catechol-O-methyltransferase Research Articles

Pharmacogenetic landscape of pain management variants among Mediterranean populations.

Chronic pain is a major socioeconomic burden in the Mediterranean region. However, we noticed an under-representation of these populations in the pharmacogenetics of pain management studies. In this context, we aimed 1) to decipher the pharmacogenetic variant landscape among Mediterranean populations compared to worldwide populations in order to identify therapeutic biomarkers for personalized pain management and 2) to better understand the biological process of pain management through in silico investigation of pharmacogenes pathways. We collected genes and variants implicated in pain response using the Prisma guidelines from literature and PharmGK database. Next, we extracted these genes from genotyping data of 829 individuals. Then, we determined the variant distribution among the studied populations using multivariate (MDS) and admixture analysis with R and STRUCTURE software. We conducted a Chi2 test to compare the interethnic frequencies of the identified variants. We used SNPinfo web server, miRdSNP database to identify miRNA-binding sites. In addition, we investigated the functions of the identified genes and variants using pathway enrichment analysis and annotation tools. Finally, we performed docking analysis to assess the impact of variations on drug interactions. We identified 63 variants implicated in pain management. MDS analysis revealed that Mediterranean populations are genetically similar to Mexican populations and divergent from other populations. STRUCTURE analysis showed that Mediterranean populations are mainly composed of European ancestry. We highlighted differences in the minor allele frequencies of three variants (rs633, rs4680, and rs165728) located in the COMT gene. Moreover, variant annotation revealed ten variants with potential miRNA-binding sites. Finally, protein structure and docking analysis revealed that two missense variants (rs4680 and rs6267) induced a decrease in COMT protein activity and affinity for dopamine. Our findings revealed that Mediterranean populations diverge from other ethnic groups. Furthermore, we emphasize the importance of pain-related pathways and miRNAs to better implement these markers as predictors of analgesic responses in the Mediterranean region.

Association between executive functions and COMT Val108/158Met polymorphism among healthy younger and older adults: A preliminary study.

Genetic variability in the dopaminergic system could contribute to age-related impairments in executive control. In this study, we examined whether genetic polymorphism for catechol-O-methyltransferase (COMT Val158Met) is related to performance on updating, shifting and inhibition tasks. We administered a battery of executive tasks assessing updating, shifting and inhibition functions to 45 older and 55 younger healthy participants, and created composite z-scores associated to each function. Six groups were created based on genetic alleles (Val/Val, Val/Met, Met/Met) derived from the COMT gene and age (younger, older). Age and genotype effects were assessed with t-test and ANOVA (p<0.05). A lower performance was observed in the older group for the three executive processes, and more particularly for inhibition. Moreover, older participants homozygous for the Val allele have a lower performance on the inhibition composite in comparison to younger Val/Val. These results confirm presence of executive performance decrease in healthy aging. With regard to genetic effect, older participants seem particularly disadvantaged when they have a lower baseline dopamine level (i.e., Val/Val homozygous) that is magnified by aging, and when the executive measure emphasize the need of stable representations (as in inhibition task requiring to maintain active the instruction to not perform an automated process).

Genetic influence on treatment outcomes in patients with pain-related temporomandibular disorders.

Single nucleotide polymorphisms (SNPs) may influence pain susceptibility and impact treatment response in pain-related temporomandibular disorders (TMDp). Explore the role of COMT (rs4646310, rs6269, rs4818, rs4680) and OPRM1 (rs1799971) genotypes in regulating treatment response. Sixty TMDp patients (55 females and 5 males), diagnosed with the Diagnostic Criteria for TMD (DC/TMD), underwent standardised treatment (information and education, home physical therapy, occlusal splint) for 6 months. Treatment outcomes included: pain intensity, pain-free mouth opening, jaw functional limitation, depression, and anxiety. Genotyping for COMT and OPRM1 SNPs was performed using DNA from buccal mucosa swabs and TaqMan assays. Statistical analysis was carried out to compare the changes in treatment outcomes and the influence of genotypes on treatment response. Significantly less pain reduction was observed in minor allele carriers of rs4646310, and rs4680 compared to dominant homozygous (p < .025). Minor allele carriers of rs1799971 and rs4646310 demonstrated worsening in pain-free mouth opening while dominant homozygous exhibited improvement (p < .025). Significantly less anxiety reduction was observed in minor allele carriers of rs4646310 compared to dominant homozygous (p = .003). Of the all variables assessed in the regression model, carrying a minor allele of rs1799971 predicted a poorer treatment response considering pain-free mouth opening while carrying a minor allele of rs4646310 predicted less pain and less anxiety reduction. Our findings indicate that certain SNP variants of the COMT and OPRM1 genes were associated with poorer treatment response and may therefore play a significant role in the classification of TMDp patients. Also, assessment of patient genotype could potentially aid in predicting treatment response.

