A mouse model of chronic primary pain that integrates clinically relevant genetic vulnerability, stress, and minor injury.

Chronic primary pain conditions (CPPCs) affect over 100 million Americans, predominantly women. They remain ineffectively treated, in large part because of a lack of valid animal models with translational relevance. Here, we characterized a CPPC mouse model that integrated clinically relevant genetic (catechol-O-methyltransferase; COMT knockdown) and environmental (stress and injury) factors. Compared with wild-type mice, Comt+/- mice undergoing repeated swim stress and molar extraction surgery intervention exhibited pronounced multisite body pain and depressive-like behavior lasting >3 months. Comt+/- mice undergoing the intervention also exhibited enhanced activity of primary afferent nociceptors innervating hindpaw and low back sites and increased plasma concentrations of norepinephrine and pro-inflammatory cytokines interleukin-6 (IL-6) and IL-17A. The pain and depressive-like behavior were of greater magnitude and longer duration (≥12 months) in females versus males. Furthermore, increases in anxiety-like behavior and IL-6 were female-specific. The effect of COMT genotype × stress interactions on pain, IL-6, and IL-17A was validated in a cohort of 549 patients with CPPCs, demonstrating clinical relevance. Last, we assessed the predictive validity of the model for analgesic screening and found that it successfully predicted the lack of efficacy of minocycline and the CB2 agonist GW842166X, which were effective in spared nerve injury and complete Freund's adjuvant models, respectively, but failed in clinical trials. Yet, pain in the CPPC model was alleviated by the beta-3 adrenergic antagonist SR59230A. Thus, the CPPC mouse model reliably recapitulates clinically and biologically relevant features of CPPCs and may be implemented to test underlying mechanisms and find new therapeutics.

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.

Preliminary Evidence for a Positive Relation Between the COMT rs4680 Met/Met Genotype and Math Achievement.

To identify if COMT polymorphisms interact with executive functions as predictors of math skills, we assessed 38 adolescents (mean age = 16.4 ± 0.80 years, IQ > 80) from a larger study of high-school students screened for their mathematical abilities. Adolescents were genotyped for the COMT Val158Met polymorphism (grouped as Met/Met or Val-carriers) and completed the WRAT math achievement test, working-memory, inhibitory-control, and shifting tasks. Met/Met-carriers achieved higher WRAT scores than the Val-carriers (W = 229, p = .009). Genotype group was a moderate-to-strong predictor of WRAT scores (ß = 0.56 to 0.74). No genotype/executive-function interaction was detected. Our findings suggest that the rs4680 Met/Met genotype is positively associated with math achievement.

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

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

Moderating effects of preoperative knee pain and pain catastrophizing on the relation between COMT rs4680 genotypes and chronic postsurgical pain in total knee arthroplasty patients.

BACKGROUND: The Catechol-O-methyltransferase (COMT) gene, responsible for encoding an enzyme crucial in the metabolism of catecholamines, is known to play a significant role in pain perception. Polymorphisms within this gene, particularly the COMT rs4680 genotypes, have been linked to various acute pain phenotypes. This prospective cohort study examines interactions among the genetic polymorphism COMT rs4680 genotypes, preoperative knee pain, and pain catastrophizing in chronic postsurgical pain (CPSP) at 3, 6, and 12 months post-total knee arthroplasty (TKA). STUDY DESIGN: A total of 280 patients undergoing primary unilateral TKA participated, sharing demographic details, preoperative knee pain levels, psychological variables (pain catastrophizing), and COMT rs4680 genotyping via venous blood samples. Telephone interviews at specified intervals enabled the application of binary logistic regressions and interaction models. RESULTS: Significant influences of preoperative knee pain and pain catastrophizing on postsurgical outcomes were observed. Specifically, at the first time point (T1, 3 months post-TKA), a notable moderation effect was identified in preoperative knee pain (R2 change = 0.026, p = 0.026). The Johnson-Neyman regions of significance (RoS) indicated these moderation effects were significant above a threshold of 17.18 (p = 0.05), accounting for 26.4%. At the third time point (T3, 12 months post-TKA), a complex three-way interaction among genotypes (GG, GA, and AA carriers) was evident, resulting in an R2 change of 0.051 (p = 0.009). Here, the RoS for pain catastrophizing was above 32.74 for 30.5% of GG genotype carriers, above 22.38 for 50.8% of GA carriers, and below 11.94 for 63.2% of AA carriers. CONCLUSION: This study illuminates the significant role of the COMT Val158Met rs4680 polymorphism in susceptibility to prolonged pain following TKA. It also elucidates how these genetic genotypes interplay with preoperative knee pain and pain catastrophizing. Such intricate genetic-psychological-pain relationships necessitate additional investigation to confirm these findings and potentially guide post-TKA pain management strategies.

