RESUMO
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.
Assuntos
Catecol O-Metiltransferase , Dor Lombar , Canal de Sódio Disparado por Voltagem NAV1.7 , Adulto , Feminino , Humanos , Masculino , Estudos de Casos e Controles , Catecol O-Metiltransferase/genética , Dor Lombar/genética , Canal de Sódio Disparado por Voltagem NAV1.7/genéticaRESUMO
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.
Assuntos
Catecol O-Metiltransferase , Cárie Dentária , Criança , Humanos , Catecol O-Metiltransferase/genética , Estudos Transversais , Cárie Dentária/genética , Dor , Polimorfismo GenéticoRESUMO
A computational protocol aimed to design new antioxidants with versatile behavior is presented. It is called Computer-Assisted Design of Multifunctional Antioxidants and is based on chemical properties (CADMA-Chem). The desired multi-functionality consists of in different methods of antioxidant protection combined with neuroprotection, although the protocol can also be used to pursue other health benefits. The dM38 melatonin derivative is used as a study case to illustrate the protocol in detail. This was found to be a highly promising candidate for the treatment of neurodegeneration, in particular Parkinson's and Alzheimer's diseases. This also has the desired properties of an oral-drug, which is significantly better than Trolox for scavenging free radicals, and has chelates redox metals, prevents the âOH production, via Fenton-like reactions, repairs oxidative damage in biomolecules (lipids, proteins, and DNA), and acts as a polygenic neuroprotector by inhibiting catechol-O-methyl transferase (COMT), acetylcholinesterase (AChE) and monoamine oxidase B (MAOB). To the best of our best knowledge, CADMA-Chem is currently the only protocol that simultaneously involves the analyses of drug-like behavior, toxicity, manufacturability, versatile antioxidant protection, and receptor-ligand binding affinities. It is expected to provide a starting point that helps to accelerate the discovery of oral drugs with the potential to prevent, or slow down, multifactorial human health disorders.
Assuntos
Antioxidantes , Química Computacional , Humanos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Antioxidantes/química , Catecol O-Metiltransferase/metabolismo , Inibidores da Colinesterase/farmacologia , Estresse Oxidativo , Química Computacional/métodosRESUMO
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.
Assuntos
Asma , Catecol O-Metiltransferase , Feminino , Humanos , Catecol O-Metiltransferase/genética , Saúde Bucal , Genética Reversa , Percepção da Dor , Dor/genética , Asma/genética , Canal de Sódio Disparado por Voltagem NAV1.7/genéticaRESUMO
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.
Assuntos
Catecol O-Metiltransferase , Função Executiva , Humanos , Catecol O-Metiltransferase/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Receptores de Dopamina D2/genética , Exercício Físico , Genótipo , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina QuinasesRESUMO
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.
Assuntos
Experiências Adversas da Infância , Catecol O-Metiltransferase , Depressão , Catecol O-Metiltransferase/genética , Depressão/genética , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Objective: To evaluate the association of bruxism phenotypes with single nucleotide polymorphisms in FKBP5, DRD2, ANKK1, and COMT.Methods: Clinical oral examination was performed to diagnose bruxism phenotypes in 150 children. DNA was collected from saliva. Logistic univariate regression, Chi-square, and Fisher's exact tests were performed (p < 0.05).Results: Bruxism was associated with DRD2 (p = 0.02). Tooth grinding while awake was associated with ANKK1 (p < 0.001), and tooth grinding while asleep was associated with DRD2 in the additive (p = 0.030) and dominant (p = 0.008) model. Tooth clenching while awake was associated with ANKK1 in the additive (p = 0.005) and dominant (p = 0.008) models, whereas tooth clenching while asleep was associated with ANKK1 (p < 0.001) and with COMT in the additive (p = 0.001) and dominant (p = 0.003) models.Discussion: Polymorphisms in DRD2, ANKK1, and COMT are associated with bruxism phenotypes.
Assuntos
Bruxismo , Polimorfismo de Nucleotídeo Único , Receptores de Dopamina D2/genética , Bruxismo/genética , Catecol O-Metiltransferase , Genótipo , Humanos , Fenótipo , Proteínas Serina-Treonina QuinasesRESUMO
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.
Assuntos
Amidoidrolases , Catecol O-Metiltransferase , Esquizofrenia , Transtornos Relacionados ao Uso de Substâncias , Amidoidrolases/genética , Catecol O-Metiltransferase/genética , Frequência do Gene/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
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.
Assuntos
Catecol O-Metiltransferase , Transtorno Depressivo Maior , Tentativa de Suicídio , Adolescente , Catecol O-Metiltransferase/genética , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Monoaminoxidase/genética , Polimorfismo de Nucleotídeo Único , Receptores de Dopamina D2/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genéticaRESUMO
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.