COMT and SCN9A gene variants do not contribute to chronic low back pain in Mexican-Mestizo patients.

BACKGROUND: Chronic low back pain (CLBP) is a complex condition in which genetic factors play a role in its susceptibility. Catechol-O-methyltransferase (COMT) and sodium channel NaV1.7 (SCN9A) genes are implicated in pain perception. The aim is to analyze the association of COMT and SCN9A with CLBP and their interaction, in a Mexican-Mestizo population. METHODS: A case-control study was conducted. Cases corresponded to adults of both sexes with CLBP. Controls were adults with no CLBP. Variants of SCN9A and COMT were genotyped. Allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE) were calculated. Association was tested under codominant, dominant, and recessive models. Multifactor dimensionality reduction was developed to detect epistasis. RESULTS: Gene variants were in HWE, and there was no association under different inheritance models in the whole sample. In women, in codominant and dominant models, a trend to a high risk was observed for AA of rs4680 of COMT (OR = 1.7 [0.5-5.3] and 1.6 [0.7-3.4]) and for TT of rs4633 (OR = 1.6 [0.7-3.7] and 1.6 [0.7-3.4]). In men, a trend to low risk was observed for AG genotype of rs4680 in the same models (OR = 0.6 [0.2-1.7] and 0.7 [0.3-1.7]), and for TC genotype of rs4633 in the codominant model (OR = 0.6 [0.2-1.7]). In the interaction analysis, a model of the SCN9A and COMT variants showed a CVC of 10/10; however, the TA was 0.4141. CONCLUSION: COMT and SCN9A variants are not associated with CLBP in the analyzed Mexican-Mestizo population.

Dental pain report in children and genetic polymorphism (rs4818) in Catechol-O-Methyltransferase (COMT) gene: a cross- sectional study.

AIM: Polymorphisms in the COMT gene can alter enzymatic functions, raising levels of endogenous catecholamines, which stimulates beta-adrenergic receptors related to pain. This study aimed to evaluate whether a polymorphism in the COMT gene (rs4818) is associated with dental pain in children. METHODOLOGY: A cross-sectional study was conducted with a representative sample of 731 pairs of children and parents randomly selected from a population-based sample of eight-year-old children. Reports of dental pain was evaluated using a question directed at the parents and self-reported pain using the Faces Pain Scale - Revised. Dental caries experience was determined using the Decayed, Missing, and Filled Teeth (DMFT) index. For genetic analysis, DNA was obtained from oral mucosa epithelial cells of 352 children randomly selected from the initial sample. RESULTS: Children with the CC genotype had higher odds of reporting moderate to intense pain than those with the GG genotype (OR=3.60; 95% CI=0.80-16.20; p=0.03). These same children had greater odds of parental reports of pain (OR=1.93; 95% CI=0.91-4.08; p=0.02). Moreover, lower schooling of parents/guardians and caries experience in the primary dentition were significantly associated with greater odds of a parental report of dental pain (OR=2.06; 95% CI=1.47-2.91; p<0.001; OR=6.26; 95% CI=4.46-8.78; p<0.001). CONCLUSIONS: The rs4818 polymorphism of the COMT gene is associated with dental pain. Children with the C allele are more likely to report higher levels of pain. Clinical Relevance: Even though the experience of pain is subjective and multifactorial, this study raises the hypothesis that there is a genetic predisposition to dental pain that should be considered in clinical practice.

Pain perception genes, asthma, and oral health: A reverse genetics study.