The influence of the COMT Val158Met polymorphism on prefrontal TDCS effects on aggression.

Increasing dorsolateral prefrontal cortex (DLPFC) activity by anodal transcranial direct current stimulation (tDCS) enhances cognitive control and might reduce aggression. The Val158Met polymorphism within the catechol-O-methyltransferase gene (rs4680) plays a pivotal role in prefrontal dopamine signaling, displaying associations with aggressive behavior, and potentially influencing the effects of tDCS. In a double-blind, sham-controlled study, we investigated the influence of rs4680 on tDCS effects on aggression. While undergoing functional magnetic resonance imaging, 89 healthy male participants performed the Taylor aggression paradigm before and immediately after tDCS. Actively stimulated participants (n = 45) received anodal tDCS (1.5 mA) for 20 min targeting the right DLPFC. Carriers of the val-allele (val+; n = 46; active tDCS n = 23) were compared to met-allele homozygotes (val-; n = 43; active tDCS n = 22). Analysis revealed decreased aggressive behavior in the val- group following active tDCS (p < 0.001). The val+ group showed increased aggression during the second session (p < 0.001) with an even higher increase following active as compared to sham tDCS (p < 0.001). No effects of stimulation or rs4680 on brain activation were found. Our study provides evidence for opposite tDCS effects on aggressive behavior in val-carriers and val-noncarriers. By shedding light on genetic factors predicting tDCS responsivity, the study will help to pave the way toward individualized-and thus more effective-tDCS treatment options.

Interactions between tDCS treatment and COMT Val158Met in poststroke cognitive impairment.

OBJECTIVE: This study aimed to explore the effect of catechol-O-methyltransferase (COMT) Val158Met and brain-derived neurotrophic factor (BDNF) Val66Met to post-stroke cognitive impairment (PSCI) and the interaction with transcranial direct current stimulation (tDCS). METHODS: Seventy-six patients with PSCI were randomly assigned to Group (1) (n = 38) to receive anodal tDCS of left dorsolateral prefrontal cortex or Group (2) (n = 38) to receive sham stimulation. The intensity of the tDCS was 2 mA, and the stimulations were applied over the left DLPFC for 10 sessions. The Montreal Cognitive Assessment (MoCA) and backward digit span test (BDST) were assessed before, immediately after, and one month after stimulation. RESULTS: After stimulation, patients in the tDCS group showed better improvement in both MoCA and BDST than those in the sham group. The results of GLMs also supported the main effects of tDCS on general cognitive function and working memory. Then we found that COMT genotype may have a main effect on the improvement of MoCA and BDST, and there may be an interaction between COMT genotype and tDCS in enhancing BDST. In contrast, BDNF genotype showed no significant main or interaction effects on any scales. CONCLUSIONS: These findings demonstrate that tDCS can improve cognition after stroke. Gene polymorphisms of COMT can affect the efficacy of tDCS on PSCI, but BDNF may not. SIGNIFICANCE: This study found that COMT Val158Met has an interaction on the efficacy of prefrontal tDCS in cognitive function, which provides reference for future tDCS research and clinical application.

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

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

To Each His Own Fear: Gender-Related Association of Anxiety, Substance Use, and Eating Disorders in a Representative Birth Cohort Sample of Young Adults with Either COMT Val158Met allele.

