy. A total of 96 patients with adenocarcinoma of the colon or rectum (n = 84), or stomach (n = 12) who had developed oxaliplatin-induced painful neuropathy were enrolled. Ultracet was administered at 1 tablet every 6 hours, and pain was assessed and scored using a visual analog scale (VAS). The OPRM1 A118G polymorphism was examined with a polymerase chain reaction-direct sequencing method. The allelic frequency of variant (118G) allele was 39.6%, and the prevalence of OPRM1-118 AA, AG, and GG genotypes was 31.3% (n = 30), 58.3% (n = 56), and 10.4% (n = 10), respectively. For all patients, the mean pre-treatment and post-treatment VAS scores were 3.1 and 2.1, respectively (P < .001). Patients with AA genotype had a better analgesic effect than those with G allele variants (AG or GG genotypes). Pre-treatment and post-treatment VAS scores for patients with G allele variants were 3.1 and 2.6, respectively; however, for patients with AA genotype, pre-treatment and post-treatment VAS scores were 3.0 and 0.9, respectively (P < .001). The requirement for rescue analgesia was also higher for patients with G allele variants (P = .01). These data suggest that Ultracet is effective in the management of oxaliplatin-induced painful neuropathy. A118G polymorphism of OPRM1, by altered function of the mu-opioid receptor and consequential analgesic effect on opioid agents, could be a key determinant for decreased response to Ultracet.

Challenges in Interpreting Joined Allelic Combinations of OPRM1 and COMT Genes

To the Editor Although Kolesnikov et al.1 are to be congratulated for describing the effect of COMT and OPRM1 polymorphisms on clinical efficacy and side effects of IV morphine, several aspects of the study design, analysis, and, therefore, conclusions require discussion. The study was designed to identify differences in total IV patient-controlled analgesia morphine use over the first 48 hours postradical prostatectomy or women undergoing hysterectomy under general anesthesia. Given that the patient-controlled analgesia pump was set to deliver a background infusion of 1 mg/h morphine and a 1-mg bolus dose with a lockout time of 10 minutes, all patients were expected to receive a total dose of at least 48 mg over the study period. The authors report that the average morphine consumption was in the range of 62 to 66 mg over 48 hours and they found no difference between genotypic groups based on Val158Met polymorphism of COMT (Table 21) and A118G polymorphism of OPRM1 (Table 31). However, the continuous infusion may have masked a possible effect of COMT genotype on morphine analgesic efficacy preventing a significant difference in the patient-administered analgesic bolus from becoming apparent. In addition, the mixed-gender study population and 2 distinct surgical models may have increased variability in postoperative morphine consumption. A further observation is that the joint COMT/OPRM1 allelic distribution is not reported for the entire cohort of patients enrolled in the study. With 2 polymorphisms, there should be 9 possible combinations, with the exception that some combinations may be extremely rare among Caucasians.2 The frequency for possible allelic combinations is not reported; therefore, the joint allelic distribution in 70 patients (68% of the cohort) remains unknown. Consequently, when the authors analyzed the joint allelic effect on morphine dose, they only compared morphine dose among all AA individuals (n = 82) irrespective of COMT genotype to a selected subgroup of individuals with A118G/Val158Met (n = 11). The groups that preferably should have been analyzed are Met/Met and AA patients (n = 18; Table 31) with Met/Val and AG (n = 11; Table 31), and the difference between these 2 groups would most likely not be significant (66.2 ± 29.7 mg vs 51.9 ± 12.1 mg, respectively). Another analysis to be considered would be to compare Met/Met and AA (n = 18) versus all the other patients (n = 84; data not presented in Table 3). This comparison would be of interest because Met/Met and AA individuals have been found to need less oral morphine dosing for pain relief than patients that are neither Met/Met nor AA.2 Ruth Landau, MD Clemens Ortner, MD Department of Anesthesiology University of Washington Medical Center Seattle, Washington [email protected] Brendan Carvalho, MD Department of Anesthesia Stanford University Stanford, California

Variation in the μ-opioid receptor gene (OPRM1) moderates the influence of early maternal care on fearful attachment

There is evidence that both early experience and genetic variation play a role in influencing sensitivity to social rejection. In this study, we aimed at ascertaining if the A118G polymorphism of the μ-opioid receptor gene (OPRM1) moderates the impact of early maternal care on fearful attachment, a personality trait strongly related to rejection sensitivity. In 112 psychiatric patients, early maternal care and fearful attachment were measured using the Parental Bonding Inventory and the Relationship Questionnaire (RQ), respectively. The pattern emerging from the RQ data was a crossover interaction between genotype and maternal caregiving. Participants expressing the minor 118 G allele had similar and relatively high scores on fearful attachment regardless of the quality of maternal care. By contrast, early experience made a major difference for participants carrying the A/A genotype. Those who recalled higher levels of maternal care reported the lowest levels of fearful attachment whereas those who recalled lower levels of maternal care scored highest on fearful attachment. Our data fit well with the differential susceptibility model which stipulates that plasticity genes would make some individuals more responsive than others to the negative consequences of adversity and to the benefits of environmental support and enrichment.