Pain is an experience of a subjective nature, interpreted in a personal way and according to an extensive palette of factors unique to each individual. Orofacial pain can be acute or chronic and it is usually the main reason for the patient to seek dental care. Pain perception varies widely among individuals. This variability is considered a mosaic of factors, which include biopsychosocial factors and genetic factors. Understanding these differences can be extremely beneficial for pain management in a personalized and more efficient way. We performed association studies to investigate phenotypes associated with genetic markers in pain-related genes in two groups of patients who received more or less anesthesia during dental treatment. The study group was comprised of 1289 individuals participating in the Dental Registry and DNA Repository Project (DRDR) of the University of Pittsburgh, with 900 participants in the group that received the most anesthesia and 389 constituting the comparison group that received less anesthesia. We tested 58 phenotypes and genotypic data of seven SNPs in genes that are associated with pain perception, pain modulation and response to drugs used in pain treatment: COMT (rs4818 and rs6269), GCH1 (rs3783641), DRD2 (rs6276), OPRM1 (rs1799971), SCN9A (rs6746030) and SCN10A (rs6795970). The analysis revealed a protective effect of rs1799971 on asthma in the total sample. rs3783641 was associated with salivary secretion disorders in females who received more anesthesia. rs1799971 was also associated with periodontitis in Whites who received less anesthesia. rs4818 was associated with disease and other tongue conditions in the group composed of Blacks who received less anesthesia. In conclusion, our study implicated variants in pain-related genes in asthma and oral phenotypes.

Are COMT Val158Met (rs4680), DRD2 TaqIA (rs1800497), and BDNF Val66Met (rs6265) polymorphisms associated with executive functions performance at rest and during physical exercise?

Executive functions (EFs) encompass a wide array of cognitive processes, which appear to be influenced by genetic variants of the COMT, DRD2/ANKK1, and BDNF polymorphisms. The present study aimed to investigate whether COMT Val158Met (rs4680), DRD2/ANKK1 (rs1800497), and BDNF Val66Met (rs6265) polymorphisms were associated with EFs assessed at rest and during moderate acute physical exercise. Sixty physically active individuals underwent four laboratory visits. First, they filled out the pre-exercise survey, researchers collected their anthropometric data, and then performed a maximal cardiopulmonary exercise test. In the second and third sessions, participants performed EFs test in a randomized order: while the individual was seated on a cycle ergometer without pedaling (i.e., rest condition); and during physical exercise (pedaling for 30 minutes at moderate intensity before starting the EFs test during exercising). On the fourth day, blood samples were drawn. Our results showed that the response time of the COMT Val homozygotes group was significantly shorter than the COMT Met-carrier group [t(39.78) = 2.13, p = .039,d = 0.56] at rest condition. No significant association was found for the other analyses (DRD2/ANKK1 and BDNF). In conclusion, the present study suggests that COMT Val158Met (rs4680) polymorphisms may be associated with EFs at rest condition. However, further studies are needed to validate this association.

Interaction between COMT Val158 Met polymorphism and childhood trauma predicts risk for depression in men.

Depression is a disabling illness with complex etiology. While the catechol-O-methyltransferase (COMT) gene, in particular the functional Val158 Met polymorphism, has been related to depression, the mechanisms underlying this gene-disease association are not completely understood. Therefore, we explore the association of COMT Val158 Met polymorphism with depression as well as its interaction with childhood trauma in 1136 young adults from a population-based study carried out in the city of Pelotas, Brazil. The diagnosis was performed through the Mini International Neuropsychiatric Interview 5.0 (MINI 5.0), and trauma was assessed with the Childhood Trauma Questionnaire (CTQ). Total DNA was extracted and genotyped by real-time PCR, and the QTLbase dataset was queried to perform large-scale quantitative trait locus (QTL) analysis. Our research showed no direct association between the Val158 Met polymorphism and the diagnosis of depression (women: χ2  = 0.10, d = 1, p = 0.751; men: χ2  = 0.003, df = 1, p = 0.956). However, the Met-allele of the Val158 Met polymorphism modified the effect of childhood trauma in men (OR = 2.58 [95% CI: 1.05-6.29]; p = 0.038) conferring risk for depression only on those who suffer from trauma. The conditional effect from moderation analysis showed that trauma impacts the risk of depression only in men carrying the Met-allele (effect: 0.9490, standard error [SE]: 0.2570; p = 0.0002). QTLbase and dataset for Val158 Met polymorphism were consistent for markers that influence chromatin accessibility transcription capacity including histone methylation and acetylation. The changes caused in gene regulation by childhood trauma exposure and polymorphism may serve as evidence of the mechanism whereby the interaction increases susceptibility to this disorder in men.

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.

Association study of Catechol-O-Methyltransferase (COMT) rs4680 Val158Met gene polymorphism and suicide attempt in Mexican adolescents with major depressive disorder.

