COMT Rs4680 Research Articles

The Moderating Role of Genetics on the Effectiveness of the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR(BC)) Program on Cognitive Impairment.

Genetics may influence symptoms experienced by breast cancer survivors (BCS) by moderating the effects of stress-reducing interventions, including the Mindfulness-Based Stress Reduction (MBSR(BC)) program, to reduce symptom severity. As part of a larger clinical trial, the aim of this study was to evaluate genetic variants as moderators of MBSR(BC) on improvements among BCS in cognitive functioning and symptoms. BCS (n = 128) were randomized to MBSR(BC) or the Breast Cancer Education Support Program. Objective neuropsychological and subjective measures of cognitive performance, and psychological and physical symptoms were collected at baseline, 6, 12, and 26 weeks. Linear mixed models were implemented to identify MBSR(BC)'s effects over time. A total of 22 single nucleotide polymorphisms (SNPs) from 20 genes known to be related to these symptoms were investigated using genomic DNA. These SNPs were tested as moderators of MBSR(BC) program effects. Results showed MBSR(BC) participants experienced significantly greater benefits in cognitive functioning, however, the level of benefit varied based on one's genetic profile. Effects sizes, consistency across similar measures were investigated. Among 22 candidate SNPs, rs4680 in COMT, rs1800497 in ANKK1, and rs6277 in DRD2 demonstrated the strongest, most consistent positive effects in moderating MBSR(BC)'s impact on cognitive outcomes. Although the effects were small, this translational research may potentially identify BCS with genotypes that would be most influenced by the MBSR(BC) program. These results may be used to develop personalized intervention programs tailored to the genetic profile of each breast cancer survivor who received chemotherapy or chemotherapy and radiation. ClinicalTrials.gov, https://www.ClinicalTrials.gov Registration Number: NCT02786797.

Investigation of the effect of catechol-o-methyltransferase gene rs4680 polymorphism on trigeminal neuralgia susceptibility

Research has been conducted to explore the genetic basis of trigeminal neuralgia, a persistent pain condition that impacts the trigeminal nerve. COMT is an enzyme responsible for inactivating substances and hormones containing catechol and catecholamines. Previous research has linked COMT gene polymorphism with various pain conditions, including migraine. Our research aimed to investigate the correlation between trigeminal neuralgia and the rs4680 polymorphism of the COMT gene. We conducted a research project which included 10 individuals diagnosed with trigeminal neuralgia and 30 healthy individuals as controls. Following collection of blood samples, we isolated DNA from the samples and then genotyping of COMT rs4680 polymorphism was performed with Real-Time PCR, using TaqMan SNP Genotyping Assay. Among the trigeminal neuralgia patients, 2 of them exhibited the AA genotype, 6 had the AG genotype, and 2 had the GG genotype for COMT rs4680. The AG genotype was notably prevalent. No statistically significant differences in the distributions of COMT genotypes and allele frequencies were found between the experimental (patients) and the control group. However, the AG genotype appeared to be more frequent in the patient group. Moving forward, we plan to expand our study by increasing the number of patients and control subjects. This will enable us to further elucidate the potential relationship between COMT gene polymorphism and trigeminal neuralgia.

Epistatic interactions between oxytocin- and dopamine-related genes and trust.

Trust is an essential human trait. Although research suggests that the interplay between oxytocinergic and dopaminergic systems affects trust formation, little research has focused on epistatic (i.e., gene by gene) interaction effects of oxytocin- and dopamine-related genes on trust. Using a sample of 348 adults (114 men), we aimed to investigate the associations between genetic variants in oxytocin- and dopamine-related genes and the general, neighborhood, and institutional trust with consideration of sex differences. Three-way interaction between oxytocin-related gene genotypes, dopamine-related genotypes, and sex was found for the oxytocin receptor gene (OXTR)rs1042778 and the Catechol-O-Methyltransferase gene (COMT) rs4680 genotypes (p = 0.02) and for OXTR rs2254298 and the dopamine D2 receptor gene (DRD2) rs1800497 genotypes (p = 0.01). Further sex-stratified analyses revealed that the interaction between OXTR rs1042778 and COMT rs4680 genotypes was associated with neighborhood trust among men (p = 0.0007). Also, the interaction between OXTR rs2254298 and DRD2 rs1800497 genotypes was associated with institutional trust among men (p = 0.005). Post-hoc analyses found that men with OXTR rs1042778 TG/TT and COMT rs4680 GG genotypes reported higher neighborhood trust than those with GG + AG/AA (B = 13.49, SE = 4.68, p = 0.02), TG/TT + AG/AA (B = 23.00, SE = 5.99, p = 0.001), and GG + GG (B = 18.53, SE = 5.25, p = 0.003). Similarly, men with OXTR rs2254298 AG/AA and DRD2 rs1800497 CC genotypes showed higher institutional trust than those with AG/AA + TT/TC (B = 15.67, SE = 5.30, p = 0.02). We could not find any interacting associations among women. While we note that our sample size and candidate gene approach have a potential risk of chance findings, our study provides an important foundation toward further exploration of sex-specific epistatic interaction effects of oxytocin- and dopamine-related genes on trust, indicating the importance of both systems in trust formation.