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.

Influence of the OPRM1 gene polymorphism upon children's degree of withdrawal and brain activation in response to facial expressions

Genetic variation of the A118G polymorphism of the μ-opioid receptor gene (OPRM1) predicts individual sensitivity to social rejection and fMRI activation during simulated social rejection in adults, while data on these relationships during childhood are lacking. We investigated whether this polymorphism predicts childhood withdrawal – a predictor of sensitivity to social rejection –, and the face-specific N170 event-related waveform in response to facial expressions. Among facial expressions, ‘anger’ was expected to be particularly evocative, as it communicates social rejection.Forty-nine children aged 8–10 years were characterised for their OPRM1 genotype, their score at the Withdrawn Scale of the Child Behavior Checklist (CBCL), and for N170 latencies and amplitudes recorded during a task of implicit processing of happy, neutral, and angry expressions of other children. Children carrying the OPRM1-G allele had higher CBCL Withdrawn scores and enhanced N170 amplitudes in response to facial expressions. Multiple linear regressions showed that the Withdrawn scale score predicts larger N170 amplitudes at the Pz and C4 electrodes, only for the anger expression.Children who carry one or two copies of the OPRM1 G-allele are more likely to manifest withdrawn behaviours, and differ for electrophysiological responses to the early phases of processing affective stimuli.

Mu‐opioid receptor A118G polymorphism in healthy volunteers affects hypothalamic–pituitary–adrenal axis adrenocorticotropic hormone stress response to metyrapone

The mu-opioid receptor encoded by the gene OPRM1 plays a primary role in opiate, alcohol, cocaine and nicotine addiction. Studies using opioid antagonists demonstrate that the mu-opioid receptor (MOP-r) also mediates the hypothalamic-pituitary-adrenal (HPA) axis stress response. A common polymorphism in exon one of the MOP-r gene, A118G, has been shown to significantly alter receptor function and MOP-r gene expression; therefore, this variant likely affects HPA-axis responsivity. In the current study, we have investigated whether the presence of the 118AG variant genotype affects HPA axis responsivity to the stressor metyrapone, which transiently blocks glucocorticoid production in the adrenal cortex. Forty-eight normal and healthy volunteers (32 men, 16 women) were studied, among whom nine men and seven women had the 118AG genotype. The 118G allele blunted the adrenocorticotropic hormone (ACTH) response to metyrapone. Although there was no difference in basal levels of ACTH, subjects with the 118AG genotype had a more modest rise and resultant significantly lower ACTH levels than those with the prototype 118AA at the 8-hour time point (P < 0.02). We found no significant difference between genders. These findings suggest a relatively greater tonic inhibition at hypothalamic-pituitary sites through the mu-opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele.

The Effect of Naltrexone on Alcohol’s Stimulant Properties and Self‐Administration Behavior in Social Drinkers: Influence of Gender and Genotype

Few pharmacological treatments for alcohol dependence are available. Moreover, the best supported treatment, naltrexone hydrochloride, appears to work for only some. To investigate potential predictors of these differential responses, 40 social drinkers (20 women) were administered 6 days of treatment with naltrexone vs. placebo in a double-blind, counterbalanced, crossover design. At the end of each treatment period, participants received a single dose of their preferred alcoholic beverage followed by the opportunity to work for additional alcohol units using a progressive ratio (PR) breakpoint paradigm. All subjects but one were genotyped for the A118G polymorphism of the mu opioid receptor gene (OPRM1). Naltrexone decreased the ethanol-induced 'euphoria' to a priming dose of alcohol in two subgroups: (i) in women, and (ii) in subjects with the A118G polymorphism of the mu opioid receptor gene (OPRM1). Naltrexone did not decrease motivation to work for additional alcoholic beverages on the PR task regardless of gender or genotype. The results add to the evidence that naltrexone decreases positive subjective effects of alcohol, with preferential effects in distinct subgroups. Similar effects in heavier drinkers might decrease alcohol use.