AIM: We analyzed the association between SLC6A4, DRD2, COMT and MAOA genes and suicide attempt (SA) in Mexican adolescent patients with major depressive disorder (MDD). METHODS: The sample included 197 adolescents (127 females and 70 males) with principal diagnosis of MDD. Among them, 63 patients had SA at least once and 134 had not SA. The mean age of patients with and without SA was 15 ± 1.4 and 14 ± 1.5 years, respectively. We analyzed the genotype and allele distribution between patients with and without SA of SLC6A4 (5HTTLPR/rs25531), DRD2 (rs6275), COMT (rs4680), and MAOA (uVNTR). RESULTS: We did not find genotype or allele association between SA and SLC6A4 (χ2=0.67, p = 0.71; χ2=0.07, p = 0.77, respectively), DRD2 (χ2=0.05, p = 0.97; χ2=0.003, p = 0.95), and MAOA (females: χ2=0.86, p = 0.64; χ2=0, p = 1/males: χ2=0.008, p = 0.92) genes. However, there were differences in genotype frequencies of COMT/rs4680 between patients with SA and without SA (χ2=11.17, p = 0.003). Also, we observed a high frequency of Met158 allele showing an increased risk of having presented at least one SA (χ2=10.6, p = 0.001; OR = 1.43; 95% CI, 1.17-1.74). CONCLUSIONS: Our findings showed an association between low activity genotype and allele of Val158Met polymorphism of COMT gene and SA in Mexican adolescents with MDD.

Influence of COMT polymorphism in cognitive performance on dementia in community-dwelling elderly Mexican (SADEM study).

There is an inconsistent finding about the relationship of catechol-O-methyltransferase (COMT) with dementia susceptibility, as well as with cognitive impairment. To substantiate this, we examined COMT genotype effects in certain cognitive domains in dementia. To evaluate the effects of COMT Val158Met on cognitive performance, we used The Mini-Mental State Examination (MMSE), the cognitive subscale of the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) and the Syndrome Kurz Test (SKT). The results show COMT Val/Met, Val/Val genotype polymorphisms had a significant effect on cognition performance (OR = 1.75 (95 %CI 1.22-2.54) and (OR = 2.76 (95 %CI 1.78-4.26), p < 0.001), and with adjustment for all cognitive test scores together, Val/Val (OR = 4.98 (95 % CI 1.47-16.86) and Val/Met (OR = 3.62 (95 % CI 1.37-9.56) had effect. Our study allows us to understand the role of COMT in cognitive performance in dementia, as well as interaction with other known risk factors for this pathology. This data might help in developing new therapeutic targets for cognitive impairment, main symptom of dementia. Other risk genotypes or haplotypes should be evaluated to determine the association with cognitive decline in dementia.

Polymorphisms in COMT, ADRB2 and HTR1A genes are associated with temporomandibular disorders in individuals with other arthralgias.

Objective: To evaluate the association between polymorphisms in genes and comorbid presence of arthralgias and TMD.Methods: This is a case-control study. The groups formed were individuals with chronic arthralgia and 1) myofascial pain (n = 42); 2) articular (n = 16); 3) multiple diagnoses (n = 69); 4) with TMD and without some other arthralgia (n = 16); 5) without TMD but with pain in other joints (n = 82); and 6) a control group (n = 72). SNPs in COMT, ADRB2, and HTR1A genes were investigated.Results: The CT genotype for the COMT (rs9332377) gene was associated with the absence of myofascial pain (p = .05). In the ADRB2 (rs1042713) gene, the AA genotype was associated with the absence of myofascial pain (p = .03).Discussion: This study supports the hypothesis that alterations in the COMT, ADRB2, and HTR1A genes influence the presence of chronic pain and TMD.

COMT rs4818, pain sensitivity and duration, and alveolar bone grafting of oral clefts.

