Catechol-O-methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children.код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:1431– 1435 (2008) Brief Research Communication Catechol-O-Methyltransferase Val158Met Polymorphism Is Associated With Methylphenidate Response in ADHD Children Eva Kereszturi,1 Zsanett Tarnok,2 Emese Bognar,2 Krisztina Lakatos,3 Luca Farkas,2 Julia Gadoros,2 Maria Sasvari-Szekely,1 and Zsofia Nemoda1* 1 Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary Vadaskert Child and Adolescent Psychiatric Clinic, Budapest, Hungary 3 Institute for Psychology, Hungarian Academy of Sciences, Budapest, Hungary 2 Methylphenidate is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD) but it is not effective in every case. Therefore, identifying genetic and/or biological markers predicting drugresponse is increasingly important. Here we present a case-control study and pharmacogenetic association analyses in ADHD investigating three dopaminergic polymorphisms. Previous studies suggested variable number of tandem repeats (VNTR) in the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1) genes as genetic risk factors for ADHD and as possible markers of methylphenidate response. Our results did not indicate substantial involvement of these two VNTRs in ADHD, however, both the case-control and the pharmacogenetic analyses showed significant role of the high activity Val-allele of cathecolO-methyltransferase (COMT) Val158Met polymorphism in our ADHD population. The Val-allele was more frequent in the ADHD group (n ¼ 173) compared to the healthy population (P ¼ 0.016). The categorical analysis of 90 responders versus 32 non-responders showed an association between the Val-allele or Val/Val genotype and good methylphenidate response (P ¼ 0.009 and P ¼ 0.034, respectively). Analyzing symptom severity as a continuous trait, significant interaction of COMT genotype and methylphenidate was found on the Hyperactivity-Impulsivity scale (P ¼ 0.044). Symptom severity scores of all three genotype groups decreased following methylphenidate administration (P < 0.001), however Val/Val homozygote children had significantly less severe symptoms than those with Met/Met genotype after treatment (P ¼ 0.015). This interaction might reflect the regulatory effect of COMT dominated prefrontal None of the authors reported biomedical financial interests or potential conflicts of interest. Grant sponsor: NKFP; Grant number: 1A/008/2002; Grant sponsor: OTKA; Grant number: T 048576. *Correspondence to: Dr. Zsofia Nemoda, Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, POB 260, Budapest H-1444, Hungary. E-mail: email@example.com Received 26 July 2007; Accepted 29 November 2007 DOI 10.1002/ajmg.b.30704 Published online 23 January 2008 in Wiley InterScience (www.interscience.wiley.com) ß 2008 Wiley-Liss, Inc. dopamine transmission on subcortical dopamine systems, which are the actual site of methylphenidate action. ß 2008 Wiley-Liss, Inc. KEY WORDS: attention deficit hyperactivity disorder; dopaminergic polymorphism; DRD4; DAT1; pharmacogenetics Please cite this article as follows: Kereszturi E, Tarnok Z, Bognar E, Lakatos K, Farkas L, Gadoros J, Sasvari-Szekely M, Nemoda Z. 2008. Catechol-O-Methyltransferase Val158Met Polymorphism Is Associated With Methylphenidate Response in ADHD Children. Am J Med Genet Part B 147B: 1431–1435. INTRODUCTION Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset psychiatric disorders, affecting 5% of school-age children worldwide [Polanczyk et al., 2007]. The strong genetic component of ADHD has been demonstrated by family- and twin-studies; based on neurobiological theories, most of the candidates genes belonging to the dopaminergic system [Faraone et al., 2005]. Early diagnosis of ADHD and its well-chosen treatment plan are especially important, as later illicit substance abuse could be reduced among appropriately treated ADHD adolescents [Faraone and Wilens, 2003]. The psychostimulant drugs methylphenidate (MPH) and dextroamphetamine are the most commonly used medications; and over the last decades, pharmacogenetic analyses tried to determine the genetic background of stimulant drug responsiveness [McGough, 2005]. Pharmacokinetic and pharmacodynamic variability exists between ADHD children, possibly reflecting the underlying biological and genetic influences on drug response [Masellis et al., 2002]. However, the factors affecting drug response are not yet clearly understood. Most of the pharmacogenetic studies addressed the possible involvement