COMT Variants are Associated With Breast and Nipple Pain

Estimates suggest that only 24.9% of infants born in 2019 were exclusively breastfed before 6 months of age, despite the known health benefits of exclusive breastfeeding. Breast and nipple pain is one of the primary determinants of exclusive breastfeeding. Environmental contributions to breastfeeding success have been reported extensively in the literature, but the contribution(s) of maternal genetics has yet to be discovered. The purpose of the study was to identify an association between pain and lactation-related gene variants with exclusive breastfeeding determinants. We selected 4 genes having single nucleotide polymorphisms (SNPs) with potential functional significance in breastfeeding and pain: prolactin receptor (PRLR), oxytocin receptor (OXTR), catechol-O-methyltransferase (COMT), and milk fat globule epidermal growth factor and factor V/VIII domain containing (MFGE8). We performed a cross-sectional secondary analysis of a longitudinal randomized controlled trial study, Promoting Self-Management of Breast and Nipple Pain with Biomarkers and Technology for Breastfeeding Women (NCT05262920). Breast and nipple pain, perceived insufficient milk, and breastfeeding self-efficacy were examined using total scale scores for the Brief Pain Inventory, Visual Analog Scale, H&H Lactation Scale, and the Breastfeeding Self-efficacy Scale-short form, respectively. Of the candidate genes examined, SNPs within COMT were significantly associated with breastfeeding-related outcomes. Specifically, COMT rs4633 and rs4680 minor allele carriers (T, A) reported higher breast and nipple pain intensity than women homozygous for the major allele (C, G). COMT is the most widely researched “pain gene” and has been linked to cold, postoperative, and postpartum pain. This study is the first to identify a contribution of COMT variants to breast and nipple pain and, as a result, to breastfeeding exclusivity. PerspectiveTwo SNPs in the pain gene COMT are associated with breast and nipple pain. Clinically, a minor allele in COMT rs4633 and rs4680 may increase a woman’s rating of moderate breast and nipple pain. Trial registrationPROMPT was registered in ClinicalTrials.gov (protocol #NCT05262920).

Sex-Specific Regulation of Catecholamine Signaling in Rats Exposed to Dexamethasone In Utero and Angiotensin in Adulthood