PURPOSE: Verifying whether the mutation in COMT rs4818 could be involved in pain modulation. METHODS: Thirty-two individuals born with cleft lip and palate that underwent bone graft from the iliac crest bone were assessed at 12, 24, 48, 72 h, and 7 days regarding their pain experience using a visual analogic scale. DNA from each participant was collected from saliva samples, and genotyping of rs4818 was performed using TaqMan chemistry. Overrepresentation of rs4818 alleles was tested using chi-square or Fisher's exact tests with an alpha of 0.05. RESULTS: Of the 32 individuals, eighteen reported long pain duration, nine reported high pain intensity, and fourteen low pain intensity up to 48 h. No differences were found in the distribution of individuals depending on the reported pain by sex (p = 0.12), age (p = 0.42), or cleft type (p = 0.5). The distribution of COMT r4818 alleles was different depending on the intensity and duration of pain. Carriers of the C wild-type allele were four times more likely to show high pain intensity and duration (odds ratio = 4.29, 95% confidence interval 1.13-16.18), meaning that the G variant allele is protective. CONCLUSION: COMT rs4818 is associated with postoperative pain after alveolar bone grafting.

Is catechol-O-methyltransferase gene associated with temporomandibular disorders? A systematic review and meta-analysis.

BACKGROUND: Temporomandibular disorder (TMD) is a condition, in which multiple factors act synergistically to determine the outcome of the disorder. AIM: A systematic review and meta-analysis was conducted to evaluate the association between genetic polymorphisms in catechol-O-methyltransferase (COMT) and TMD. DESIGN: Observational studies that investigated this association were included. The risk of bias and study quality were evaluated according to the Newcastle-Ottawa tool. The meta-analysis was performed for each polymorphism associated with TMD signs and symptoms. RESULTS: A total of 1903 articles were identified. Ten remained in the qualitative analysis: six were classified as low risk of bias and four with moderate risk of bias, and three were included in the meta-analysis. The polymorphism rs6269, in the genotypic model (0.65; CI = 0.44-0.97; P = .04) and in the allelic model (0.73; CI = 0.54-0.98; P = .04), was associated with myofascial pain. The rs9332377 was associated with myofascial pain in the genotypic model (2.69; CI = 1.51-4.76; P = .0007) and in the allelic model (1.46; CI = 1.01-2.13; P = .05) and with painful TMD in the genotypic model (2.08; CI = 1.27-3.40; P = .004) and in the allelic model (1.34 CI = 0.98-1.82; P = .06). CONCLUSION: The polymorphisms in COMT were significantly associated with TMD.

Pharmacogenetic profile and the development of the dyskinesia induced by levodopa-therapy in Parkinson's disease patients: a population-based cohort study.

Levodopa-induced dyskinesia (LID) is an adverse effect that negatively impacts the quality of life of patients with Parkinson's disease (PD). Studies report that genetic variations in the genes of the pharmacogenetic pathway of the levodopa (L-DOPA) might be associated with LID development. The goal of the present study was to investigate a possible influence of functional genetic variants in the DRD1 (rs4532), DRD2 (rs1800497), DAT1 (rs28363170), and COMT (rs4680) genes with LID development. A total of 220 patients with idiopathic PD were enrolled. The genotyping for DRD1 (rs4532), DRD2 (rs1800497), DAT1 (rs28363170), and COMT (rs4680) polymorphisms were performed using Restriction Fragment Length Polymorphism (PCR-RFLP). Univariate and multivariate analyses were performed to assess the association of these polymorphisms and risk factors with LID development. Multivariate Cox regression analysis showed increased risk to LID development for both Levodopa Dose Equivalency (LED) (Hazard ratios (HR) = 1.001; 95% CI 1.00-1.01; p = 0.009) and individuals carrying the COMT L/L genotype (HR = 2.974; 95% CI 1.12-7.83; p = 0.010). Furthermore, when performed a Cox regression analysis adjusted for a total LED, we observed that the genotype COMT L/L had a 3.84-fold increased risk for LID development (HR = 3.841; 95% CI 1.29-11.37; p = 0.012). Our results suggest that before treating LID in PD patients, it is important to take into consideration genetic variant in the COMT gene, since COMT LL genotype may increase the risk for LID development.

The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial.