INTRODUCTION: The role of catechol-O-methyltransferase (COMT) in catecholamine neurotransmitter metabolism has led to the investigation of variants of the corresponding gene in the etiology of different psychiatric disorders, but the results are inconclusive. METHODS: We have examined the relationship between COMT Val158Met single nucleotide polymorphism (rs4680) and the occurrence of psychiatric disorders in a highly representative birth cohort sample of young adults in the Estonian Children Personality Behaviour and Health Study (original n = 1,238). The lifetime occurrence of psychiatric disorders at the age of 25 years was assessed with the Mini-International Neuropsychiatric Interview. RESULTS: Both Val- and Met-alleles of the COMT Val158Met were associated with specific psychiatric disorders. Met-allele carriers had a significantly higher occurrence of agoraphobia (3.2% vs. 0.5%; χ2 = 4.10; p < 0.05) compared to Val/Val homozygotes. Also, the occurrence of panic disorder was significantly higher in female Met-allele carriers than in Val/Val homozygote females (10.2% vs. 3.6%; χ2 = 4.62 p = 0.03). In contrast, the occurrence of generalized anxiety disorder was higher in Val/Val females when compared to Met-allele carriers (12.7% vs. 6.8%; χ2 = 4.16; p = 0.04). Also, female Val/Val homozygotes (15.5%) had a higher occurrence of eating disorders than Met-allele carriers (6.1%) of the COMT Val158Met polymorphism (χ2 = 10.39; p = 0.002). In the whole sample, Met-allele homozygotes had a higher occurrence of alcohol use and substance use disorders than Val-allele carriers (χ2 = 3.62 and 3.68, respectively; p < 0.05). CONCLUSION: In a regional highly birth cohort representative sample, either COMT rs4680 variant was observed in association with specific psychiatric disorders.

The association of gene polymorphisms in catechol-O'methyltransferase (COMT) and ß2-adrenergic receptor (ADRB2) with temporomandibular joint disorders.

OBJECTIVE: Temporomandibular disorder (TMD) has a multifactorial etiology that includes environmental, psychological, and genetic factors. This study aimed to evaluate the possible relationship between polymorphisms in Catechol-O-methyltransferase (COMT) and ß2-adrenergic receptor (ADRB2) genes with TMD. DESIGN: This observational case-control study included 80 patients and 70 healthy controls. The diagnosis of TMD was made using the diagnostic criteria for TMD and the following TMD categories were used for the case group: muscular TMD and articular TMD (disc displacement and arthralgia). A genotyping study of gene polymorphisms in COMT (rs 9332377) and ADRB2 (rs20530449) was performed from genomic DNA isolated from blood. The chi-square test was used to analyze the relationships. P < 0.05 was accepted as a significant difference. RESULTS: The polymorphic TT and CT genotype for COMT (rs rs9332377) was significantly higher in the articular TMD group while the non-polymorphic CC genotype was significantly lower in the articular TMD group (P < 0.05). Regarding ADRB2 (rs20530449), the polymorphic GG genotype was similarly considerably more common in the articular TMD group (p < 0.05). In addition, the T allele in the COMT (rs rs9332377) gene was found to be significantly higher in the articular TMD group (p < 0.05). CONCLUSIONS: In the Turkish population, gene polymorphisms in COMT (rs9332377) and ADRB2 (rs2053044) were associated with articular TMD. This study supports the hypothesis that changes in COMT and ADRB2 genes may play a role in temporomandibular joint pain and predisposition to TMD.

Associations between Catechol-O-methyltransferase (COMT) polymorphisms and cognitive impairments, psychiatric symptoms and tardive dyskinesia in schizophrenia.