Influence of COMT (rs4680) and OPRM1 (rs1799971) on Cancer Pain, Opioid Dose, and Adverse Effects.

Background: The influence of pharmacogenomics on opioid response, particularly with COMT (rs4680) and OPRM1 (rs1799971) variants, has been studied individually and in combination. However, most studies are in a noncancer context and not all their possible variant combinations have been examined. Objectives: This study examined COMT (rs4680) and OPRM1 (rs1799971), and their allele combinations, in advanced cancer to examine associations with pain scores, opioid dose, and adverse effects. Setting/Subjects: This multicenter prospective cohort study recruited patients receiving opioids for advanced cancer pain in Melbourne, Australia. Clinical data (demographics, opioids), validated instruments (pain and adverse effects), and blood (DNA) were collected. Descriptive analyses were used. Univariate and multivariate logistic regression analyses were used to evaluate associations between clinical outcomes (opioid dose, pain, adverse effects) and genotypes of interest. Results: Fifty-four participants were recruited to the study. Those with COMT A allele required lower opioid doses [130 mg (interquartile range [IQR] 67.5,230) versus 180 mg (IQR 55,322.5), p = 0.047] and experienced greater adverse effects [sickness response aOR (adjusted odds ratio) 7.1 (95% CI 1.51,33.41), p = 0.01]. Those with the COMT GG/OPRM1 G allele combination required higher opioid doses [322.5 mg (IQR 264,360) versus 125 mg (65,225), (p = 0.04)]. Those with COMT AG/OPRM1 AA experienced higher average pain [aOR 1.55 (95% CI 1.03, 2.33), p = 0.04] and moderate-severe nausea [aOR 5.47 (95% CI 1.35, 22.21), p = 0.02] but reduced drowsiness [aOR 0.25 (95% CI 0.06, 1.02), p = 0.05]. Conclusions: Patients with cancer with the COMT alternate (A) allele have greater sickness response adverse effects, which may be responsible for the lower opioid doses observed. Significant results of two new COMT/OPRM1 genotype combinations are presented that have not previously been studied, with plausible phenotype descriptions suggested.

P-556 Genetic variation in genes related to folliculogenesis and steroidogenesis in Caucasian and Asian women: Baby steps towards a pharmacogenetic approach in assisted reproductive techniques

Abstract Study question What is the impact of single nucleotide polymorphisms (SNPs) in genes related to the folliculogenesis and steroidogenesis on ovarian response to stimulation? Summary answer SMAD2 rs13381619 and COMT rs4680 variants are associated with the follicular output rate (FORT). What is known already The prediction of ovarian response (OR) is crucial for an optimal and individualized management. Despite the good accuracy of ovarian reserve markers in the prediction of OR, a proportion of patients are unexpected hypo-responders. Therefore, a link between OR and individual genotype has been suggested. However, the available evidence is limited by small sample sizes and heterogeneous study designs, including patients with different profiles and allowing for dose adjustments during treatment. Our aim was to analyze the association between SNPs in genes related to folliculogenesis and steroidogenesis and OR in an ethnic diverse population treated with the same fixed-dose protocol. Study design, size, duration This is a secondary analysis of a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia) recruited from 11/2016-06/2019. The study included predicted normal responders <38 years old undergoing their first or second ovarian stimulation (OS) cycle. All patients underwent OS in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Participants/materials, setting, methods First, an interactome was developed using “FSHR” and “LHCGR” as keyword imputed in the Homo sapiens STRING database for protein network analysis. Genetic information from sixty-eight final SNPs involved in the folliculogenesis and steroidogenesis was obtained and used for clustering analysis. Secondly, genotype-phenotype analysis was performed. The prevalence of hypo-responders (<10 oocytes retrieved), number of oocytes retrieved, FORT and follicle to oocyte index (FOI) were compared between different SNPs genotypes. Main results and the role of chance Clustering analysis revealed four distinct genetic clusters according to the selected SNPs related to folliculogenesis and steroidogenesis. Principal component analysis (PCA) was used to display individuals’ distribution according to the fertility centre, resulting in an obvious distribution according to ethnicity. However, PCA failed to demonstrate a clinically significant association between our interactome and the outcomes of interest. We further refined our SNP panel by categorizing SNPs according to their physiological pathway and analyzed their individual impact on OR. Following multivariable linear regression adjusting for patient’s age, Anti-Mullerian hormone (AMH), duration of stimulation and ethnicity, SMAD2 rs13381619 genotype GC (estimated mean difference (EMD) 11.57, 95% Confidence interval (CI) 2.66-20.49), and COMT rs4680 genotype AA (EMD 18.31, 95% CI 4.91-31.72) were associated with improved FORT. No impact of the studied polymorphisms was found on the prevalence of hypo-response, number of oocytes retrieved nor FOI. Limitations, reasons for caution The study was performed in young women with a normal ovarian reserve to eliminate biases related to age-related fertility decline, precluding the extrapolation of the results to other populations. Moreover, the low prevalence of some genotypes might have limited the analysis of some of the included variants. Wider implications of the findings Our findings confirm the variation of SNPs prevalence according to ethnic diversity, highlighting the importance of the intercontinental design of our study. Moreover, a novel association between SMAD2 and COMT variants and OR was reported, opening new opportunities for further pharmacogenetics studies and paving the way towards personalized medicine. Trial registration number Not applicable