Pregnant women who are at risk of pre-term delivery are given the synthetic glucocorticoid dexamethasone (DEX) to stimulate fetal lung development as it is not degraded by 11ß-hydroxysteroid dehydrogenase, enabling DEX to freely cross through the placenta and act on the developing fetus. Our lab has previously found that in-utero DEX exposure increases stress-induced blood pressure and heart rate responses in female, as well as autonomic dysregulation in the adult offspring. Angiotensin II (Ang II) induces hypertension and cardiac remodeling in part through activation of the sympathetic nervous system. Given these prior findings, this project explores whether prenatal DEX exposure alters the response of Ang II on cardiac sympathetic nervous system regulation. Pregnant rats were administered either vehicle (20% w/v 2-hydroxypropyl ß-cyclodextran) or the glucocorticoid DEX (0.4 mg/kg body weight, i.p) on gestation days 18-21. When offspring reached ~15 weeks of age, groups were administered either subcutaneous AngII (200 ng/kg per min) as a cardiovascular challenge or saline as experimental control for four weeks. To measure local sympathetic signaling, tyrosine hydroxylase (TH) was analyzed as it serves as the rate limiting step of catecholamine synthesis while catechol-O-methyltransferase (COMT) was selected as it catalyzes catecholamine breakdown. Gene expression of adrenoreceptor ß1 ( Adrb1) was measured to assess receptor availability for sympathetic activity. Data were analyzed by 3-way ANOVA with sex, prenatal treatment (i.e., DEX vs. Vehicle), and postnatal treatment (i.e., saline vs. AngII) as the variables. There was an overall main effect of prenatal DEX treatment to reduce TH expression in the LV (p=0.018), an effect that was more pronounced in males. COMT expression was found to be significantly impacted by sex, prenatal treatment, and post-natal treatment (3-way interaction, p=0.016). Thus, the degree to which DEX and Ang II impacted COMT expression differed by sex. There was a sex x postnatal treatment interaction (p=0.013) on ADRB1 expression whereby expression was increased by Ang II only in female hearts. Although prior studies have shown that Ang II can increase local sympathetic activity in the heart, the present data suggest that prenatal treatments disrupt this response in a sex-specific manner. Moreover, sex and prenatal treatment were greater drivers of local sympathetic regulation than Ang II. NIMH/ORWH 1U54MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Longitudinal study investigating the influence of COMT gene polymorphism on cortical thickness changes in Parkinson's disease over four years

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting over 3% of those over 65. It's caused by reduced dopaminergic neurons and Lewy bodies, leading to motor and non-motor symptoms. The relationship between COMT gene polymorphisms and PD is complex and not fully elucidated. Some studies have reported associations between certain COMT gene variants and PD risk, while others have not found significant associations. This study investigates how COMT gene variations impact cortical thickness changes in PD patients over time, aiming to link genetic factors, especially COMT gene variations, with PD progression. This study analyzed data from 44 PD patients with complete 4-year imaging follow-up from the Parkinson Progression Marker Initiative (PPMI) database. Magnetic resonance imaging (MRI) scans were acquired using consistent methods across 9 different MRI scanners. COMT single-nucleotide polymorphisms (SNPs) were assessed based on whole genome sequencing data. Longitudinal image analysis was conducted using FreeSurfer's processing pipeline. Linear mixed-effect models were employed to examine the interaction effect of genetic variations and time on cortical thickness, while controlling for covariates and subject-specific variations. The rs165599 SNP stands out as a potential contributor to alterations in cortical thickness, showing a significant reduction in overall mean cortical thickness in both hemispheres in homozygotes (Left: P = 0.023, Right: P = 0.028). The supramarginal, precentral, and superior frontal regions demonstrated significant bilateral alterations linked to rs165599. Our findings suggest that the rs165599 variant leads to earlier manifestation of cortical thinning during the course of the disease. However, it does not result in more severe cortical thinning outcomes over time. There is a need for larger cohorts and control groups to validate these findings and consider genetic variant interactions and clinical features to elucidate the specific mechanisms underlying COMT-related neurodegenerative processes in PD.

Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives.

Nitrocatechols are the standard pharmacophore to develop potent tight-binding inhibitors of catechol O-methyltransferase (COMT), which can be used as coadjuvant drugs to manage Parkinson's disease. Tolcapone is the most potent drug of this class, but it has raised safety concerns due to its potential to induce liver damage. Tolcapone-induced hepatotoxicity has been attributed to the nitrocatechol moiety; however, other nitrocatechol-based COMT inhibitors, such as entacapone, are safe and do not damage the liver. There is a knowledge gap concerning which mechanisms and chemical properties govern the toxicity of nitrocatechol-based COMT inhibitors. Using a vast array of cell-based assays, we found that tolcapone-induced toxicity is caused by direct interference with mitochondria that does not depend on bioactivation by P450. Our findings also suggest that (a) lipophilicity is a key property in the toxic potential of nitrocatechols; (b) the presence of a carbonyl group directly attached to the nitrocatechol ring seems to increase the reactivity of the molecule, and (c) the presence of cyano moiety in double bond stabilizes the reactivity decreasing the cytotoxicity. Altogether, the fine balance between lipophilicity and the chemical nature of the C1 substituents of the nitrocatechol ring may explain the difference in the toxicological behavior observed between tolcapone and entacapone.