INTRODUCTION: Catechol-O-methyltransferase (COMT) is a crucial enzyme involved in dopamine metabolism and has been implicated in the etiology of tardive dyskinesia (TD). We aimed to investigate the associations between COMT gene polymorphisms and the occurrence and severity of TD in a Chinese population, as well as the impact on the psychiatric symptoms and cognitive impairments observed in TD patients. METHODS: A total of 216 chronic schizophrenia patients, including 59 TD patients and 157 NTD patients, were recruited for this study. Three SNPs of the COMT gene (rs4680, rs165599 and rs4818) were selected and genotyped using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). TD severity, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. RESULTS: In TD patients, total AIMs scores were higher in carriers of the rs4680 AA genotype than in carriers of the AG and GG genotypes (p = 0.01, 0.006), carriers of the rs4818 GC and CC genotypes had higher orofacial scores than in GG genotypes (p = 0.032, 0.002). In male TD patients, carriers of the rs165599 GA genotype scored lower in the extremities and trunk scores than AA genotype carriers (p = 0.015). Moreover, in male TD patients, COMT rs4818 was associated with cognition, since the C allele carriers had significantly higher immediate memory (p = 0.043) and verbal function (p = 0.040) scores than the G allele carriers. In addition, rs165599 genotype interacted with TD diagnosis on depressed factor (p = 0.031). CONCLUSION: Within the Chinese population, COMT gene polymorphisms could potentially serve as biomarkers for the symptoms and prognosis of TD patients.

A preliminary study on the association of single nucleotide polymorphisms and methylation of dopamine system-related genes with psychotic symptoms in patients with methamphetamine use disorder.

Methamphetamine use disorder (MAUD) can substantially jeopardize public security due to its high-risk social psychology and behaviour. Given that the dopamine reward system is intimately correlated with MAUD, we investigated the association of single nucleotide polymorphisms (SNPs), as well as methylation status of dopamine receptor type 4 (DRD4), catechol-O-methyltransferase (COMT) genes, and paranoid and motor-impulsive symptoms in MAUD patients. A total of 189 MAUD patients participated in our study. Peripheral blood samples were used to detect 3 SNPs and 35 CpG units of methylation in the DRD4 gene promoter region and 5 SNPs and 39 CpG units in the COMT gene. MAUD patients with the DRD4 rs1800955 C allele have a lower percentage of paranoid symptoms than those with the rs1800955 TT allele. Individuals with paranoid symptoms exhibited a reduced methylation degree at a particular DRD4 CpG2.3 unit. The interaction of the DRD4 rs1800955 C allele and the reduced DRD4CpG2.3 methylation degree were associated with a lower occurrence of paranoid symptoms. Meanwhile, those with the COMT rs4818 CC allele had lower motor-impulsivity scores in MAUD patients but greater COMT methylation levels in the promoter region and methylation degree at the COMT CpG 51.52 unit. Therefore, based only on the COMT rs4818 CC polymorphism, there was a negative correlation between COMT methylation and motor-impulsive scores. Our preliminary results provide a clue that the combination of SNP genotype and methylation status of the DRD4 and COMT genes serve as biological indicators for the prevalence of relatively high-risk psychotic symptoms in MAUD patients.

Interaction between vitamin E intake and a COMT gene variant on colorectal cancer risk among Korean adults: a case-control study.

OBJECTIVES: Previous human trials have not supported the anticarcinogenic effect of vitamin E despite biological plausibility and considerable epidemiological evidence. A possible explanation for this inconsistency is the interactive effect of the catechol-O-methyltransferase (COMT) gene and supplemental vitamin E on cancer. We examined whether a COMT gene variant modulates the effect of dietary vitamin E intake on colorectal cancer (CRC) risk. METHODS: In this case-control study of Korean adults (975 cases and 975 age- and sex-matched controls), dietary vitamin E density (mg/1,000 kcal) was measured using a semiquantitative food frequency questionnaire, COMT single nucleotide polymorphism (SNP) rs740603 (A>G) was genotyped, and CRC was verified histologically. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models with adjustments for potential confounders. RESULTS: Higher vitamin E density was associated with a lower risk of CRC (highest vs. lowest quartiles: OR, 0.72; 95% CI, 0.55 to 0.96; p-for-trend=0.002). When stratified by COMT SNP rs740603 genotype, the inverse association between vitamin E density and CRC risk was confined to those with at least 1 A allele (≥median vs.

Association of DRD2, DRD4 and COMT genes variants and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia.