COMT and Neuregulin 1 Markers for Personalized Treatment of Schizophrenia Spectrum Disorders Treated with Risperidone Monotherapy.

Pharmacogenetic markers are current targets for the personalized treatment of psychosis. Limited data exist on COMT and NRG1 polymorphisms in relation to risperidone treatment. This study focuses on the impact of COMT rs4680 and NRG1 (rs35753505, rs3924999) polymorphisms on risperidone treatment in schizophrenia spectrum disorders (SSDs). This study included 103 subjects with SSD treated with risperidone monotherapy. COMT rs4680, NRG1 rs35753505, and rs3924999 were analyzed by RT-PCR. Participants were evaluated via the Positive and Negative Syndrome Scale (PANSS) after six weeks. Socio-demographic and clinical characteristics were collected. COMT rs4680 genotypes significantly differed in PANSS N scores at admission: AG>AA genotypes (p = 0.03). After six weeks of risperidone, PANSS G improvement was AA>GG (p = 0.05). The PANSS total score was as follows: AA>AG (p = 0.04), AA>GG (p = 0.02). NRG1 rs35753504 genotypes significantly differed across educational levels, with CC>CT (p = 0.02), and regarding the number of episodes, TT>CC, CT>CC (p = 0.01). The PANSS total score after six weeks of treatment showed a better improvement for TT<CT genotypes (p = 0.01). NRG1 rs3924999 genotypes revealed GG<AG (p = 0.02) for PANSS G scores after six weeks, with AG and GG requiring higher doses (p = 0.007, p = 0.02). Overall, our study suggests that the genetic polymorphisms COMT rs4680, NRG1 rs35753505, and rs3924999 significantly impact the treatment response to risperidone in patients with SSD.

Relationship between energy balance and reward system gene polymorphisms and appetitive traits in young Mexican subjects.

Appetitive traits are influenced by the interplay between genetic and environmental factors. This study aimed to explore the relationship between gene polymorphisms involved in the regulation of energy balance and food reward and appetitive traits in young Mexican subjects. This cross-sectional study involved 118 university freshman undergraduates who completed the Adult Eating Behaviour Questionnaire for Spanish speakers (AEBQ-Esp) to assess their appetitive traits. A real-time PCR system was employed to determine gene polymorphisms involved in energy balance (LEP rs7799039, MC4R rs17782313, FTO rs9939609, GHRL rs696217), and reward system (DRD2/ANKK1 Taq1A rs1800497 and COMT rs4680). The mean age of participants was 20.14 ± 3.95 years, 71.2% were women and their mean BMI was 23.52 ± 4.05 kg/m2. COMT Met allele carriers presented a significantly higher "Emotional overeating" mean score than Val allele carriers (2.63 ± 0.70 vs. 2.23 ± 0.70, p = 0.028). The MC4R CC + CT genotype correlated positively with "Emotional overeating" (Phi = 0.308, p = 0.01). The COMT MetMet+MetVal genotype correlated with higher "Emotional overeating" (r = 0.257, p = 0.028; Phi = 0.249, p = 0.033). The protective genotype FTO TT correlated positively with "Emotional undereating" (Phi = 0.298, p = 0.012). Carriers of the risk genotype MC4R CC + CT presented a higher risk of "Emotional overeating" than TT carriers (OR = 2.4, 95% CI 1.3-4.8, p = 0.034). Carriers of the risk genotype COMT MetMet+MetVal (OR = 3.4, 95% CI 1.1-10.3, p = 0.033), were associated with a higher risk of "Emotional overeating" than ValVal carriers. The protective FTO genotype TT was associated with "Emotional undereating" (OR = 1.8, 95% CI 1.1-9.1, p = 0.014). The study found a relationship between the protective genotypes of FTO TT and "Emotional undereating" and risk genotypes of COMT Met/Met+Met/Val and MC4R CC + CT with "Emotional overeating." These genetic factors may increase weight gain by enhancing hedonic food consumption and reducing satiety control. Future studies should focus on replication studies in ethnically diverse young adults and life stages to explore the relationship between polymorphisms and appetitive traits and weight. This will help tailor personalized nutrigenetic strategies to counteract disordered eating patterns leading to obesity and associated co-morbidities.