The influence of COMT and ABCB1 gene polymorphisms on sufentanil analgesic effect for postoperative pain in children with fracture.

The aim of this observational study was to investigate the effects of catechol-O-methyltransferase (COMT) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on the postoperative analgesic effect of sufentanil in Chinese Han pediatric patients with fractures. A total of 185 pediatric patients who underwent fracture surgery were included. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the polymorphisms of COMT and ABCB1 genes. Sufentanil was used for postoperative analgesia. The pain level of the patients was evaluated using the face, legs, activity, cry, and consolability scale before surgery, during awakening, at 2, 6, 12, and 24 hours after surgery. The postoperative Ramsay sedation score, sufentanil consumption, and incidence of adverse reactions were also recorded. Pediatric patients with different genotypes of ABCB1 and COMT showed no statistically significant differences in general data such as age, gender, weight, height, surgical duration, and American Society of Anesthesiologists classification (P > .05). There were no statistically significant differences in sedation scores after surgery between different genotypes of ABCB1 and COMT (P > .05). Among patients with CC genotype in ABCB1, the pain scores and total consumption of sufentanil at awakening, 2 and 6 hours after surgery were higher compared to TT and CT genotypes (P < .05), while there were no statistically significant differences between TT and CT genotypes (P > .05). Among patients with AA genotype in COMT, the pain scores and total consumption of sufentanil at awakening, 2, 6, 12, and 24 hours after surgery were higher compared to AG and GG genotypes (P < .05), while there were no statistically significant differences between AG and GG genotypes (P > .05). There were no statistically significant differences in adverse reactions between different genotypes of ABCB1 and COMT (P > .05). The polymorphisms of COMT gene rs4680 and ABCB1 gene rs1045642 are associated with the analgesic effect and consumption of sufentanil in pediatric patients after fracture surgery.

Mechanisms and Preventative Strategies for Persistent Pain following Knee and Hip Joint Replacement Surgery: A Narrative Review.

Chronic postsurgical pain (CPSP) following total knee arthroplasty (TKA) and total hip arthroplasty (THA) is a prevalent complication of joint replacement surgery which has the potential to decrease patient satisfaction, increase financial burden, and lead to long-term disability. The identification of risk factors for CPSP following TKA and THA is challenging but essential for targeted preventative therapy. Recent meta-analyses and individual studies highlight associations between elevated state anxiety, depression scores, preoperative pain, diabetes, sleep disturbances, and various other factors with an increased risk of CPSP, with differences observed in prevalence between TKA and THA. While the etiology of CPSP is not fully understood, several factors such as chronic inflammation and preoperative central sensitization have been identified. Other potential mechanisms include genetic factors (e.g., catechol-O-methyltransferase (COMT) and potassium inwardly rectifying channel subfamily J member 6 (KCNJ6) genes), lipid markers, and psychological risk factors (anxiety and depression). With regards to therapeutics and prevention, multimodal pharmacological analgesia, emphasizing nonopioid analgesics like acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), has gained prominence over epidural analgesia. Nerve blocks and local infiltrative anesthesia have shown mixed results in preventing CPSP. Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, exhibits antihyperalgesic properties, but its efficacy in reducing CPSP is inconclusive. Lidocaine, an amide-type local anesthetic, shows tentative positive effects on CPSP. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have mixed results, while gabapentinoids, like gabapentin and pregabalin, present hopeful data but require further research, especially in the context of TKA and THA, to justify their use for CPSP prevention.

Medical Management of Uterine Fibroids-A hope for Fertile Women!