Antipsychotic drugs are the first line of treatment in schizophrenia; although antipsychotic responses indicate a wide interindividual variety in patients with schizophrenia. This study aimed to investigate the association between four polymorphisms in DRD2, DRD4 and COMT genes and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia. A total of 101 patients with schizophrenia were recruited and stratified in treatment responder and treatment resistant groups based on the published criteria of resistant to treatment using PANSS. Clinical and demographic factors were analyzed. Genomic DNA was extracted from whole blood and genotyping for the four polymorphisms were done by ARMS-PCR, PCR-RFLP and gap-PCR. Gene-gene interactions were analyzed by logistic regression. In case of DRD2 A-241G, G allele was significantly associated with resistant to treatment. Regarding DRD4 120-bp duplication, 240/240 genotype was significantly associated with resistant to treatment comparing to other genotypes in a dominant model. The genotype combination of DRD4 240/240 and COMT Val/Val was significantly associated with treatment resistant. Among DRD2 AA genotype, COMT met allele carriers which also had a 120 bp allele of DRD4 had a significantly better response to antipsychotics. Moreover, analysis of clinical and demographic factors demonstrated a significantly longer duration of hospitalization and higher chlorpromazine-equivalent daily dose in resistant to treatment patients. Discovering the polymorphisms which effect treatment response to antipsychotics will provide the possibility of genetic screening before starting an antipsychotic treatment which enhances the chance of responding to antipsychotics and decreases drugs side effects and costs.

Dysregulated COMT Expression in Fragile X Syndrome.

Transcriptional and proteomics analyses in human fragile X syndrome (FXS) neurons identified markedly reduced expression of COMT, a key enzyme involved in the metabolism of catecholamines, including dopamine, epinephrine and norepinephrine. FXS is the most common genetic cause of intellectual disability and autism spectrum disorders. COMT encodes for catechol-o-methyltransferase and its association with neuropsychiatric disorders and cognitive function has been extensively studied. We observed a significantly reduced level of COMT in in FXS human neural progenitors and neurons, as well as hippocampal neurons from Fmr1 null mice. We show that deficits in COMT were associated with an altered response in an assay of dopaminergic activity in Fmr1 null mice. These findings demonstrate that loss of FMRP downregulates COMT expression and affects dopamine signaling in FXS, and supports the notion that targeting catecholamine metabolism may be useful in regulating certain neuropsychiatric aspects of FXS.

Effect of kava (Piper methysticum) on peripheral gene expression among individuals with generalized anxiety disorder: A post hoc analysis of a randomized controlled trial.

Kava is a South Pacific plant-based medicine with anxiolytic properties, but little is known about the impact kava has on gene expression or whether gene expression can serve as a marker of kava response. This study aimed to determine whether kava treatment alters the expression of genes with physiological relevance to anxiety pathophysiology and whether the baseline expression of these physiologically relevant genes modifies the efficacy of kava treatment. In this post hoc analysis, we examined the expression of 48 genes relevant to the pathophysiology of anxiety collected from a double-blind randomized controlled trial that assessed the efficacy of kava treatment in generalized anxiety disorder. Peripheral blood gene expression was measured in 71 (34 kava, 37 placebo) adults at baseline and in 40 (19 kava, 21 placebo) after 8 weeks of treatment by reverse transcription polymerase chain reaction (PCR). Results revealed that kava decreased the expression of a subunit of the GABAA -rho receptor gene (GABRR2) and catechol-O-methyltransferase (COMT), a gene related to catecholamine metabolism. Kava efficacy was not found to be modified by baseline (pretreatment) expression of relevant genes. Although these results did not withstand statistical correction for multiple comparisons and require external validation, they support the notion that kava's mechanism of action includes interaction with GABAergic and catecholaminergic systems.

The Effect of Genetic Variation on the Sensitivity to Opioid Analgesics in Patients With Postoperative Pain: An Updated Meta-analysis.