Atorvastatin (ATV) is a blood cholesterol-lowering drug used to prevent cardiovascular events, the leading cause of death worldwide. As pharmacokinetics, metabolism and response vary among individuals, we wanted to determine the most reliable metabolic ATV phenotypes and identify novel and preponderant genetic markers that affect ATV plasma levels. A controlled, randomized, crossover, single-blind, three-treatment, three-period, and six-sequence clinical study of ATV (single 80-mg oral dose) was conducted among 60 healthy Mexican men. ATV plasma levels were measured using high-performance liquid chromatography mass spectrometry. Genotyping was performed by real-time PCR with TaqMan probes. Four ATV metabolizer phenotypes were found: slow, intermediate, normal and fast. Six gene polymorphisms, SLCO1B1-rs4149056, ABCB1-rs1045642, CYP2D6-rs1135840, CYP2B6-rs3745274, NAT2-rs1208, and COMT- rs4680, had a significant effect on ATV pharmacokinetics (P < 0.05). The polymorphisms in SLCO1B1 and ABCB1 seemed to have a greater effect and were especially important for the shift from an intermediate to a normal metabolizer. This is the first study that demonstrates how the interaction of genetic variants affect metabolic phenotyping and improves understanding of how SLCO1B1 and ABCB1 variants that affect statin metabolism may partially explain the variability in drug response. Notwithstanding, the influence of other genetic and non-genetic factors is not ruled out.

Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial

Objective: We investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression. Methods: Data from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately. Results: Pairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group. Conclusion: Larger, combined datasets are necessary to identify candidate genes for tDCS response.

Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial.

OBJECTIVE: We investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression. METHODS: Data from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately. RESULTS: Pairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group. CONCLUSION: Larger, combined datasets are necessary to identify candidate genes for tDCS response.

Association Between the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Manual Performance Asymmetries.

Within the cognitive domain, neuroscience and cognitive psychology researchers have investigated the relationship between handedness and cognitive skills. However, there have been few studies of the three-way association between manual asymmetry, its genetic components, and cognition even though this line of research could further an understanding of asymmetry. One enzyme involved in cognitive functions related to the dopaminergic system and to the prefrontal cortex is the catechol-O-methyltransferase (COMT), and it has a trimodal activity distribution in the human population due to its functional polymorphism known as Val158Met. This study investigated whether this COMT polymorphism is associated with asymmetries in the performance of a manual dexterity task. Forty-two right-handed undergraduate students ( Mage = 25.12, SD = 5.84; 15 women, 27 men) performed two trials each of place and remove conditions of the Grooved Pegboard Test with each hand (right and left), counterbalancing the order of the initial or starting hand. We calculated the mean time to perform the task for both hands on both trials and found, as hypothesized, that the Met/Met group gave a more asymmetrical performance than the Val/Met group under the place condition because dopamine levels reduced flexible behavior for the Val/Met group. We suspect that the place condition requires greater interhemispheric connectivity, as it requires a greater cognitive flexibility, and highly asymmetrical individuals are said to be less flexible. The findings of this study suggest a significant association between the COMT polymorphism and manual asymmetry in healthy populations.

The Impact of Variants in Genes Associated with Estradiol Synthesis on Hormone Levels and Oocyte Retrieval in Patients Who Underwent Controlled Ovarian Hyperstimulation.

AIMS: To correlate differences in estradiol levels in serum and follicular fluid with genetic variants and to determine if they play a role in the results following assisted reproductive technology (ART). PATIENTS AND METHODS: A cross-sectional study was developed at the Ideia Fértil Institute of Reproductive Health. Two hundred two female patients were selected and underwent controlled ovarian hyperstimulation cycles. Patients for this study were chosen based on their male partners' infertility. Genotypes of selected variants of CYP19A1, CYP17A1, HSD17, and COMT were compared to the estradiol measurements from follicular fluid and serum, as well as to the number and maturation status of the oocytes retrieved. RESULTS: Patients with the variant homozygous genotype AA of CYP19A1 (rs10046) showed increased serum concentrations of estradiol when compared to patients with other genotypes (p = 0.005). The same polymorphism effect was not observed in follicular fluid. This CYP19A1 variant did not affect the number of oocytes recovered nor their maturation level. CONCLUSION: The CYP19A1 variant is associated with an estradiol imbalance in serum. Other pathways, however, may contribute to the formation of the final estradiol metabolite in follicular fluid as well as its impact on the oocyte maturation.