Uterine fibroids or Myomas or Leiomyoma of uterus are the most common type of benign tumor of uterus and most common pelvic tumour in women with unclear etiology. Uterine fibroids or Myomas or Leiomyoma of uterus are the most common type of benign tumor of uterus. In India the incidence of fibroids is most common in women of 31- 40 years of age i.e. as more than 1/3 (35%) of them get affected. Recent understanding of etiology suggests increased number of estrogen and Progesterone Receptors, increased COMT gene expression and TGF-B3. Risk factors for developing fibroids are age, early age at menarche, reduced fertility, frequent caffeine consumption, obesity, hypertension, diabetes mellitus, alcohol consumption and previous pelvic inflammatory disease (PID). Rural women are at a much higher risk of uterine fibroids than urban women in India. (37.65% vs.24%) probably due to multiparty at a young age disturbing Estrogen and Progesterone Receptors. Treatment options for symptomatic uterine fibroids include medical, surgical, and radiologically guided interventions. Although curative treatment relies on surgical therapies- either myomectomy or hysterectomy, medical treatments are considered the first-line treatment to preserve fertility and avoid or delay surgery. Medical therapy is in nascent stage in India. Medical treatment must be individualized based on age, signs &amp; symptoms, sustained reduction of the size and sustenance of fertility if desired with minimal side effects. Materials and Methods: This article is based on a literature review on medical therapy being tried on a case the author is managing now. The initial results are encouraging and need to monitor the reduction of the size or volume of the Fibroid in coming months.

Rescuing a Troubled Tolcapone with PEGylated PLGA Nanoparticles: Design, Characterization, and Hepatotoxicity Evaluation.

Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor used as adjuvant therapy in Parkinson's disease. However, it has a highly hepatotoxic profile, as recognized by the U.S. Food and Drug Administration. As a possible solution, nanoscience brought us several tools in the development of new functional nanomaterials with tunable physicochemical properties, which can be part of a solution to solve several drawbacks, including drug's short half-life and toxicity. This work aims to use PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a stable carrier with lower hydrodynamic size and polydispersity to encapsulate tolcapone in order to overcome its therapeutic drawbacks. Using the nanoprecipitation method, tolcapone-loaded nanoparticles with a DLC% of 5.7% were obtained (EE% of 47.0%) and subjected to a lyophilization optimization process to obtain a final shelf-stable formulation. Six different cryoprotectants in concentrations up to 10% (w/v) were tested. A formulation of PLGA nanoparticles with 3% hydroxypropyl-β-cyclodextrin (HPβCD) as a cryoprotectant (PLGA-HP@Tolc), presenting sub-200 nm sizes and low polydispersity (PdI < 0.200) was selected. Cytotoxicity assays, namely, MTT and SRB, were used to study the metabolic activity and cell density of tolcapone and PLGA-HP@Tolc-treated cells. In both assays, a hepatocarcinoma cell line (HepG2) growing in glucose or glucose-free media (galactose-supplemented medium) was used. The results demonstrated that the treatment with the PLGA-HP@Tolc formulation led to a decrease in cytotoxicity in comparison to free tolcapone-treated cells in both media tested. Moreover, the elected formulation also counteracted ATP-depletion and excessive ROS production induced by tolcapone. The results suggest that HPβCD might have a dual function in the formulation: cryoprotectant and anticytotoxic agent, protecting cells from tolcapone-induced damage. Using an in vitro COMT inhibition assay, the PLGA-HP@Tolc formulation demonstrated to inhibit COMT as efficiently as free tolcapone. Overall, the results suggest that tolcapone-loaded PLGA NPs could be an interesting alternative to free tolcapone, demonstrating the same in vitro efficacy in inhibiting COMT but with a safer cytotoxic profile.

Association of COMT rs4680 Polymorphism with High-Level Performance in Track Field Athletes

The catechol-O-methyltransferase (COMT) gene rs4680 polymorphism, primarily linked to psychological traits, has been limitedly studied in the key athletic abilities including endurance, speed, and power. Thus, the current investigation sought to explore any possible connections between the rs4680 polymorphism in the COMT gene and competitive performance among Turkish high-level track &amp; field athletes. As a part of an ongoing project, this study engaged 60 elite athletes, categorized into two distinct groups based on their specialty (31 sprint/power athletes and 29 endurance athletes). To provide a comparative baseline, a control group consisting of twenty sedentary individuals aged between 18 and 35 was also incorporated. The assessment of participants' performance levels is conducted using the methodology established by the International Association of Track &amp; Field Federations (IAAF), which is based on personal bests (PBs). Whole exome sequencing (WES) was used in the research to analyze genomic DNA that was taken out of participant blood samples. The distribution of the COMT gene rs4680 polymorphism in terms of genotypes (AA, GA, and GG) did not change significantly between the athlete and the control group or within the athletic groups, according to the research (p&gt;0.05). In a similar vein, the research did not discover any connections of note between athletes' PBs in the sprint/power or endurance categories and the rs4680 polymorphism. Based on these findings, the research concludes that there is no meaningful relationship between the COMT gene's rs4680 polymorphism and the competitive performance of the Turkish high-level track and field athletes under investigation.