BACKGROUND: Responsiveness to opioid analgesics differs among patients with acute postoperative pain. OBJECTIVE: Our study presents the most recent evidence on the effect of genetic variations on postoperative pain, opioid consumption, nausea, and vomiting in patients treated with opioids. STUDY DESIGN: An updated systematic review and meta-analysis on the association between single-nucleotide polymorphisms and opioids administered to patients with acute postoperative pain. METHODS: PubMed, Embase, ISI Web of Science, and the Cochrane Library databases were searched for articles published from February 1, 2014, through December 31, 2021. RESULTS: Added to the previous meta-analysis, 39 studies (a total of 7,455 patients) were included in the final meta-analysis. Highlights of the findings include: 1) human µ-opioid receptor gene 118G allele carriers required more opioids during the first postoperative 24 hours (standard mean difference [SMD] = -0.27; 95% CI,-0.40 to -0.14; P < 0.0001) and 48 hours (SMD = -0.52; 95% CI, -0.83 to -0.20; P = 0.001), and reported higher pain scores during the first 24 hours but not at the 48-hour postoperative period (SMD = -0.09, 95% CI, -0.15 to -0.03; P = 0.002) compared to homozygous 118AA patients. 2) patients with the CYP3A4 *1G allele required fewer opioids during the first 24-hour postoperative period (SMD = 0.59; 95% CI, 0.05 to 1.14; P = 0.03) compared to patients with the homozygous CYP3A4*1/*1 allele. 3) Adenosine triphosphate-binding cassette subfamily B member-1 (ABCB1) 3435T allele carriers required more opioids during the 48-hour postoperative period (SMD = -0.21; 95% CI, -0.38 to -0.04; P = 0.02) compared to homozygous CC carriers. 4) Catechol-O-methyl transferase 158A allele carriers required fewer opioids during the first 24-hour postoperative period (SMD = 0.33; 95% CI, 0.15 to 0.51; P = 0.0004) compared to homozygous GG carriers. No significant differences were observed in patients with CYP2D6*10 and ABCB1 G2677A/T genetic polymorphisms. LIMITATIONS: Several loci were not analyzed in detail due to insufficient clinical data. Furthermore, nongenetic factors that affected analgesic efficacy and the clinical outcome of postoperative pain were not discussed and were not the aim of this meta-analysis. CONCLUSIONS: In combination with previous systematic reviews and meta-analyses, our results indicate that the A118G allele variant of OPRM1 and the *1*1G allele variant of CYP3A4 have a profound influence on individual differences in opioid reactivity in patients with postoperative pain. Our results, together with the identification of additional single nucleotide polymorphisms in future studies, may provide a theoretical basis for precise clinical analgesia. KEY WORDS: Single nucleotide polymorphism, postoperative pain, opioid, meta-analysis.

Prognostic and immunomodulatory roles of schizophrenia-associated genes HTR2A, COMT, and PRODH in pan-cancer analysis and glioma survival prediction model.

Background: The shortened life expectancy in schizophrenia (SCZ) patients may be correlated with most cancers, yet there is heterogeneity in the studies examining these correlations. This study explored the expression of SCZ-related genes (HTR2A, COMT, and PRODH) in pan-cancer analysis. It helped to enhance the mechanistic understanding of the SCZ-cancer relationship and their immune mechanisms at the genetic level. Additionally, this study established a survival prediction model for glioblastoma and low-grade glioma (GBMLGG). Methods and results: SCZ-associated genes (HTR2A, COMT, and PRODH) were subjected to pan-cancer analysis. COX regression analysis and survival analysis were carried out for differentially expressed genes in multiple cancers, and finally, GBMLGG was derived as the focus for further detailed analysis. The immune scores and immune cell infiltration analyses were performed. All three genes were considerably linked with immune infiltration in GBMLGG, consistent with survival analysis. Based on the immunocyte analysis, it was observed that CD8+ T cells might be critically involved in the survival of GBMLGG. Genomic heterogeneity studies identified correlations of three genes with GBMLGG in tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH). HTR2A and COMT were significantly negatively correlated in TMB. Furthermore, it was found that HTR2A had a significant positive correlation with MATH, whereas PRODH had a significant negative correlation with MATH. Accordingly, a survival prediction model was constructed for GBMLGG using these three genes and clinical data, with better results obtained when evaluated in two separate datasets. Finally, gene expression validation and further immunocyte analysis were carried out in the single-cell RNA sequencing (scRNA-seq) data of glioma. Conclusion: SCZ-associated genes (HTR2A, COMT, and PRODH) were significantly differentially expressed in the carcinogenesis and survival of multiple cancers. The up or downregulation of gene expression varied across cancer types. In the GBMLGG analysis, upregulation of HTR2A and COMT was significantly positively correlated with carcinogenesis, while the opposite was noted for PRODH. Furthermore, a negative correlation was found between the upregulation of HTR2A and COMT and the survival of GBMLGG, and the opposite was also noted for PRODH. As reflected in the immunocyte analysis, abnormal expression of the three genes might be linked with CD8+ T cell infiltration, which might be critically involved in the survival of GBMLGG patients. The expression of HTR2A and COMT may inversely affect the efficacy of immunotherapy through the TMB pathway and further affect the prognosis of patient survival. The expression of HTR2A might positively indicate the degree of tumor heterogeneity through MATH and further affect the survival and prognosis of patients. The negative correlation of PRODH led to the opposite effect. Finally, the constructed survival prediction model demonstrated good predictive value, which was well validated in scRNA-seq analysis.