Association of OPRM1 rs1799971, HTR1B rs6296 and COMT rs4680 polymorphisms with clinical phenotype among women with fibromyalgia

To investigate the association between three selected pain polymorphisms and clinical, functional, sensory-related, psychophysical, psychological or cognitive variables in a sample of women with fibromyalgia (FMS). One hundred twenty-three (n = 123) women with FMS completed demographic (age, height, weight), clinical (years with pain, intensity of pain at rest and during daily living activities), functional (quality of life, physical function), sensory-related (sensitization-associated and neuropathic-associated symptoms), psychophysical (pressure pain thresholds), psychological (sleep quality, depressive and anxiety level) and cognitive (pain catastrophizing, kinesiophobia) variables. Those three genotypes of the OPRM1 rs1799971, HTR1B rs6296 and COMT rs4680 single nucleotide polymorphisms were obtained by polymerase chain reactions from no-stimulated whole saliva collection. No significant differences in demographic, clinical, functional, sensory-related, psychophysical, psychological and cognitive variables according to OPRM1 rs1799971, HTR1B rs6296 or COMT rs4680 genotype were identified in our sample of women with FMS. A multilevel analysis did not either reveal any significant gene-to-gene interaction between OPRM1 rs1799971 x HTR1B rs6296, OPRM1 rs1799971 x COMT rs4680 and HTR1B rs6296 x COMT rs4680 for any of the investigated outcomes. This study revealed that three single nucleotide polymorphisms, OPRM1 rs1799971, HTR1B rs6296 or COMT rs4680, mostly associated with chronic pain were not involved in phenotyping features of FMS. Potential gene-to-gene interaction and their association with clinical phenotype in women with FMS should be further investigated in future studies including large sample sizes.

The Influence of Genetic Polymorphic Variability of the Catechol-O-methyltransferase Gene in a Group of Patients with a Diagnosis of Behavioural Addiction, including Personality Traits.

Gambling Disorder (GD) is characterised by a harmful, enduring, and recurrent involvement in betting-related behaviours. Therefore, GD shares similar biological mechanisms and symptoms to substance use disorders (SUD). Therefore, in this study, we chose the behavioural addictions group. During the examination and recruitment to the study, it turned out that all the people undergoing treatment for gambling addiction were also addicted to amphetamines, which is consistent with the biological mechanism related to cerebral neurotransmission. The aim of the study was to investigate the association of the COMT gene polymorphism with behavioral addiction. The study group consisted of 307 participants: 107 men with gambling disorder and amphetamine dependency (mean age = 27.51, SD = 5.25) and 200 non-addicted, nor dependent, free from neuro-psychiatric disorders control group men (mean age = 20.20, SD = 4.51). Both groups were subjected to psychometric evaluation using the State-Trait Anxiety Inventory and the NEO Five-Factor Personality Inventory. Genomic DNA was extracted from venous blood following standard protocols. Determination of the rs4680 polymorphism in the COMT gene was performed using the real-time PCR technique. Statistically significant differences in the frequency of rs4680 genotypes were found in the tested sample of subjects compared with the control group (p = 0.03543). Subjects with gambling disorder and amphetamine use disorder compared to the control group obtained higher scores in the assessment of the STAI trait scale (p = 0.0019), state scale (p < 0.0000), and NEO-FFI Neuroticism scale (p < 0.0000). Significantly lower results were obtained for the NEO-FFI Agreeability scale (p < 0.0000). Additionally, a significant statistical impact of gambling disorder and amphetamine use disorder, and the COMT rs4680 genotype was demonstrated for the score of the STAI trait (p = 0.0351) and state (p = 0.0343) and the NEO-FFI Conscientiousness scale (p = 0.0018). We conclude that COMT and its polymorphic variant influence the development of addiction. Still, considering its multifactorial and polygenic nature, it should be combined with other factors such as personality.