S12-03 Individual differences in social affiliation: The role of the A118G polymorphism of the mu-opioid receptor gene (OPRM1)

IntroductionMost of us find social encounters rewarding, especially when we encounter those with whom we are familiar and have built up a relationship. From an evolutionary point of view, this is not surprising considering that human beings are fundamentally social organisms. Considering that endogenous opioids mediate hedonic responses to a variety of natural rewards, the common A118G polymorphism in the mu-opioid receptor gene (OPRM1) might also modulate individual differences in the capacity to experience social reward.AimsIn the present study, we hypothesized that, compared to individuals with the A118A genotype, individuals expressing the minor 118G allele had an increased need for affiliation and an increased capacity to experience social reward.MethodsIn a mixed sample (N = 214) of adult healthy volunteers and psychiatric patients, we analyzed the association between the A118G polymorphism of the OPRM1 and two different psychological constructs reflecting individual differences in the capacity to experience social reward.ResultsCompared to individuals expressing only the major allele (A) of the A118G polymorphism, subjects expressing the minor allele (G) had an increased tendency to become engaged in affectionate relationships, as indicated by lower scores on a self-report measure of avoidant attachment, and experienced more pleasure in social situations, as indicated by lower scores on a self-report measure of social anhedonia.ConclusionsThe results reported here are in agreement with the brain opioid hypothesis of social attachment and raise several questions about the maintenance of the A118G polymorphism in the evolution of human social behavior.

Combined Catechol-O-Methyltransferase and μ-Opioid Receptor Gene Polymorphisms Affect Morphine Postoperative Analgesia and Central Side Effects

Previous studies have generated controversial results regarding the influence of the genetic variations of μ-opioid receptors on morphine analgesia and opioid-related side effects in the postoperative period. Few studies have been conducted attempting to assess the combined effects of variation within ≥2 genes in relation to morphine response. In this study, we investigated whether combined catechol-O-methyltransferase and μ-opioid receptor polymorphisms contribute to the morphine response in postoperative analgesia. One hundred two surgical patients were enrolled in this prospective, observational study. All patients received general anesthesia and were screened for μ-opioid receptor polymorphism A118G (Asn40Asp) and catechol-O-methyltransferase G1947A (Val158Met) polymorphism using a blood sample of DNA. Patient-controlled analgesia was provided postoperatively and morphine consumption was observed. Any pain at rest or side effects were measured with rating scales. The heterozygous patients with μ-opioid receptor A118G and catechol-O-methyltransferase G1947A mutation consumed significantly less morphine in the postanesthetic recovery room and 48 hours after surgery compared with homozygous patients of the A118 variant. Nausea and sedation scores were also significantly lower during all observed postoperative periods for heterozygous patients and only 2 patients (18%) from this group received antinausea treatment. This study has demonstrated the importance of the gene-gene approach in understanding the morphine response in patients after lower abdominal surgery. More studies are needed to characterize the combined effects of multiple genes and demographic as well as clinical variables in predicting the correct morphine dosage and corresponding opioid-related side effects.

Human opioid μ‐receptor A118G polymorphism may protect against central pruritus by epidural morphine for post‐cesarean analgesia

Intrathecal or epidural morphine used for post-operative analgesia frequently induces central type pruritus. The purpose of this study was to investigate the association between the severity of central type pruritus induced by epidural morphine for post-cesarean analgesia and the A118G polymorphism of the human μ-opioid receptor gene (OPRM1). Pregnant women (212) received pure epidural morphine (2 mg) twice per day for post-cesarean analgesia. Blood samples were collected and sequenced with high-resolution melting analysis to detect three different genotypes of OPRM1 (AA, AG and GG). We interviewed all candidates 24 h post-operatively to record the clinical phenotype with subjective complaints and objective observations. The genotyping revealed that 99 women (46.7%) were AA, 88 (41.5%) were AG and 25 (11.8%) were GG. Sixty-two of 212 women suffered from significant pruritus (29.2%), and 150 of 212 women had non-significant pruritus (70.8%). In genotype AA, 33 patients (53.2%) experienced significant pruritus, 26 (41.9%) in genotype AG and 3 (4.8%) in genotype GG. The G allele was a statistically independent protective factor for individuals developing pruritus, and the multivariate-adjusted odds ratio was 0.27. There was a trend for progressively decreasing severity scores among the three groups, with the lowest severity score (0.72) for pruritus in the GG group. The incidence of significant pruritus in the recessive type (GG) was significantly lower compared with the dominant types (AA+AG). The recessive G allele in the A118G polymorphism may have protective effects against significant pruritus after epidural morphine for post-cesarean analgesia.