Genetic Variations of OPRM1, OPRK1, and COMT Genes and Their Possible Associations with Oral Pain in a Population from Argentina.

AIMS: To analyze in a population from Argentina the variation of three genes involved in the control of pain pathways-two genes that code for opioid receptors (OPRM1 and OPRK1) and COMT, which codes for an important enzyme in the control of neurotransmission-and to evaluate the associations of these genes with oral pain and the need for analgesics in the population under study. METHODS: A total of 134 volunteer donors from the city of Resistencia and 27 donors from the Wichí community for comparison were analyzed for 13 single nucelotide polymorphisms (SNPs) and 1 insertion/deletion (Indel) localized in the three genes using polymerase chain reaction-restriction fragment length polymorphism or standard PCR and electrophoresis. All 134 individuals from Resistencia provided biologic samples for DNA analysis, and a subset (n = 81) agreed to answer a questionnaire for an association analysis. Statistical tests for a possible association between genetic variation and self-reported ethnic origin, oral pain, and need for analgesic drugs were performed. RESULTS: Significant differences were found when the study population was compared to populations from other continents, as well as between the two studied populations (P < .05). A positive association was suggested for the COMT gene from Resistencia with both oral pain intensity and analgesic requirements. CONCLUSION: The admixture process that occurred in the past of Resistencia probably contributed to a genetic differentiation in this population, and this genetic variation might influence phenotypic expressions of pain perception and analgesic requirements.

Catalytic Reaction Mechanism in Native and Mutant Catechol- O-methyltransferase from the Adaptive String Method and Mean Reaction Force Analysis.

Catechol- O-methyltransferase is an enzyme that catalyzes the methylation reaction of dopamine by S-adenosylmethionine, increasing the reaction rate by almost 16 orders of magnitude compared to the reaction in aqueous solution. Here, we combine the recently introduced adaptive string method and the mean reaction force method, in combination with the structural and electronic descriptors to characterize the reaction mechanism. The catalytic effect of the enzyme is addressed by the comparison of the reaction in the human wild-type enzyme, in the less effective Y68A mutant, and in aqueous solution. The influence of these different environments at different stages of the chemical process and the significance of the key collective variables describing the reaction were quantified. Our results show that the native enzyme limits the access of water molecules to the active site, enhancing the interaction between the reactants and providing a more favorable electrostatic environment to assist the SN2 methyl transfer reaction.

Association study of functional polymorphisms of dopaminergic pathway in epilepsy-related factors of temporal lobe epilepsy in Brazilian population.

BACKGROUND AND PURPOSE: There are few data about the role of neurotransmission modulated by dopamine in epilepsy, especially temporal lobe epilepsy (TLE). This is the first study that aimed to analyze the dopaminergic polymorphisms in an etiologically homogeneous group of patients with TLE with hippocampal sclerosis. Selected polymorphisms were: (i) the most expressed D2-like receptors in the limbic system (DRD2/ANKK1 TAQ-1A, D4_VNTR and D4_rs1800955); (ii) the dopamine transporter (DAT) 3'-untranslated region and intron 8; and (iii) two degrading enzymes regulating the synaptic activity, i.e. the main metabolizer of dopamine, catechol-O-methyltransferase, and monoamine oxidase A. METHODS: We assessed 119 patients with unequivocal TLE with hippocampal sclerosis and 112 healthy volunteers. Individuals were genotyped for the polymorphisms of the gene encoding dopaminergic pathway transporter DAT haplotype, dopaminergic receptors, catechol-O-methyltransferase and monoamine oxidase A. We also evaluated epilepsy-related factors (e.g. seizure frequency, age of onset, duration and status epilepticus). RESULTS: There was no difference between the groups for the studied polymorphisms. The polymorphism DRD4_VNTR was associated with family history of epilepsy (P = 0.003), DRD2_rs1800497 was related to status epilepticus (P = 0.022), and intron 8 VNTR DAT was related to higher seizure frequency (P = 0.019) and family history of epilepsy (P = 0.011). CONCLUSIONS: Our findings demonstrated that polymorphisms of the dopaminergic pathway are associated with significant clinical features of this form of epilepsy, such as seizure frequency, family history of epilepsy and status epilepticus.