Acute effects of Δ9-tetrahydrocannabinol (THC) on resting state connectivity networks and impact of COMT genotype: A multi-site pharmacological fMRI study.

BACKGROUND: Cannabis produces various acute psychotropic effects, with marked individual differences. Cannabis use is a risk factor for developing psychotic disorders. The main component responsible for these effects is Δ9-tetrahydrocannabinol (THC). Here we investigated the neural basis of acute THC effects and its modulation by catechol-methyl-transferase (COMT) Val158Met genotype. METHODS: Resting state functional MRI data of healthy occasional cannabis users were combined and re-analyzed from three double-blind, placebo-controlled, within-subject pharmacological functional magnetic resonance imaging studies (total N=87). Functional connectivity after placebo and THC was compared in three functional networks (salience, executive and default mode network) and a network implicated in psychosis (the hippocampus-midbrain-striatum network). COMT genotype modulation of subjective effects and connectivity was examined. RESULTS: THC reduced connectivity in the salience network, specifically from the right insula to both the left insula and anterior cingulate cortex. We found a trend towards decreased connectivity in the hippocampus-midbrain-striatum network after THC. COMT genotype modulated subjective effects of THC, with strongest dysphoric reactions in Met/Met individuals. In addition, reduced connectivity after THC was demonstrated in the hippocampus-midbrain-striatum network of Met/Met individuals only. CONCLUSIONS: In this large multisite study we found that THC robustly decreases connectivity in the salience network, involved in processing awareness and salient information. Connectivity changes in the hippocampus-midbrain-striatum network may reflect the acute psychotic-like effects of THC. COMT genotype modulation of THC's impact on subjective effects and functional connectivity provides further evidence for involvement of prefrontal dopamine levels in the acute effects of cannabis.

Effect of OPRM1/COMT gene polymorphisms on sufentanil labor analgesia: a cohort study based on propensity score matching.

Background: This study investigated the use of COMT G1947A and OPRM1 A118G polymorphisms as predictive markers for sufentanil epidural analgesia. Methods: The visual analogue scale (VAS) score, and sufentanil consumption of 136 pairs of parturients using sufentanil with lidocaine and ropivacaine for epidural analgesia were used for analysis. Results: OPRM1 AG/GG had lower VAS score difference between fifth and 0 min (1.55 vs 1.87; p = 0.012) and higher consumption (19.65 µg vs 17.11 µg; p = 0.049) than AA carriers. COMT GA/AA had higher VAS score difference than GG carriers (1.86 vs 1.55; p = 0.021). Conclusion: Sufentanil may provide better epidural labor analgesia in OPRM1 AA and COMT GA/AA carriers compared with OPRM1 AG/GG and COMT GG carriers. Clinical Trial Registration: ChiCTR1900026897 (Chinese Clinical Trial Center Registry).