Opicapone to Treat Early Wearing-off in Parkinson's Disease Patients: The Korean ADOPTION Trial.

Increasing levodopa (L-dopa)/dopa decarboxylase inhibitor (DDCI) daily dose or adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/DDCI therapy are strategies used to manage wearing-off symptoms in Parkinson's disease (PD) patients. To evaluate the COMT inhibitor opicapone versus an additional dose of levodopa to treat early wearing-off in PD patients. ADOPTION was a randomized, parallel-group, open-label, Phase 4 study conducted in Korea. At baseline, eligible patients were randomized (1:1) to opicapone 50 mg (n = 87) or L-dopa 100 mg (n = 81) (added to current L-dopa/DDCI therapy) for 4 weeks. The main efficacy endpoint was change from baseline to end of study in absolute off time. Other endpoints included changes in on time, in Movement Disorder Society-Unified Parkinson's Disease Rating Scale and 8-item PD Questionnaire scores, and the Clinical and Patient Global Impression of Improvement/Change. The adjusted mean in absolute off time was significantly greater for opicapone 50 mg than for L-dopa 100 mg (-62.1 vs. -16.7 minutes; P = 0.0015). Opicapone-treated patients also reported a greater reduction in the percentage of off time (P = 0.0015), a greater increase in absolute on time (P = 0.0338) and a greater increase in the percentage of on time (P = 0.0015). There were no significant differences in other secondary endpoints. The L-dopa equivalent daily dose was significantly higher in the opicapone group (750.9 vs. 690.0 mg; P = 0.0247), when a 0.5 conversion factor is applied. Opicapone 50 mg was more effective than an additional 100 mg L-dopa dose at decreasing off time in patients with PD and early wearing-off.

Evaluation of the effect of COMT gene polymorphism in rs4680 on the occurrence of concomitant head, neck and back pain in patients with temporomandibular joint disorders

Background: Temporomandibular disorders (TMD) include a number of clinical conditions involving the masticatory muscles, temporomandibular joint (TMJ), and adjacent structures. The main feature of TMD is pain. According to past studies, TMD can have genetic causes. One of the genes that seems to be important in this regard is COMT. This study aims to compare the effect of COMT gene polymorphism rs4680 on the occurrence of simultaneous head, neck and back pain in patients with TMD.&#x0D; Methods: This study was conducted as a case-control study on patients aged between 18 and 65 with TMD disorder. After meeting the conditions for entering the study, a written informed consent was obtained from the people participating in this project. Then a blood sample of 5cc was prepared from each person and poured into tubes containing EDTA anticoagulant and used for DNA extraction and identification. The COMT gene was sent to the genetics laboratory and was compared in terms of the polymorphism of the COMT gene using the PCRARMS technique.&#x0D; Results: The sample size was 100 people aged 18 to 65 years. Variables with normal distribution were analyzed with Chi-Square test and variables with non-normal distribution with Mann-Whitney test. After genetic analysis in terms of rs4680 gene polymorphism, 18 people (18%) were identified with AA, 80 people (80%) with GA and 2 people (2%) with GG. "temporal headache in the last 30 days", "temporal headache change with chewing hard foods", "temporal headache change with opening the mouth or moving the jaw forward or to the sides", " Temporal headache changes with jaw habits such as teeth touching, pressing or grinding teeth together, chewing gum ", " Temporal headache changes with jaw activities such as talking, kissing or yawning ", " having Back pain during the last 4 weeks", having pain in the arm, leg, joints (neck) during the last 4 weeks", “headache during 4 last weeks” and "time of onset of headache in the temporal region" did not have significant relationships with COMT gene polymorphism rs4680 in patients with TMD.(repectively, p value=0.873، p value=0.658، p value=0.518 p value=0.685، p value=0.884،p value=0.654، p value=0.723، p value=0.831، p value=0.692 ).&#x0D; Conclusion: According to previous studies, there is a significant relationship between rs4680 polymorphism in the COMT gene and the occurrence of temporomandibular disorders (TMD), although in our study, no significant relationship was found between headache and neck and back pain with this polymorphism.

Pain-related single nucleotide polymorphisms: association with lumbar spinal stenosis patient experience and non-surgical treatment outcomes.

Lumbar spinal stenosis (LSS) is common in our aging population resulting in pain and functional impairment. Recent advances in pain research have identified several single nucleotide polymorphisms (SNP) associated with inter-individual symptom and treatment response. The goal of the current study was to investigate the association of SNPs in Neuropeptide Y (NPY) and Catechol-O-methyltransferase (COMT) with pain, function, and treatment outcomes in Lumbar spinal stenosis (LSS) patients receiving non-surgical treatments. An exploratory observational biomarker study was performed ancillary to a previously published clinical trial evaluating three different non-surgical treatments for LSS. Saliva samples were obtained for single nucleotide polymorphism genotyping and blood samples were collected for NPY protein. Data on pain and function collected as part of the clinical trial at baseline, 2 and 6 months were examined for association with known polymorphisms in NPY and COMT. Subjects with the NPY rs16147 TT genotype exhibited higher baseline symptom severity but also a higher likelihood of responding to non-surgical treatments. Subjects with the COMT rs4680 GG genotype also exhibited higher baseline symptom severity but did not demonstrate greater response to treatment. NPY rs16147 and COMT rs4680 are important potential biomarkers associated with pain and function. NPY genotype may be useful in predicting response to non-surgical treatments in older adults with LSS.

Differential DNA methylation in iPSC-derived dopaminergic neurons: a step forward on the role of SNORD116 microdeletion in the pathophysiology of addictive behavior in Prader-Willi syndrome.

A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) features. PWS is a neurodevelopmental disorder clinically characterized by endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116 MD in DNA methylation, as well as the impact of the oxytocin (OXT) on it, have never been investigated in human neurons. We studied the methylation marks in induced pluripotent stem-derived dopaminergic neurons carrying a SNORD116 MD in comparison with those from an age-matched adult healthy control. We also performed identical neuron differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from the iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in these iPSC-derived dopaminergic neurons differentiated with or without OXT. The analysis revealed that 153,826 cytosines were differentially methylated between SNORD116 MD neurons and control neurons. Among the differentially methylated genes, we determined a list of genes also differentially expressed. Enrichment analysis of this list encompassed the dopaminergic system with COMT and SLC6A3. COMT displayed hypermethylation and under-expression in SNORD116 MD, and SLC6A3 displayed hypomethylation and over-expression in SNORD116 MD. RT-qPCR confirmed significant over-expression of SLC6A3 in SNORD116 MD neurons. Moreover, the expression of this gene was significantly decreased in the case of OXT adjunction during the differentiation. SNORD116 MD dopaminergic neurons displayed differential methylation and expression in the COMT and SLC6A3 genes, which are related to dopaminergic clearance.

Catechol-O-methyltransferase and monoamine oxidase B inhibitory activities of Australian bee pollen.

Bee pollen is an apicultural product collected by honeybees from flower stamens and used as a functional food worldwide. In the present study, we aim to elucidate the functions of Australian bee pollen. Australian bee pollen extracts and their main components were tested for catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) inhibitory activities. These enzymes are key neurotransmitters involved in Parkinson's disease and depression. Myricetin (5), tricetin (6), and luteolin (7) exhibited high COMT inhibitory activities (half maximal inhibitory concentration [IC50] = 23.3, 13.8, and 47.4 µM, respectively). In contrast, 5, 7, and annulatin (8) exhibited MAOB inhibitory activities (IC50 = 89.7, 32.8, and 153 µM, respectively). Quantitative analysis via high-performance liquid chromatography revealed that 5 was abundant in Australian bee pollen extracts. Our findings suggest that 5 contributes to the COMT and MAOB inhibitory activities of Australian bee pollen.

Evolution of Depression and Anxiety among Breast Cancer Patients: a prospective analysis using clinical, biological and genetic factors

IntroductionNumerous studies have explored the symptoms and course of depression and anxiety in breast cancer patients and identified various clinical, sociodemographic, and genetic factors associated with their evolution. Nevertheless, these studies have been limited in duration and have focused on specific time points during chemotherapy or post-treatment follow-up. Furthermore, these studies included patients receiving different treatment regimens and used different tools to assess symptoms.Objectives To assess the prospective evolution of depression in breast cancer patients over eight consecutive chemotherapy cycles, taking into account sociodemographic, clinical, biological, and genetic factors.MethodsA prospective longitudinal study was conducted on 69 breast cancer patients treated with intravenous chemotherapy at the oncology outpatient unit of the Hôtel-Dieu de France hospital (2017-2019; Ethics: CEHDF1016). The Hospital Anxiety and Depression Scale (HADS) was used to evaluate anxiety and depression in patients. Genotyping was performed for several genes (ABCB1, COMT, DRD2, OPRM1, CLOCK, CRY2, PER2) using the Lightcycler® 2.0 (Roche).ResultsUnivariate repeated measures analysis showed differences in the evolution of depression and anxiety over time. For depression, a polynomial linear contrast for HADS-D scores was noted from cycle 1 to cycle 8, with a significant increase in depression at cycles 7 and 8 compared with cycle 1 (p-value cycle7=0.004 and p-valuecycle8=0.009; Figures 1 &amp; 2). Repeated measures analysis for anxiety showed a decrease in anxiety scores between cycles 1 and 6 of chemotherapy, followed by an increase starting cycle 6 (a polynomial trend for contrasts) (p-value cycle6 versus 1=0.038; Figures 1 &amp; 2). Multivariable analysis showed that higher anxiety and depression scores at baseline were both associated with higher depression and anxiety scores over time. Other clinical and genetic factors, including polymorphisms in the OPRM1, PER2, and COMT genes, were also significantly associated with higher depression and anxiety scores.Image:Image 2:ConclusionsOur findings highlight the importance of understanding the trajectories of depression and anxiety over time in women with breast cancer and identifying the triggering factors. Such personalized approaches would improve patient quality of life.Disclosure of InterestNone Declared

Predictor of academic performance: personality traits and catechol-O-methyltransferase polymorphisms

Personality traits and genetics are important factors in determining academic performance. Although there have been studies on the association between genetics and academic performance, there is limited data on the effect of personality traits and the catechol-O-methyltransferase (COMT) rs4680 polymorphism on academic performance, particularly among university students in Malaysia. The objective of this study was to correlate the relationship between personality traits, COMT rs4680 polymorphism, and academic performance among health sciences undergraduate students at a Malaysian university. The research design was a correlational study where 221 students were recruited based on the convenient sampling approach. The demographic and international personality item pool (IPIP) questionnaires were administered online, whereas the COMT rs4680 single nucleotide polymorphism (SNP) was determined using a tetra-primer allele-specific polymerase chain reaction (PCR). From the IPIP results, the conscientiousness trait was positively and significantly correlated with academic performance (r=0.141, p=0.036). Participants with homozygous Met/Met allele of the COMT rs4680 polymorphism tended to perform better in academics (p=0.009) as compared to participants with homozygous Val/Val and heterozygous Val/Met alleles. As a conclusion, students with a higher conscientiousness score and carriers of the homozygous Met/Met allele of COMT rs4680 showed better academic performance.

Association of Catechol-O-Methyltransferase (COMT) val158met genetic polymorphism and outcomes following sacral neuromodulation or onabotulinumtoxina in women with urgency irinary incontinence

Association of Catechol-O-Methyltransferase (COMT) val158met genetic polymorphism and outcomes following sacral neuromodulation or onabotulinumtoxina in women with urgency irinary incontinence