of the dopamine transporter gene (DAT1, SLC6A3), since dopamine transporter is the main target of MPH. The most frequently investigated polymorphism of the DAT1 gene is the 40 bp VNTR (Variable Number of Tandem Repeats) located in the 30 untranslated region. Three groups found association between homozygosity of the 10-repeat allele and poor response to methylphenidate [Winsberg and Comings, 1999; Roman et al., 2002; Cheon et al., 2005], although several negative findings have also been published [Langley et al., 2005; van der Meulen et al., 2005; 1432 Kereszturi et al. Mick et al., 2006; Zeni et al., 2007]. Making the picture more complex, an Irish group reported association between the 10repeat allele and better response to MPH in a family-based study [Kirley et al., 2003]. In line with these results, a Canadian group observed poor response in children with homozygous 9/9 genotype [Joober et al., 2007]. Two other studies described association between poor response and the rare 9/9 genotype in ADHD children and healthy adults [Lott et al., 2005; Stein et al., 2005]. Another frequently studied polymorphism is the 48 bp VNTR located in exon III of the dopamine D4 receptor (DRD4) gene. The published results are controversial: Hamarman et al.  found that patients carrying the 7-repeat allele required higher dose of MPH for symptom improvement, but opposite findings were described by van der Meulen et al. . In a Korean ADHD population the 4-repeat allele was associated with good response to MPH [Cheon et al., 2007]. In addition, two studies resulted in negative findings [Winsberg and Comings, 1999; Zeni et al., 2007]. Although dopamine transporter is the key regulator of dopamine neurotransmission, the main determinant of extracellular dopamine level in the prefrontal cortex is the cathecol-O-methyltransferase (COMT) metabolizing enzyme. A human-specific single nucleotide polymorphism (SNP) has been described in the COMT gene, altering valine 158 to methionine in the membrane-bound form and reducing the enzyme activity threefold [reviewed by Tunbridge et al., 2006]. The present study aimed to evaluate the association between methylphenidate response and polymorphisms of three dopaminergic genes: DAT1, DRD4, and COMT. MATERIALS AND METHODS Previously published cohorts of 173 ADHD patients and 284 sex-matched Hungarian control subjects participated in this study [Kereszturi et al., 2007]. Both the clinical and control samples were ethnically homogenous and of Caucasian origin. The study was approved by the Local Ethics Committee (TUKEB), patients and their parents provided written informed consent for their participation. DNA sampling and genotyping methods of the three dopaminergic polymorphisms have been described earlier [Tarnok et al., 2007]. No significant deviations from Hardy–Weinberg equilibrium were detected for any of the polymorphisms either in the case or in the control population. Transmission Disequilibrium Test (TDT) was calculated using 272 parental data, since genetic data were available only in 104 trios and 64 duos. Chi-square analyses were carried out, and P-value threshold for multiple comparison was calculated by the False Discovery Rate adjustment [Benjamini and Hochberg, 1995]. A prospective methylphenidate-response analysis was conducted in 122 inpatients (45 children were not given any drug treatment, and 6 patients received antipsychotic or antidepressant treatment because of their comorbid disorders). The initial psychiatric evaluation of these 122 children (mean age: 9.6 2.6; 88.5% male, and 11.5% female) was carried out in a drug-free period. ADHD-subtypes were evaluated based on DSM-IV criteria [American Psychiatric Association, 1994] by two independent child psychiatrists both specialists in the assessment and treatment in ADHD. The Attention-Deficit Hyperactivity Disorder Rating Scale [ADHD-RS; DuPaul, 1998] was used for dimensional measurement. Comorbid conditions were assessed by the Hungarian child version of the Mini-International Neuropsychiatric Interview [MINIKid; Balazs et al., 2004]. Socioeconomic status (SES) assessment was based on family composition and the parents’ education level, occupation, and income (1 ¼ far below average, 2 ¼ below average, 3 ¼ average, 4 ¼ above average, 5 ¼ far above average). Patients participating in the drug response study were given 10–30 mg methylphenidate according to their body weight, in two doses (morning and noon). The daily dose thereby ranged from 0.22 to 0.95 mg/kg/day, in average 0.55 0.15 mg/kg/day. The primary outcome measures of MPH-treatment were the ADHD-RS Inattention and Hyperactivity-Impulsivity severity scores (0–3 points for 9–9 items), and the seven-point Severity of Illness subscale of the Clinical Global Impression scale [CGIS; Guy, 1976]. ADHD-RS and CGI-S were collected at the beginning of the treatment (baseline levels) and every month in the first 6 months when the children and their parents came back for control examinations and drug-prescription. Drug response was assessed by both categorical and dimensional approaches. The categorical definition of drug-response was obtained according to previous studies [Buitelaar et al., 2004; Kemner et al., 2005]: children were evaluated as responders after 6 months of treatment if they had at least 25% decrease in ADHD-RS total score, and their CGI-S score was two points or less (corresponding to no or minimal symptoms) in the last two consecutive months. Categorization of the non-responder children was done during the first 3 months, as they had less than 10% decrease in their ADHD-RS total score and discontinued the treatment. According to these criteria, 90 children were categorized as responder, whereas 32 children as non-responder. There were no significant differences in the demographic variables, comorbid conditions, frequencies of ADHD type or severity between the responder and nonresponder groups (Supplementary Table I), neither showed a multivariate analysis of variance significant effect of group membership on ADHD-scales [F(2,119) ¼ 2.25, P ¼ 0.110]. CGI-S baseline scores differed between the two groups [responder: 5.94 0.88, non-responder: 5.53 0.92, t(1,120) ¼ 2.26, P ¼ 0.026], although the extent of the difference of the means was small. Therefore, responder and non-responder status was ignored for further analyses of variance investigating the effect of MPH on ADHD-RS and CGI-S scores in a repeated measures design including genotype as a betweensubject factor. RESULTS The case-control analyses of the three dopaminergic polymorphisms (DAT1 40 bp VNTR, DRD4 48 bp VNTR, and COMT Val158Met) were carried out on 173 ADHD children and 284 sex-matched (but not age-matched) control subjects. There were no significant differences in the allele- or genotypefrequencies of the investigated VNTRs between the ADHD and control groups (Table I). However, significant differences were detected both in allele- and genotype-distributions of the COMT Val158Met polymorphism: the Val-allele and the Val/Val genotype were more frequent in the ADHD group compared to healthy population [w2 (df ¼ 1) ¼ 5.82, P ¼ 0.016, and w2 (df ¼ 2) ¼ 6.60, P ¼ 0.037, respectively]. After the False Discovery Rate adjustment for multiple testing, the allele-wise P-value of the COMT Val158Met remained significant (P < 0.0167). TDT analyses gave similar results: in the available heterozygote parental data we could not detect any preferable transmission of the DRD4 7-repeat allele (passed: 34 times, not-passed: 33 times, TDT w2 ¼ 0.01, P ¼ 0.903) or the DAT1 10-repeat allele (53 vs. 40 transmission from the 9/10 parents, TDT w2 ¼ 1.82, P ¼ 0.178; and 56 vs. 43 transmission from any kind of heterozygote parents, TDT w2 ¼ 1.71, P ¼ 0.191). On the other hand, there was a tendency for the over-transmission of the COMT Val-allele (71 vs. 52 times, TDT w2 ¼ 2.93, P ¼ 0.087). In the second set of analyses the methylphenidate response was assessed in 122 ADHD children. Using the categorical grouping system, 90 patients (73.8%) were described as responder, while 32 (26.2%) were non-responder. The allele COMT Val158Met and Methylphenidate Response in ADHD 1433 TABLE I. Genotype Frequencies of the DAT1, COMT, and DRD4 Polymorphisms in ADHD Patients and Controls DAT1 40 bp VNTRa Polymorphic sites Genotype ADHD n (total 173) Frequency (%) Control n (total 284) Frequency (%) Allele-wise P (df ¼ 1) Genotype-wise P (df ¼ 2) DRD4 48 bp VNTRb COMT Val158Met 9/9 9/10 10/10 Others Met/Met Met/Val Val/Val 7þ 7 10 5.8 62 35.8 95 54.9 6 3.5 37 21.4 87 50.3 49 28.3 53 30.6 120 69.4 28 9.9 100 35.2 150 52.8 6 2.1 80 28.2 151 53.2 0.016 0.037 53 18.7 107 177 37.7 62.3 0.325 (df ¼ 3) 0.235 (df ¼ 5) 0.223 0.286 a The rare DAT1 40 bp VNTR genotypes were grouped as ‘‘others’’ and left out from the analyses (four 10/11, one 6/10, one 9/11 genotype in the ADHD group, and single 6/10, 7/9, 9/15, 10/11, 10/13, 10/14 genotype in the control group). b In the Chi-square analyses of the DRD4 48 bp VNTR only the most frequent alleles (2, 3, 4, and 7) were used. In the genotype-wise analyses the following genotype groups were used: 2/4, 2/7, 3/4, 4/4, 4/7, and 7/7. For more detailed genotype distribution see Supplementary Table II. and genotype frequencies of the dopaminergic polymorphisms were compared by Chi-square analyses between the two patient groups. We could not detect any biased distribution in the allele- and genotype-frequencies of either the DRD4 48 bp VNTR or the DAT1 40 bp VNTR (Table II). The Val-allele of the COMT polymorphism, however, showed a significant association with good methylphenidate response [w2 (df ¼ 1) ¼ 6.87, P ¼ 0.009]. The Val/Val genotype was twice as frequent in the responder group compared to the non-responders [w2 (df ¼ 2) ¼ 6.78, P ¼ 0.034]. The ratio of Val/Met heterozygotes was similar in the two groups. In the dimensional approach repeated measures analyses of variance were carried out to test the effect of MPH on ADHD-RS and CGI-S scores, and its potential interaction with COMT genotype. Severity scores after the first month of MPH treatment were used (for the baseline and after-treatment scores see Supplementary Table III). The Inattention and Hyperactivity-Impulsivity scales of the ADHD-RS were entered into the same analysis, while the CGI-S scores were analyzed separately. Methylphenidate significantly reduced ADHD-RS scores after 1 month of treatment [F(2,118) ¼ 104.73, P < 0.001, Z2 ¼ 0.640], for both Inattention [F(1,119) ¼ 201.52, P < 0.001, Z2 ¼ 0.629] and Hyperactivity-Impulsivity [F(1,119) ¼ 169.45, P < 0.001, Z2 ¼ 0.587]. The marginal multivariate interaction of MPH-effect and COMT genotype [F(4,234) ¼ 1.99, P ¼ 0.097, Z2 ¼ 0.033] remained a tendency for Inattention [F(2,119) ¼ 2.44, P ¼ 0.091, Z2 ¼ 0.039], however was significant for Hyperactivity-Impulsivity [F(2,119) ¼ 3.42, P ¼ 0.036, Z2 ¼ 0.054]. The Hyperactivity-Impulsivity severity score was significantly reduced in all genotype groups (P < 0.001); and significant genotype difference was detected only in the post- MPH scores [F(2,119) ¼ 4.11, P ¼ 0.019, Z2 ¼ 0.065], with Val/Val children scoring lower than Met/Met ones (Bonferroni test, P ¼ 0.015). The extent of decrease was also related to COMT genotype: using the difference of baseline minus aftertreatment scores, the univariate analysis of variance revealed significant genotype effect [F(2,119) ¼ 3.42, P ¼ 0.036, Z2 ¼ 0.054], with the decrease in the Val/Val group being significantly larger, than that in the Met/Met group (Bonferroni test, P ¼ 0.031). Methylphenidate also significantly decreased the CGI-S scores [F(1,119) ¼ 154.75, P < 0.001, Z2 ¼ 0.57], but this reduction was not modified by COMT genotypes [F(2,119) ¼ 0.89, P ¼ 0.41, Z2 ¼ 0.015]. DISCUSSION In contrast to previous studies, we found no association between ADHD and the common 48 bp VNTR of the DRD4 gene using a case-control approach. The frequency of the 7-repeat allele in our Hungarian population was comparable to that of other European populations [Li et al., 2006], however, the frequency of this risk allele was slightly decreased (but not reaching significance) in our ADHD population compared to the controls (18.2% vs. 21.3%). Similarly, the TDT did not reveal any biased transmission of the 7-repeat allele (Supplementary Table II). We found no biased distribution or transmission of the DAT1 40 bp VNTR alleles either. This negative result, however, is not so surprising, as the most recent meta-analysis has found no significant evidence for this polymorphism in the etiology of ADHD neither in European nor in Asian populations [Li et al., 2006]. Concerning the COMT polymorphism, the first association analysis by TABLE II. Genotype Frequencies of the DAT1, COMT, and DRD4 Polymorphisms in Methylphenidate-Treated ADHD Patients DAT1 40 bp VNTRa Polymorphic sites Genotype Responder n (total 90) Frequency (%) Non-responder n (total 32) Frequency (%) Allele-wise P (df ¼ 1) Genotype-wise P (df ¼ 2) DRD4 48 bp VNTRb COMT Val158Met 9/9 9/10 10/10 Others Met/Met Met/Val Val/Val 7þ 7 8 8.9 35 38.9 45 50.0 2 2.2 14 15.6 42 46.7 34 37.8 26 28.9 64 71.1 1 3.1 14 43.8 15 46.9 2 6.3 10 31.3 17 53.1 0.009 0.034 5 15.6 10 22 31.3 68.8 0.903 (df ¼ 2) 0.868 (df ¼ 3) 0.667 0.539 a The rare DAT1 40 bp VNTR genotypes were grouped as ‘‘others’’ and left out from the analyses (one 6/10 and one 10/11 genotype in the responder group, and two 10/11 genotype in the non-responder group). b In the Chi-square analyses of the DRD4 48 bp VNTR only the most frequent alleles (2, 4, and 7) were used. In the genotype-wise analyses the following genotype groups were used: 2/4, 4/4, 4/7, and 7/7. For more detailed genotype distribution see Supplementary Table II. 1434 Kereszturi et al. Eisenberg et al.  found an over-transmission of the Valallele in ADHD trios, but the subsequent family-based studies have not confirmed this finding [for a meta-analysis see Cheuk and Wong, 2006]. Our results partly support the original finding: while the TDT analysis showed a tendency (Val-allele was transmitted 71 vs. 52 times, P ¼ 0.087), the case-control analysis gave a significant association between ADHD and the high activity Val-allele of the COMT SNP (P ¼ 0.016 for allele, and P ¼ 0.037 for genotype distribution). This finding raises the possibility that the COMT polymorphism might be important in the development of certain ADHD-symptoms connected with prefrontal cortex dopamine neurotransmission. The COMT Val158Met polymorphism has been widely studied in relation to cognitive functions: Egan et al.  found that the low activity Met-allele associated with better performance on Wisconsin Card Sorting Test in healthy subjects as well as in schizophrenic patients. In accordance with this, Mattay et al.  showed that healthy people with the Val/Val genotype perform worse in working memory tasks, but after amphetamine administration the efficiency of PFCfunctions increases in this group. Therefore, we aimed to study the methylphenidate response in ADHD children treated with stimulant drug. Children with at least one Val-allele were indeed more likely to benefit from the MPH-treatment (while 58.3% of the Met/Met genotype group was classified as responder, the percentages were 71.2 for the Val/Met and 87.2 for the Val/Val groups). For the ADHD combined type only, these ratios were slightly different (58.3% responder of the Met/Met genotype group, 68.2% of the Val/Met group, and 88.9% of the Val/Val group). It is important to note that the demographic and clinical variables did not differ significantly among the three COMT genotype groups (see Supplementary Table III) except for the ADHD-type frequencies: in the Met/Met group there were only combined-type ADHD children. Therefore, we repeated the pharmacogenetic analyses for the combined-ADHD-type patients only. In this sub-sample the difference in COMT allele- and genotype-frequencies of the responder versus nonresponder groups was significant [w2 (df ¼ 1) ¼ 6.39, P ¼ 0.011; w2 (df ¼ 2) ¼ 6.30, P ¼ 0.043, respectively], similarly to the total group’s results (Table II). The dimensional analyses also gave similar findings in the combined-type-only sub-sample: after 1 month of treatment MPH significantly reduced ADHDRS scores [F(2,91) ¼ 90.86, P < 0.001]. The multivariate interaction of MPH-effect and COMT genotype [F(4,180) ¼ 2.69, P ¼ 0.033] was a tendency for Inattention [F(2,92) ¼ 2.75, P ¼ 0.069], and was significant for Hyperactivity-Impulsivity [F(2,92) ¼ 5.02, P ¼ 0.009], with the decrease in the Val/Val group being significantly larger, than that in the Met/Met group (Bonferroni test, P ¼ 0.006). Methylphenidate treatment also significantly decreased the CGI-S scores [F(1,92) ¼ 116.76, P < 0.001], and this reduction was not modified by the COMT genotype in this sub-sample either [F(2,92) ¼ 0.81, P ¼ 0.45]. We propose that the COMT interaction effect reflects an attenuated prefrontal dopaminergic negative control on subcortical dopaminergic systems, with the high activity Val/Val group having lower cortical dopamine level, hence a more active striatal dopamine neurotransmission [Tunbridge et al., 2006]. MPH increases dopamine level predominantly in the striatum acting on dopamine transporter, and presumably improving the signal-to-noise in target neurons [Swanson and Volkow, 2002]. In patients with COMT Val/Val genotype this beneficial MPH-effect could be more pronounced with a lower inhibitory tone from the prefrontal cortex. Since Hyperactivity-Impulsivity phenotype is more closely linked to basal ganglia function, MPH-effect might be better observed on this ADHD-RS scale. To date, only Tahir et al.  reported a genetic association analysis between methylphenidate response and the COMT polymorphism with a non-significant result, but they tested only 72 children, which might be an inadequate group-size for this type of analysis. Since our study is the first reporting positive association between the Val-allele of the COMT polymorphism and methylphenidate response, independent investigations are needed to clarify the role of the COMT polymorphism in ADHD treatment. 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