Search for Association of Polymorphisms rs6280 of the DRD3 Gene, rs4680 of the COMT Gene, rs6265 of the Gene BDNF with Schizophrenia Resistant to Antipsychotic Therapy in Russian Populations

Background: resistant schizophrenia, despite the introduction of new antipsychotics and diagnostic methods, still reaches 50%of cases among all patients with schizophrenia. The search for new methods of early diagnosis using personalized genetic analysis tools seems relevant and promising at the present time. The aim of the study was to analyze the associations of polymorphisms COMT rs4680, DRD3 rs6280, BDNF rs6265 with the development of a therapeutic resistance in patients with schizophrenia. Patients and methods: а real-time genetic analysis of 264 patients with schizophrenia examined by clinical and psychometric methods. A prospective follow-up for 6 weeks was carried out with further division of the sample into 2 groups: respondents and patients with resistance based on the evaluation of the effectiveness of psychopharmacotherapy. Results: a significant association with the ineffectiveness of psychopharmacotherapy found in patients with schizophrenia being homozygotes in the recessive model and being heterozygotes in the codominant model of the rs6265 polymorphism of the BDNF gene. Conclusions: the rs6265 polymorphism of the BDNF gene can be considered as a diagnostic marker for the development of treatment resistant schizophrenia, but requires further study to confirm sensitivity and specificity.

Effects of polygenes, parent-child relationship and frustration on junior high school students' aggressive behaviors.

The effects of the interaction between polygenes and the parent-child relationship on junior high school students' aggressive behaviors were explored through the frameworks of gene-endophenotype-behavior and neurophysiological basis. A total of 892 junior high school students participated in this study. They were asked to complete self-reported questionnaires, and saliva samples were collected. Results showed that 5-HTTLPR, MAOA-uVNTR, COMT (rs4680), and Taq1 (rs1800497) of the DRD2 gene affected students' aggressive behaviors in an accumulative way. The polygenic risk score explained 3.4% of boys' aggression and 1.1% of girls' aggression. The interactions between polygenic risk score and parent-child conflict significantly affected the aggressive behaviors of male students, but did not show any significant effect on those of female students. The interactional effect of polygenic risk score and parent-child conflict on junior high school students' aggressive behaviors was completely mediated by frustration. However, the interaction effect of polygenic risk score and parent-child affinity on aggression was not affected by frustration. This study helps us better understand junior high school students' aggressive behaviors and promotes the prevention and correction of adolescents' problem behaviors.

Predictive biomarkers for cognitive decline in patients with idiopathic REM sleep behavior disorder

AbstractBackgroundIdiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is regarded as an early stage of the synucleinopathy, which may precede the onset of cognitive impairment or parkinsonism. Biomarkers for cognitive decline in patients with iRBD would be helpful to early intervention. Our aim was to identify biomarkers for predicting the cognitive deterioration risk in patients with iRBD.MethodWe involved patients with polysomnographically confirmed iRBD who has at least 2 visits from the Parkinson’s Progression Markers Initiative (PPMI) database. Progression of cognitive state to MCI or dementia during follow‐up was defined as the endpoint. Baseline clinical features, biofluid and genetic biomarkers were compared between iRBD with or without progression of cognitive decline. Predictive biomarkers were identified with Kaplan‐Meier and Cox proportional hazards analysis, adjusting for age, sex, and years of education.ResultA total of 38 patients with iRBD were enrolled (average age: 69.53 ± 5.54, male: 84.21%) . During follow‐up (median 5.45, IQR 4.08‐7.1 years), Progression of cognitive decline occurred in 57.89% (22/38) patients with iRBD. Baseline clinical features including hallucinations and psychosis (HR = 13.783, p = 0.022) and higher confidence abnormalities consistent with a neurodegenerative parkinsonian syndrome (HR = 2.258, p = 0.017) increased the risk. Patients with a lower loge‐transformed the ratio of Aβ 1‐42 in cerebrospinal fluid (CSF) to ΝfL in serum (Aβ/NfL, HR = 0.375, p = 0.044) and t‐tau in CSF to ΝfL in serum (t‐tau/NfL, HR = 0.277, p = 0.044) had a higher risk of cognitive decline. Genetic biomarkers consisting of GBA rs75548401(HR = 13.783, p = 0.022), STK39 rs1955337 (HR = 11.882, p&lt;0.001), and COMT rs4680 (HR = 2.376, p = 0.021) variants increased the risk, while MCCC1 rs12637471 (HR = 0.408, p = 0.024), COMT rs165656 (HR = 0.451, p = 0.033), COMT rs4633 (HR = 0.421, p = 0.021), and COMT rs165599 (HR = 0.427, p = 0.023) variants decreased the risk. A model combining age and variables with p&lt;0.05 exhibited above presented the best predictive performance, with an AUC of 0.963 (95% CI 0.896–1.000, p&lt;0.001).ConclusionOur findings provide potential biomarkers to evaluate the risk of progression to MCI or dementia in patients with iRBD. Combination of clinical features, biofluid and genetic biomarkers performs optimal predicting accuracy.