A genetic determinant of the striatal dopamine response to alcohol in men

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a four-fold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

Social hedonic capacity is associated with the A118G polymorphism of the mu-opioid receptor gene (OPRM1) in adult healthy volunteers and psychiatric patients

A large body of evidence links altered opioid signaling with changes in social behavior in animals. However, few studies have attempted to determine whether similar links exist in humans. Here we investigate whether a common polymorphism (A118G) in the mu-opioid receptor gene (OPRM1) is associated with alterations in personality traits linked to affiliative behavior and attachment. In a mixed sample (N = 214) of adult healthy volunteers and psychiatric patients, we analyzed the association between the A118G polymorphism of the OPRM1 and two different psychological constructs reflecting individual differences in the capacity to experience social reward. Compared to individuals expressing only the major allele (A) of the A118G polymorphism, subjects expressing the minor allele (G) had an increased tendency to become engaged in affectionate relationships, as indicated by lower scores on a self-report measure of avoidant attachment, and experienced more pleasure in social situations, as indicated by lower scores on a self-report measure of social anhedonia. The OPRM1 variation accounted for about 3.5% of the variance in the two measures. The significant association between the A118G polymorphism and social hedonic capacity was independent of the participants' mental health status. The results reported here are in agreement with the brain opioid hypothesis of social attachment and the established role of opioid transmission in mediating affiliative behavior.

A pharmacogenetic model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys

Background Variation at the human μ-opioid receptor has been associated with alcohol abuse. The A118G (N40D) polymorphism in humans is functionally mimicked by the C77G (P26R) polymorphism in rhesus monkeys; both show similar in vitro influences on ligand binding and in vivo correlations with physiological measures as well as behavioral measures including predilection towards alcohol consumption. Naltrexone, an antagonist at the receptor, has been used to treat alcoholism in humans and has been reported to show differences in effectiveness depending on genotype. Methods Here we describe a study in which we a priori selected rhesus monkeys based on genotype at the OPRM1 C77G single nucleotide polymorphism, trained them to self-administer alcohol, and assessed naltrexone responsiveness. Results Alcohol intake in rhesus monkeys varied with genotype across a range of alcohol concentrations (0.5–4%, w/v) such that animals with the G/G genotype drank consistently more alcohol than those animals with the C/C genotype. Additionally, naltrexone attenuated alcohol drinking in a dose- and genotype-dependent manner. Animals harboring the G/G genotype were more sensitive to the effects of naltrexone and showed greater reductions in alcohol consumption at lower naltrexone doses compared to animals with a C/G or C/C genotype. Conclusions This preliminary study demonstrates a pharmacogenomic response to naltrexone in rhesus monkeys that parallels that seen in humans. This finding provides a basis for developing a pharmacogenetic animal model for naltrexone effect that can expand further our understanding of the causes and treatments of alcohol use disorders.

A118G Polymorphism of OPRM1 Gene is Associated with Schizophrenia

Schizophrenia is ranked among multifactor diseases in whose pathogenesis, besides environmental factors, an interplay of functional polymorphisms of a larger number of candidate genes is involved. Neurodevelopmental abnormities are among the most accepted hypotheses in the etiology of schizophrenia. Recently, the role of oligodendrocytes in the development of the cortex has been cited repeatedly. During their various phases of differentiation oligodendrocytes present on their surfaces diverse receptors, among others the mu-opioid receptor (OPRM1). The study was focused on the relationship between the functional A118G polymorphism of the OPRM1 gene (rs1799971) and schizophrenia in groups of 130 male patients and 452 male controls. An association study revealed yet unpublished statistically significant difference of allelic and genotypic frequencies between the control and patient groups. According to our present knowledge, we assume that the OPRM1 gene polymorphism can influence the myelination of CNS neurons through regulations of expression of OPRM1 receptors on surfaces of oligodendrocytes. The neuronal myelination seems to be one of the important factors in the pathogenesis of schizophrenia.

Association of the A-1438G Polymorphism in Serotonin 2A Receptor in Migraine with Aura among Japanese Patients

We investigated the possible association of serotonin (5-HT) 2A receptor gene A-1438G polymorphism in Japanese patients with migraine. Genotyping of 5-HT(2A) A-1438G polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism in patients with migraine (male 17 : 3 with aura and 14 without aura, female 65 : 17 with aura and 48 without aura) and controls (male 31, female 84). The distribution of 5-HT(2A) A-1438G genotype frequency between migraine patients and controls did not differ. These results suggest that the A-1438G polymorphism of the 5-HT(2A) receptor gene is not a direct risk factor for migraine; however, the incidence of the A/A genotype between migraine with aura (MA) and without aura (MO) was significantly different. The 5-HT(2A) A-1438G polymorphism may be involved in determining the subtypes of migraine in Japanese.

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.

Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH) has been shown to block the norepinephrine transporter (NET), and genetic investigations have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T) and G1287A polymorphisms with MPH response in ADHD.MethodsThis study enrolled 112 children and adolescents with ADHD. A response criterion was defined based on the Clinical Global Impression-Improvement (CGI-I) score, and the ADHD Rating Scale-IV (ARS) score was also assessed at baseline and 8 weeks after MPH treatment.ResultsWe found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 G1287A polymorphism and response to ADHD treatment.ConclusionOur findings provide evidence for the involvement of the -3081(A/T) polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD.