Association of FAAH p.Pro129Thr and COMT p.Ala72Ser with schizophrenia and comorbid substance use through next-generation sequencing: an exploratory analysis

Objective: Individuals with schizophrenia and substance use disorders have a poor prognosis and increased psychiatric symptoms. The present study aimed to explore the association of 106 genes in individuals with schizophrenia and comorbid substance use through a next-generation sequencing (NGS) analysis and different in silico algorithms. Methods: We included 105 individuals diagnosed with schizophrenia and a family history of schizophrenia, of whom 49 (46.67%) presented comorbid substance use. Using NGS, we sequenced 106 genes previously associated with schizophrenia. Logistic regression models were used to assess differences in allele frequencies, and a generalized gene-set analysis was performed at the gene level. Functional annotations were performed using different algorithms and databases. Results: We identified a total of 3,109 variants, of which 25 were associated with schizophrenia and comorbid substance use and were located in regulatory and coding regions. We found low-frequency variants in COMT p.Ala72Ser, independently of p.Val158Met, that were associated with substance use. The endocannabinoid functional variant FAAH p.Pro129Thr was also associated with substance use. Conclusions: Genetic variants of genes related to dopaminergic and cannabinoid neurotransmitter systems were associated with comorbid substance use in schizophrenia. Nevertheless, more studies with larger sample sizes are needed to confirm our findings.

Analytical methodologies for sensing catechol-O-methyltransferase activity and their applications / 药物分析学报

Mammalian catechol-O-methyltransferases(COMT)are an important class of conjugative enzymes,which play a key role in the metabolism and inactivation of catechol neurotransmitters,catechol es-trogens and a wide range of endobiotics and xenobiotics that bear the catechol group.Currently,COMT inhibitors are used in combination with levodopa for the treatment of Parkinson's disease in clinical practice.The crucial role of COMT in human health has raised great interest in the development of more practical assays for highly selective and sensitive detection of COMT activity in real samples,as well as for rapid screening and characterization of COMT inhibitors as drug candidates.This review summarizes recent advances in analytical methodologies for sensing COMT activity and their applications.Several lists of biochemical assays for measuring COMT activity,including the probe substrates,along with their analytical conditions and kinetic parameters,are presented.Finally,the challenges and future perspec-tives in the field,such as visualization of COMT activity in vivo and in situ,are highlighted.Collectively,this review article overviews the practical assays for measuring COMT activities in complex biological samples,which will strongly facilitate the investigations on the relevance of COMT to human diseases and promote the discovery of COMT inhibitors via high-throughput screening.

Gut microbiota mediates the absorption of FLZ, a new drug for Parkinson's disease treatment

The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs. FLZ, a novel squamosamide derivative, has been shown to have neuroprotective effects on experimental Parkinson's disease (PD) models. FLZ is under phase Ⅰ clinical trial now, while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated. Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice, we focused on the gut microbiota to address how FLZ was metabolized and absorbed.

Personality traits of young men with different diplotypes

Background: Historically in psychogenetic research the attention has been paid to describing personality traits of the carriers of some sole genotypes; but in this work the characteristic traits of carriers of catecholaminergic system MAOA and COMT genes' genotypes different combinations are presented. Methods: A psychodiagnostic toolkit included 7 types of inventories. Genotyping was conducted with the help of DNA extraction from the buccal epithelium cells with subsequent PCR diagnostics and 3 types of statistical processing. Results: It was shown that carriers of a highly active diplotype have the lowest level of aggressiveness and are inclined to cooperate in the conflict; carriers of the highly active genotype MAOA in combination with the heterozygous genotype COMT have an average level of aggressiveness and high rates of emotional lability; carriers of low-level MAOA in combination with heterozygous genotype COMT have the highest rates of motivation to achieve success and verbal aggression; carriers of low-level MAOA and highly active COMT are emotionally labile and non-aggressive. Conclusion: We conclude that male carriers of a low-active diplotype have the highest level of aggressiveness and disposition to addictive behavior, which may indicate the association of this diplotype in a sample of young Russian men with social disadaptation.

Association between COMT and 5-HTTLPR Polymorphisms in Korean Patients with Panic Disorder : A Replication Study

OBJECTIVES: We investigated whether the catechol-O-methyltransferase (COMT) and serotonin related gene polymorphisms may be associated with agoraphobia in patients with panic disorder in Korea. METHODS: The COMT gene (rs4680), 5-hydroxytryptamine (serotonin) transporter linked polymorphic region (5-HTTLPR) gene (rs25531), serotonin receptor 1A (HTR1A) gene (rs6295) genotypes were analyzed in 406 patients with panic disorder and age-sex matched 206 healthy controls. Patients with panic disorder were dichotomized by the presence of agoraphobia. The following instruments were applied : the Beck Depression Inventory, the Beck Anxiety Inventory, the Panic Disorder Severity Scale. RESULTS: There was a significant difference in the distribution of 5-HTTLPR genotype between panic patients with agoraphobia and without agoraphobia (p = 0.024). That is, the panic patients with agoraphobia had a significant excess of the less active 5-HTTLPR allele (S allele). (p = 0.039) Also, we replicated previous western reports which indicated a significant difference in the distribution of COMT genotype between the patients with panic disorder and the healthy controls (p = 0.040). However, no significant associations of agoraphobia or panic disorder with HTR1A gene polymorphisms were found. CONCLUSIONS: This result supports that the COMT polymorphisms may be associated with panic disorder and suggests that the 5-HTTLPR polymorphisms may play a role in the pathogenesis of agoraphobia in the Korean patients with panic disorder.

Genetic Variations in Attention Deficit Hyperactivity Disorder Subtypes and Treatment Resistant Cases

OBJECTIVE: ObjectiveaaWe evaluated the distribution of alpha-2A adrenergic receptor (ADRA2A) and catechol-o-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) among ADHD subtypes and other homogeneous patient populations including treatment-resistant cases and patients with high symptom severity. METHODS: Methodsaa121 ADHD patients aged 6-18 years were included in the study. Diagnosis and subtypes designation were confirmed using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and symptoms were evaluated using the Conners' Parent (CPRS) and Teacher Rating Scales (CTRS). The response to methylphenidate was assessed objectively using the Clinical Global Impression-Severity Scale (CGI-S) and Global Assessment of Functioning Scale (GAS) as well as the Continuous Performance (CPT) and Trail Making tests (TMT-A, B). Patients were genotyped for ADRA2A (rs1800544) and COMT (rs4680) SNPs by PCR/RFLP and compared to a gender-matched control group. RESULTS: Although there was no association of COMT (rs4680) SNP with symptoms or diagnosis, the ADRA2A polymorphism, low socioeconomic status (SES), and comorbid psychiatric diagnosis were all associated with poor response to methylphenidate in logistic regression analysis. CONCLUSION: Clinicians may consider adjuvant strategies when these negative factors are present to increase the success of tailored ADHD treatments in the future.

The Influence of Genotype Polymorphism on Morphine Analgesic Effect for Postoperative Pain in Children

BACKGROUND: Although opioids are the most commonly used medications to control postoperative pain in children, the analgesic effects could have a large inter-individual variability according to genotypes. The aim of this study was to investigate the association between single nucleotide polymorphisms and the analgesic effect of morphine for postoperative pain in children. METHODS: A prospective study was conducted in 88 healthy children undergoing tonsillectomy, who received morphine during the operation. The postoperative pain score, frequency of rescue analgesics, and side effects of morphine were assessed in the post-anesthesia care unit. The children were genotyped for OPRM1 A118G, ABCB1 C3435T, and COMT Val158Met. RESULTS: Children with at least one G allele for OPRM1 (AG/GG) had higher postoperative pain scores compared with those with the AA genotype at the time of discharge from the post-anesthesia care unit (P = 0.025). Other recovery profiles were not significantly different between the two groups. There was no significant relationship between genotypes and postoperative pain scores in analysis of ABCB1 and COMT polymorphisms. CONCLUSIONS: Genetic polymorphism at OPRM1 A118G, but not at ABCB1 C3435T and COMT Val158Met, influences the analgesic effect of morphine for immediate acute postoperative pain in children.

Serotonin Transporter and COMT Polymorphisms as Independent Predictors of Health-related Quality of Life in Patients with Panic Disorder

There is growing evidence of poor health-related quality of life (HRQOL) in patients with panic disorder (PD). However, little is known about the factors affecting HRQOL in patients with PD. The authors examined whether 5-HTTLPR tri-allelic approach and Cathechol-O-methyltransferase (COMT) Val(158)Met polymorphism can predict HRQOL in patients with PD controlling for sociodemographic factors and disorder-related symptom levels. The sample consisted of 179 patients with PD consecutively recruited from an outpatient clinic and age- and gender ratio-matched 110 healthy controls. The SF-36 was used to assess multiple domains of HRQOL. Hierarchical multiple regression analysis was performed to determine the independent effect of the 5-HTTLPR and COMT Val(158)Met on the SF-36 in panic patients. Patients with PD showed lowered HRQOL in all sub-domains of the SF-36 compared to healthy controls. The 5-HTTLPR independently and additively accounted for 2.2% of variation (6.7% of inherited variance) of perceived general health and the COMT Val(158)Met independently and additively accounted for 1.5% of variation (5.0% of inherited variance) of role limitation due to emotional problems in patient group. The present study suggests that specific genetic polymorphisms are associated with certain domains of HRQOL and provides a new insight on exploring the factors that predict HRQOL in patients with PD.

Association between the Catechol-O-Methyltransferase (COMT) Val(158)Met Polymorphism and Alexithymia in Patients with Obsessive-Compulsive Disorder

PURPOSE: Alexithymia, defined as a deficit in the ability to recognize and describe one's own feelings, may be related to the development and maintenance of obsessive-compulsive symptoms. The aim of this study was to evaluate the association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and alexithymia in patients with obsessive-compulsive disorder (OCD). MATERIALS AND METHODS: We recruited 244 patients with OCD (169 males, 75 females). Alexithymia was assessed using the 20-item Toronto Alexithymia Scale (TAS-20), and genotyping of the COMT Val(158)Met polymorphism was evaluated. RESULTS: Patients with the COMT Val/Val genotype had significantly higher total and "difficulty identifying feelings" (DIF) subdimension scores than those with the Val/Met or Met/Met genotypes. Patients with the COMT Val/Val genotype had significantly higher "difficulty describing feelings" (DDF) subdimension scores than those with the COMT Val/Met genotype. However, there were no differences in the scores for the "externally oriented thinking" (EOT) subdimension among the three genotypes. CONCLUSION: These results indicate that the high-activity Val allele of the COMT Val(158)Met polymorphism is associated with increased alexithymic traits in patients with OCD. The present finding suggests that alexithymia is an endophenotype of OCD that is mediated by the COMT Val(158)Met polymorphism.

Association analysis of catechol-O-methyltransferase gene polymorphisms with schizophrenia in southern Chinese population / 中华行为医学与脑科学杂志

Objective To explore the association of catechol-O-methyhransferase(COMT) gene polymorphisms with schizophrenia susceptibility and its symptoms assessed by Positive and Negative Syndrome Scale (PANSS)in southern Chinese population.Methods COMT gene rs4633,rs4680 and rs8185002 polymorphisms were genotyped using Sequenom genotyping technology in 700 schizophrenia patients (300 Zhuang and 400 Han) and 700 healthy controls (300 Zhuang and 400 Han),and Positive and Negative Syndrome Scale (PANSS) was used for clinical symptoms assessment of patients.Statistical analysis was performed using PLINK software.Results rs4633,rs4680 and rs8185002 polymorphisms were not significantly associated with schizophrenia susceptibility in Zhuang or Han population respectively(P＞0.05).After merging Zhuang and Han samples,rs4633(I 2 =0.000,Pmeta =0.040) and rs4680 (I2=0.000,Pmeta =0.014) were significantly associated with the susceptibility to schizophrenia.In addition,haplotype T-A-T was significantly associated with schizophrenia susceptibility (P=0.049).However,these three polymorphisms were not significantly associated with total score,positive scale score,negative scale score and general psychopathology scale score assessed by PANSS(P＞0.05).Conclusion COMT gene rs4633 and rs4680 polymorphisms are involved in the susceptibility to schizophrenia in southern Chinese population.

Association of single nucleotide polymorphisms of ABCB1, OPRM1 and COMT with pain perception in cancer patients / 华中科技大学学报（医学）（英德文版）

Pain perception is influenced by multiple factors. The single nucleotide polymorphisms (SNPs) of some genes were found associated with pain perception. This study aimed to examine the association of the genotypes of ABCB1 C3435T, OPRM1 A118G and COMT V108/158M (valine 108/158 methionine) with pain perception in cancer patients. We genotyped 146 cancer pain patients and 139 cancer patients without pain for ABCB1 C3435T (rs1045642), OPRM1 A118G (rs1799971) and COMT V108/158M (rs4680) by the fluorescent dye-terminator cycle sequencing method, and compared the genotype distribution between groups with different pain intensities by chi-square test and pain scores between groups with different genotypes by non-parametric test. The results showed that in these cancer patients, the frequency of variant T allele of ABCB1 C3435T was 40.5%; that of G allele of OPRM1 A118G was 38.5% and that of A allele of COMT V108/158M was 23.3%. No significant difference in the genotype distribution of ABCB1 C3435T (rs1045642) and OPRM1 A118G (rs1799971) was observed between cancer pain group and control group (P=0.364 and 0.578); however, significant difference occurred in the genotype distribution of COMT V108/158M (rs4680) between the two groups (P=0.001). And the difference could not be explained by any other confounding factors. Moreover, we found that the genotypes of COMT V108/158M and ABCB1 C3435T were associated with the intensities of pain in cancer patients. In conclusion, our results indicate that the SNPs of COMT V108/158M and ABCB1 C3435T significantly influence the pain perception in Chinese cancer patients.

Association of the Catechol O-Methyltransferase Val158-Met Polymorphism and Reduced Interference Control in Korean Children with Attention-Deficit Hyperactivity Disorder

OBJECTIVE: We tested for association of the catechol-O-methyltransferase (COMT) Val158-Met (rs4680) polymorphism with attention-deficit hyperactivity disorder (ADHD) using family-based test in Korean trios. METHODS: A total of 181 subjects with ADHD along with both of their biological parents were recruited from University Hospitals in Korea. We performed a transmission disequilibrium test (TDT) on 181 trios. RESULTS: In the TDT, we found the over-transmission of the Val allele in children with ADHD (chi2=4.21, p=0.040). CONCLUSION: These results suggest that the COMT Val158-Met polymorphism is associated with ADHD among the Korean population. However, this study must be replicated in larger populations.

Possible effect of COMTVal158Met polymorphism on the association between childhood maltreatment and externalizing behavior: A preliminary study.

Aims: Over the course of the past decades, studies on child maltreatment have increasingly adopted multiple levels of analysis (particularly by the inclusion of genetics factors) on the basis of the variability in children’s responses to stressful life events. This is a preliminary study on the effects of child maltreatment in a sample of adolescents according to this perspective. Study Design: Case-control study. Methodology: We investigated the moderating effect of COMT Val158Met polymorphism onthe association of child maltreatment with a range of externalizing behavior - assessed by the Child Behavior Check List/6-18 scale - in a sample composed of 52 maltreated children and adolescents and 90 healthy controls aged 10-18. Maltreatment was recorded on the basis of the presence/absence of physical contact. Results: COMT Val158Met polymorphism interacts with physical contact abuse to influence externalizing behavior (p=.04), with both genetic (p=.03) and environmental risk factor (p=.003) having a significant main effect. Similar results were found considering the rule-breaking component of externalizing behavior, and the main effect of maltreatment was highly significant in all analyses performed. Conclusion: This preliminary study supports the hypothesis that the variability in children's responses to maltreatment might be partially explained by individual genetic differences. Considering the presence of physical contact as a risk factor we could explain inconsistence of findings in literature on GxE in maltreatment.

Polimorfismo en el gen COMT en una muestra de gestantes normales y con restricción del crecimiento intrauterino en un hospital de Lima / COMT gene polymorphism in a sample of pregnant women with intruterine growth restriction in a Lima hospital

Antecedentes: Los procesos fisiopatológicos que ocurren a nivel celular y molecular en la restricción de crecimiento intrauterino (RCIU) son aún desconocidos. La catecol-O-metiltransferasa (COMT) es una enzima de fase II que inactiva los catecol estrógenos al transferir un grupo metílico. Se conoce un polimorfismo funcional Val158 Met en el gen COMT como un marcador susceptible para diversas enfermedades maternoperinatales, existiendo estudios que sugieren que el alelo que codifica una COMT de baja actividad puede ser un marcador susceptible para RCIU. Por lo tanto, el estudio del polimorfismo COMT ofrece una nueva estrategia para la evaluación de marcadores genéticos que pueden ser utilizados para la detección de ciertas alteraciones asociadas al embarazo. Objetivos: Establecer la asociación entre el polimorfismo Val158Met catecol-O-metiltransferasa (COMT) y la restricción de crecimiento intrauterino. Institución: Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú. Diseño: Estudio tipo relacional (asociativo), con diseño observacional, tipo caso-control (no experimental). Materiales: Muestra de sangre materna de parturientas. Métodos: Durante el año 2011, se obtuvo 81 muestras para genotipaje del gen COMT. De ellas, 26 (32,1%) correspondieron a parturientas con RCIU (casos) y 55 (67,9%) a muestras de madres de hijos sin RCIU (controles). La distribución de los genotipos fue evaluada usando la prueba de chi cuadrado. Se comprobó la distribución proporcional de los genotipos en los grupos con RCIU y sin RCIU con la hipótesis nula de Hardy-Weinberg. Las madres participantes firmaron un consentimiento informado. Principales medidas de resultados: Asociación entre los genotipos COMT y la RCIU, y entre los alelos COMT Val/Met y la RCIU. Resultados: Las distribuciones de los genotipos en los grupos con RCIU y sin RCIU estuvieron de acuerdo a la hipótesis nula de Hardy-Weinberg. Al relacionar los genotipos COMT Val/Met con la condición de RCIU, la prueba X²=1.8057, gl=2, p=0.4054, no encontró asociación entre dichos genotipos y la RCIU. Al determinar la asociación entre los alelos COMT y la RCIU, tampoco se encontró asociación entre los alelos COMT Val/Met y la condición de RCIU en la muestra estudiada, con prueba X²=0.3659, gl=1, p=0.5453. Conclusiones: No se encontró asociación entre los genotipos COMT y la RCIU, ni entre los alelos COMT Val/Met y la RCIU, en la muestra estudiada.

Background: Cellular and molecular events in the pathophysiology of intrauterine growth restriction (IUGR) are still unknown. Cathecol O-methyltransferase (COMT) is a phase II enzyme that inactivates cathecol estrogens by transferring a methyl group. A functional polymorphism Val158 Met in COMT gene is known as susceptible marker for diverse maternal and perinatal diseases, and studies suggest the allele codifying a low activity COMT may be a susceptible marker for IUGR. COMT polymorphism study may be a new strategy to determine genetic markers that might be used for detection of certain disorders related to pregnancy. Objectives: To determine association of Val158Met cathecol-O-methyltransferase (COMT) polymorphism and intrauterine growth restriction. Setting: Faculty of Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru. Design: Relational (associative), observational, case-control (non-experimental) study. Materials: Maternal blood samples obtained following delivery. Methods: During 2011, 81 blood samples were obtained from post partum mothers for COMT gene genotyping, 26 (32.1%) were mothers with IUGR (cases) and 55 (67.9%) without IUGR (controls). Genotype distribution was determined by chi square test. Genotypes proportional distribution in IUGR and non-IUGR groups was determined with Hardy-Weinberg’s null hypothesis. All women signed informed consent. Main outcome measures: Association of COMT genotypes and IUGR, and between COMT Val/Met alleles and IUGR. Results: Genotype distribution in IUGR and non-IUGR groups agreed with Hardy-Weinberg null hypothesis. There was no association of COMT Val/Met genotypes and IUGR, X²=1.8057, gl=2, p=0.4054. There was no association between COMT Val/Met alleles and IUGR, X²=0.3659, gl=1, p=0.5453. Conclusions: No association was found either between COMT genotypes and IUGR or between COMT Val/Met alleles and IUGR.

Association of the Catechol-o-Methyltransferase Gene Polymorphisms with Korean Autism Spectrum Disorders

This study evaluated the family-based genetic association between autism spectrum disorders (ASDs) and 5 single-nucleotide polymorphisms (SNPs) in the catechol-o-methyltransferase gene (COMT), which was found among 151 Korean ASDs family trios (dominant model Z = 2.598, P = 0.009, P(FDR) = 0.045). We found a statistically significant allele transmission or association in terms of the rs6269 SNP in the ASDs trios. Moreover, in the haplotype analysis, the haplotypes with rs6269 demonstrated significant evidence of an association with ASDs (additive model rs6269-rs4818-rs4680-rs769224 haplotype P = 0.004, P(FDR) = 0.040). Thus, an association may exist between the variants of the COMT gene and the occurrence of ASDs in Koreans.

No Effect of Serotoninergic Gene Variants on Response to Interpersonal Counseling and Antidepressants in Major Depression

OBJECTIVE: Gene variants within the serotonin pathway have been associated with major depressive disorder (MDD) treatment outcomes, however a possible different modulation on pharmacological or psychological treatments has never been investigated. METHODS: One hundred sixty MDD patients were partially randomized to either inter-personal counseling (IPC) or antidepressants. The primary outcome was remission at week 8. Five serotonergic polymorphisms were investigated (COMT rs4680, HTR1A rs6295, HTR2A rs2224721, HTR2A rs7997012 and SLC6A4 rs421417). RESULTS: IPC (n=43) and antidepressant (n=117) treated patients did not show any difference in remission rates at week 8 (corrected for baseline severity, age and center). None of the studied gene variants impacted on response and remission rates at week 8 neither in the IPC nor in the antidepressant group. An analysis of the whole sample showed a trend of association between rs7997012 AA genotype and a better treatment outcome. CONCLUSION: Our study confirms that IPC is an effective psychological intervention comparable to antidepressants in mild-moderate MDD. Polymorphisms related to the serotonin system did not exert a major effect on clinical outcomes in none of the treatment groups.

Efectos del polimorfismo Val108/158Met del gen dopaminérgico Catecol-O-metiltransferasa COMT en las funciones ejecutivas de preescolares / Effects of dopamine gene polymorphism Val108/158Met Catechol-O-methyltransferase COMT in executive functions in preschool

El nivel de Dopamina en la Corteza Prefrontal se ha relacionado al desempeño de las Funciones Ejecutivas (FE). El objetivo de este estudio es explorar el efecto del polimorfismo funcional del gen COMT (Val/Val,Val/Met y Met/Met) en las FE de preescolares. Se utilizó la Batería Neuropsicológica de Funciones Ejecutivas para niños, y se extrajo el ADN genómico según metodología estándar (N=248) de 3 a 6 años de edad (M=4.6). Se estudiaron las frecuencias genotípicas del gen COMT y se realizó un análisis de varianza (ANOVA one-way) estableciendo diferencias significativas con una p<0.05. Los niños con el polimorfismo de baja actividad Met/Met puntúan significativamente mejor en relación a los niños con polimorfismo Val/Val en pruebas que requieren de Inhibición y los niños con el polimorfismo de alta actividad Val/Val resultan con un mejor rendimiento en pruebas relacionadas a MT, Planeación y Abstracción que los niños con polimorfismo Met/Met y Val/Met. Estos resultados parecen reflejar el papel de la enzima COMT como regulador de DA y que tanto el hipermetabolismo como el hipometabolismo tiene implicaciones importantes en las FE.

The level of DA in the prefrontal cortex has been related to the performance on executive functions (EF). The objective of this study was to explore the effect of the COMT polymorphism (Val/Val, Val/Met, Met/Met) in the performance of EF in a population of preschool children. All subjects were evaluated with a Neuropsychological Battery and genomic DNA was extracted according to standard methodology (N=248) from 3 to 6 years of age (M=4.6). We studied genotypic frequencies of the COMT gene and an analysis of variance (one-way ANOVA) with post hoc analysis, establishing significant differences at p<0.05. In Children with a low activity polymorphism Met/Met scored significantly better in relation to the children with polymorphism Val/Val in tests requiring inhibition and children with high activity polymorphism Val/Val had better performance on tests related to working memory, planning and abstraction that children with polymorphism Met/Met and Val/Met. These results seem to reflect the role of COMT enzyme as a regulator of DA and that both hypermetabolism and hypometabolism has important implications for the EF.

Is There the Preventive Effect of COMT-inhibitor on Parkinson's Disease Associated with Dementia?

BACKGROUND: Elevated homocysteine (hcy) levels are associated with dementia, which is a frequent non-motor symptom of Parkinson's disease (PD). High levels of hcy in PD patients treated with levodopa are thought to result from increased synthesis during the metabolism of levodopa by COMT, and that use of a COMT-inhibitor may reduce hcy levels. In this study, we sought to clarify the effects of COMT-inhibitors on dementia in PD patients. METHODS: Thirty-eight PD patients without dementia (PDwoD), 35 PD patients with dementia (PDD), and 48 controls were enrolled in this study. All subjects underwent neuropsychological testing and a neurological examination. The hcy levels were measured in all subjects, and the relationship between hcy levels and dementia was evaluated in two PD groups (those that underwent treatment with levodopa-alone versus treatment with levodopa plus a COMT-inhibitor). RESULTS: Patients in the PDD group showed higher hcy levels than patients in the PDwoD group, though there was no significant difference in the hcy level between PDwoD patients and healthy controls. Regarding the effects of a COMT-inhibitor, there was no correlation between hcy levels in the 2 PD subgroups, indicating that there were no significant effects of the COMT-inhibitor on PDD. In addition, the odds ratio for PDD with the use of a COMT-inhibitor was 0.864 (95% CI=0.342-2.180). CONCLUSIONS: These results are in agreement with previous studies in that levodopa treatment in PD patients leads to elevated hcy concentrations. COMT-inhibitors, on the other hand, had no preventive effect on cognitive impairment in PD patients.

Modulatory effect of plasma folate and polymorphisms in one-carbon metabolism on catecholamine methyltransferase (COMT) H108L associated oxidative DNA damage and breast cancer risk.

The present study was aimed to investigate the modulatory role of plasma folate and eight putatively functional polymorphisms of one-carbon metabolism on catecholamine methyltransferase (COMT)-mediated oxidative DNA damage and breast cancer risk. Plasma folate and 8-oxo-2’-deoxyguanosine (8-oxodG) were estimated by commercially available kits, while polymorphisms were screened by PCR-RFLP and PCR-AFLP methods. COMT H108L polymorphism showed independent association with breast cancer (OR: 1.73, 95% CI: 1.31-2.30). No significant interaction was observed between folate status and COMT genotype. Multifactor dimensionality reduction (MDR) analysis gave evidence for the significant epistatic (gene-gene) interactions (p<0.0001) of COMT H108L with reduced folate carrier 1 (RFC1) G80A, thymidylate synthase (TYMS) 5’-UTR 3R2R, TYMS 3’-UTR ins6/del6. Increased plasma 8-oxodG were observed in cases compared to controls (mean ± SE: 5.59 ± 0.60 vs. 3.50 ± 0.40 ng/ml, p<0.004). Plasma folate deficiency alone was not a significant predictor of 8-oxodG elevation. The genotype combinations namely, RFC1 G80A/methionine synthase reductase (MTRR) A66G, RFC1 G80A/SHMT C1420T/TYMS 3R2R and serine hydroxymethyltransferase (SHMT) C1420T/TYMS 3R2R/methionine synthase (MTR) A2756G/COMT H108L were strong predictors of 8-oxodG elevation in the order of risk. To conclude, the current study provides substantial evidence for a cross talk between one-carbon metabolism and COMT catalysis that might influence oxidative DNA damage and breast cancer risk.

¿Cuáles son los avances de la genómica yl a proteómica en el tamizaje y/o predicción de la preeclampsia? / What advances have been made in the areas of genomics and proteomics in screening and/or predicting preeclampsia?

Introducción: la preeclampsia constituye una causa importante de morbimortalidad materna y perinatal en el mundo. Su etiopatogenia es aún un enigma; sin embargo, los avances en genómica y proteómica prometen la identificación temprana de la enfermedad o del riesgo de padecerla. Objetivo: hacer una reflexión sobre los avances más promisorios de la genómica y proteómica, en el tamizaje y/o predicción de la preeclampsia. Conclusiones: dos polimorfismos funcionales, uno en el gen ACE (I/D) y otro en el gen COMT (Val158Met), poseen los resultados más promisorios para cumplir con el objetivo de identificar genéticamente a las mujeres con mayor riesgo de desarrollar preeclampsia durante un embarazo. Por su parte, la proteómica ha identificado a la SERPINA-1 como un biomarcador útil para detectar en la orina de las embarazadas que estén desarrollando la preeclampsia, con al menos 10 semanas de antelación a las manifestaciones clínicas de la misma y la necesidad de finalizar el embarazo. En conjunto, estos avances llevados a la práctica clínica podrían reducir el impacto de esta patología en la salud materna.

Introduction: preeclampsia is an important cause of maternal and perinatal morbi-mortality throughout the world. Its etiopathogeny still remains an enigma; however, the advances made in genomics and proteomics promise early identification of the disease or the risk of suffering from it. Objective: thoughts on the most promising advances in genomics and proteomics regarding the pressing goal of early detection and/or prediction of preeclampsia risk. Conclusions: two functional polymorphisms, one on the ACE gene (I/D) and another one in the COMT gene (Val158Met) are the most promising results of genomics for identifying women at genetically higher risk of developing preeclampsia during pregnancy. Proteomics has identified SERPINA-1 as a useful biomarker for detecting preeclampsia in the urine of pregnant women at least 10 weeks before clinical manifestations as well as the need for early termination of pregnancy. Such recent progress in genomics and proteomics adapted to clinical practice might reduce the impact of this disease on maternal health.