Association Between the rs4680 Polymorphism of the COMT Gene and Personality Traits among Combat Sports Athletes.

Physical performance has been the focus of studies examining genetic influences in martial arts. There has been little quantitative analysis of the interaction between psychological traits and gene variants in athletes. This study aimed to determine whether the rs4680 polymorphism of the COMT gene (catechol-O-methyltransferase) was linked to other sports phenotypes such as temperament, mental toughness, and stress tolerance. In our study, we concentrated on the case-control analysis of athletes in the aspect of their personality traits in association with the COMT gene polymorphism. Participants comprised 258 combat sports athletes and 278 healthy male individuals as a control group. Psychometric properties were assessed with the Revised Temperament and Character Inventory (TCI-R). COMT polymorphism testing was performed using real-time PCR. We found a statistically significant effect of a complex factor COMT rs4680 genotype with combat athletes/controls and novelty seeking (F2,530 = 5.958, p = 0.0028, η2 = 0.022), self-management (F2,530 = 6.772, p = 0.0012, η2 = 0.025), and with self-transcendence skills (F2,530 = 9.387, p = 0.00009, η2 = 0.034). The results are important for encouraging further studies on the genetic makeup of athletes in conjunction with personality traits. Due to the multigene and multifactorial nature of determinants of sports predispositions, we propose to take into account also other features, especially when studying genes related to cerebral neurotransmission. It is a holistic departure, and it clearly illustrates the relationship between the given characteristics of an athlete.

Association of Genetic Variants with Postsurgical Pain: A Systematic Review and Meta-analyses.

Postsurgical pain is a key component of surgical recovery. However, the genetic drivers of postsurgical pain remain unclear. A broad review and meta-analyses of variants of interest will help investigators understand the potential effects of genetic variation. This article is a systematic review of genetic variants associated with postsurgical pain in humans, assessing association with postsurgical pain scores and opioid use in both acute (0 to 48 h postoperatively) and chronic (at least 3 months postoperatively) settings. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from 2000 to 2022 for studies using search terms related to genetic variants and postsurgical pain in humans. English-language studies in adult patients examining associations of one or more genetic variants with postsurgical pain were included. The primary outcome was association of genetic variants with either acute or chronic postsurgical pain. Pain was measured by patient-reported pain score or analgesic or opioid consumption. A total of 163 studies were included, evaluating 129 unique genes and 594 unique genetic variants. Many of the reported significant associations fail to be replicated in other studies. Meta-analyses were performed for seven variants for which there was sufficient data (OPRM1 rs1799971; COMT rs4680, rs4818, rs4633, and rs6269; and ABCB1 rs1045642 and rs2032582). Only two variants were associated with small differences in postsurgical pain: OPRM1 rs1799971 (for acute postsurgical opioid use standard mean difference = 0.25; 95% CI, 0.16 to 0.35; cohort size, 8,227; acute postsurgical pain score standard mean difference = 0.20; 95% CI, 0.09 to 0.31; cohort size, 4,619) and COMT rs4680 (chronic postsurgical pain score standard mean difference = 0.26; 95% CI, 0.08 to 0.44; cohort size, 1,726). Despite much published data, only two alleles have a small association with postsurgical pain. Small sample sizes, potential confounding variables, and inconsistent findings underscore the need to examine larger cohorts with consistent outcome measures.

Distribution of pharmacogeneallele and phenotype frequencies in Brazilian psychiatric patients.

Purpose: This work was designed to identify the pharmacogenetic profile of Brazilian psychiatric patients receiving psychoactive drug treatment according to ethnicity. Methods: Based on the GnTech® database, this cross-sectional study analyzed data from self-reported sociodemographic and genetic results from the next-generation sequencing panel composed of 26 pharmacogenes from 359 psychotropic drug users. Results: Variant frequencies of multiple pharmacogenes presented differences between ethnicities (CYP3A5, CYP2D6, CYP1A2, CYP2B6, CYP3A4, UGT1A4, UGT2B15, ABCB1 rs1045642, ADRA2A rs1800544, COMT rs4680, GRIK4 rs1954787, GSK3B rs334558, GSK3B rs6438552, HTR1A rs6295, HTR2A rs7997012, HTR2C rs1414334, MTHFR rs1801131, OPRM1 rs1799971 and 5-HTTLPR), endorsing the necessity of individual-level analyses in drug treatment. Conclusion: A discussion of pharmacogenomic test implementation in psychiatric clinical practice is needed to improve treatment choices, especially in Brazil, a multiethnic country.

Multilocus Genetic Profile Reflecting Low Dopaminergic Signaling Is Directly Associated with Obesity and Cardiometabolic Disorders Due to Antipsychotic Treatment.

Treatment with second-generation antipsychotics (SGAs) can cause obesity and other cardiometabolic disorders linked to D2 receptor (DRD2) and to genotypes affecting dopaminergic (DA) activity, within reward circuits. We explored the relationship of cardiometabolic alterations with single genetic polymorphisms DRD2 rs1799732 (NG_008841.1:g.4750dup -> C), DRD2 rs6277 (NG_008841.1:g.67543C>T), COMT rs4680 (NG_011526.1:g.27009G>A), and VNTR in both DRD4 NC_000011.10 (637269-640706) and DAT1 NC_000005.10 (1392794-1445440), as well as with a multilocus genetic profile score (MLGP). A total of 285 psychiatric patients treated with SGAs for at least three months were selected. Cardiometabolic parameters were classified according to ATP-III and WHO criteria. Blood samples were taken for routinely biochemical assays and PCR genotyping. Obesity (BMI, waist (W)), high diastolic blood pressure (DBP), and hypertriglyceridemia (HTG) were present in those genetic variants related to low dopaminergic activity: InsIns genotype in rs1799732 (BMI: OR: 2.91 [1.42-5.94]), DRD4-VNTR-L allele (W: OR: 1.73 [1.04-2.87]) and 9R9R variant in DAT1-VNTR (W: OR: 2.73 [1.16-6.40]; high DBP: OR: 3.33 [1.54-7.31]; HTG: OR: 4.38 [1.85-10.36]). A low MLGP score indicated a higher risk of suffering cardiometabolic disorders (BMI: OR: 1.23 [1.05-1.45]; W: OR: 1.18 [1.03-1.34]; high DBP: OR: 1.22 [1.06-1.41]; HTG: OR: 1.20 [1.04-1.39]). The MLGP score was more sensitive for detecting the risk of suffering these alterations. Low dopaminergic system function would contribute to increased obesity, BDP, and HTG following long-term SGA treatment.

EXPERIENCE OF PHARMACOGENETIC TESTING IN THE TREATMENT OF ANTIPSYCHOTICS

IntroductionOne of the promising methods for optimizing treatment in order to achieve high-quality remissions is a personalized approach to prescribing therapy in the form of pharmacogenetic testing, the feasibility of which has already been substantiated and proven in a number of clinical guidelines. By the beginning of 2022, several influential regulatory and expert organizations recommend considering the results of genetic testing when prescribing therapy. Thus, personalization of antipsychotic therapy is being introduced in the world practice.ObjectivesTo establish the significance of pharmacogenetic markers that determine the efficacy and safety of antipsychotic therapy in patients with schizophrenia in clinical practice.MethodsThe study included 264 patients (141 men, 123 women; 27.3 ± 4.5 years) from among the first hospitalized in a psychiatric hospital in the period 2018-2020, meeting the inclusion criteria (psychosis within the schizophrenia spectrum disorders; consent to participate in research). Non-inclusion criteria - signs of organic brain damage; alcohol or substance abuse; somatic pathology in the stage of decompensation). The examination took place in three stages - in the first days of hospitalization at the peak of the acute condition and during the formation of remission - after 6 and 12 months. Genetic analysis was performed using high-density biochips from Illumina CoreExome Bead (Illumina Inc, USA). During the follow-up observation, some patients dropped out due to refusal to undergo examination, change of diagnosis or change of place of residence. After 6 and 12 months, it was possible to trace the dynamics of the state of 91 patients (50 men, 41 women; 24.9 ± 4.6 years).ResultsBased on the follow-up results, two types of schizophrenia dynamics were identified - with a relatively favorable and unfavorable course. The formation of a relatively stable remission corresponding to the criteria proposed by the working group was noted in 47 patients (51.6%), carriers of gene polymorphisms: DRD2 rs1799732 (del); COMT rs4680(GG); BDNF rs6265 (CC); ANKK1 rs1800497 (GG); MC4R rs489693 (AA); ABCB1 rs1045642 and ABCC1 rs212090 (GG). An unfavorable course with the ineffectiveness of antipsychotics was found in 48.4% of cases in patients with DRD2 rs1799732 (G/del) carriers; COMT rs4680(AA); BDNF rs6265 (TT); ANKK1 rs1800497 (AA); MC4R rs489693 (GG); ABCB1 rs1045642 and ABCC1 rs212090 (AA).ConclusionsAfter analyzing the results of genetic testing and clinical and dynamic characteristics of the course of schizophrenia, we can talk about the relationship between the establishment of high-quality remission in the presence of polymorphisms in the genotype, whose role has been proven in terms of the effectiveness and safety of antipsychotics.Disclosure of InterestNone Declared

Association of Gene Polymorphisms DRD3 rs6280, COMT rs4680, and HTR2A rs7322347 with Schizophrenia

Association of Gene Polymorphisms DRD3 rs6280, COMT rs4680, and HTR2A rs7322347 with Schizophrenia

Polymorphisms in COMT and OPRM1 Collectively Contribute to Chronic Shoulder Pain and Disability in South African Breast Cancer Survivors'.

Chronic shoulder pain and disability is a common adverse effect experienced by &gt;40% of breast cancer survivors (BCS). Pain management protocols for acute and chronic pain include the use of opioids and opioid derivatives. Furthermore, pain-modulating genes, such as COMT and OPRM1, have been linked to the aetiology of chronic pain. This study aimed to investigate the association between genetic variants of major pain modulator genes and chronic pain/disability in BCS. Assessment of pain, disability and combined (pain and disability) symptoms were determined using the Shoulder Pain and Disability Index (SPADI). Participants were grouped according to their scores such as no-low (&lt;30%) and moderate-high (≥30%) groups of pain, disability and combined (pain and disability). Genotyping of the COMT rs6269 (A &gt; G), rs4633 (C &gt; T), rs4818 (C &gt; G) and the functional rs4680(G &gt; A) SNPs within the BCS (N = 252) cohort were conducted using TaqMan® SNP assays. Genotype, allele, haplotype, and allele-allele combination frequencies were evaluated. Statistical analysis was applied, with significance accepted at p &lt; 0.05. The COMT rs4680:A/A genotype was significantly associated with moderate-high pain (p = 0.024, OR: 3.23, 95% CI: 1.33-7.81) and combined (pain and disability) (p = 0.015, OR: 3.81, 95% CI: 1.47-9.85). The rs4680:A allele was also significantly associated with moderate-high pain (p = 0.035, OR: 1.58, 95% CI: 1.03-2.43) and combined (pain and disability) (p = 0.017, OR: 1.71, 95% CI: 1.07-2.71). For the inferred COMT (rs6269 A &gt; G-rs4680 G &gt; A) haplotype analyses, the G-G (p = 0.026, OR: 0.67, 95% CI: 0.38-1.18) and A-A (p = 0.007, OR: 2.09, 95% CI: 0.89-4.88) haplotypes were significantly associated with reduced and increased likelihoods of reporting moderate-high pain, respectively. The inferred A-A (p = 0.003, OR: 2.18, 95% CI: 0.92-5.17) haplotype was also significantly associated with combined (pain and disability). Gene-gene interaction analyses further showed allele-allele combinations for COMT (rs4680 G &gt; A)-OPRM1 (rs1799971 A &gt; G) and COMT (rs4680 G &gt; A)-OPRM1(rs540825 T &gt; A) were associated with reporting pain and combined (pain and disability) symptoms, p &lt; 0.05. The findings of this study suggest that COMT and OPRM1 SNPs play a role in the development of chronic shoulder pain/disability in BCS in a unique South African cohort from the Western Cape.

Pharmacogenomics of Cancer Pain Treatment Outcomes in Asian Populations: A Review

In advanced cancer, pain is a poor prognostic factor, significantly impacting patients' quality of life. It has been shown that up to 30% of cancer patients in Southeast Asian countries may receive inadequate analgesia from opioid therapy. This significant under-management of cancer pain is largely due to the inter-individual variability in opioid dosage and relative efficacy of available opioids, leading to unpredictable clinical responses to opioid treatment. Single nucleotide polymorphisms (SNPs) cause the variability in opioid treatment outcomes, yet their association in Asian populations remains unclear. Therefore, this review aimed to evaluate the association of SNPs with variability in opioid treatment responses in Asian populations. A literature search was conducted in Medline and Embase databases and included primary studies investigating the association of SNPs in opioid treatment outcomes, namely pharmacokinetics, opioid dose requirements, and pain control among Asian cancer patients. The results show that CYP2D6*10 has the most clinical relevance in tramadol treatment. Other SNPs such as rs7439366 (UGT2B7), rs1641025 (ABAT) and rs1718125 (P2RX7) though significant have limited pharmacogenetic implications due to insufficient evidence. OPRM1 rs1799971, COMT rs4680 and ABCB1 (rs1045642, rs1128503, and rs2032582) need to be further explored in future for relevance in Asian populations.