catechol-O-methyltransferase Rs4680 Research Articles

Association between Catechol-O-Methyltransferase (COMT) gene rs4680 SNP and rs165599 SNP and schizophrenia: A meta-analysis of case-control studies

The relationship between schizophrenia and single-nucleotide polymorphisms (SNPs) in the Catechol-O-MethylTransferase (COMT) gene has been investigated in numerous research, yielding varying conclusions. The investigation aimed to perform a meta-analysis for the purpose of determining the combined impact measure of the association of the COMT gene rs165599 SNP and ra4680 SNP with schizophrenia. The effect size used to assess the relationship between these two SNPs and schizophrenia was the odds ratio (OR). R studio was used to achieve the pooled ORs. Additionally, for the sake of assessing bias of publications, this paper utilize the Egger's test. Meta-analyses involving 19 independent studies have not revealed a statistically significant association between rs4680 and rs165599 SNPs and schizophrenia; however, the A versus A genetic model regarding rs4680 SNP has demonstrated a positive association with schizophrenia (OR=0.86,95% CI = 0.75-0.99, I= 42%,P= 0.04), which is dependent on two studies. According to this study, there may be no association between the COMT gene rs16599 SNP and rs4680 SNP and the risk of schizophrenia or its psychopathological symptoms.

Cognitive Impairments Related to COMT and Neuregulin 1 Phenotypes as Transdiagnostic Markers in Schizophrenia Spectrum Patients.

Background: Research on the interaction between antipsychotic treatment and cognitive dysfunction in schizophrenia spectrum disorders (SSDs) is extensive, yet the role of genetic polymorphisms in catechol-O-methyltransferase (COMT) and neuregulin 1 (NRG1) remains underexplored. Methods: This study evaluates the impact of COMT (rs4680) and NRG1 (rs3924999 and rs35753505) polymorphisms on cognitive functions in SSD patients. A cross-sectional study was conducted with fifty-four patients, assessed using the Positive and Negative Syndrome Scale (PANSS) and the CNS Vital Signs battery. Results: Significant cognitive function differences were observed across SSD diagnostic categories (p < 0.001). The NRG1 rs35753505 TT genotype was significantly associated with better verbal memory performance compared to the CC genotype (p = 0.03), while no significant differences were observed for other genotypes. The NRG1 rs3924999 AA genotype showed superior reasoning performance compared to AG and GG genotypes (p = 0.01), with AG and GG associated with lower scores (p = 0.01 and p = 0.02, respectively). Additionally, the COMT Val158Met genotype significantly influenced processing speed, with patients at the first episode of psychosis showing higher scores than chronic patients (p = 0.01). Conclusions: These findings suggest that NRG1 and COMT polymorphisms may influence cognitive domains in schizophrenia spectrum disorders, potentially informing personalized treatment and cognitive rehabilitation strategies.

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).

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.

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.

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.

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

BackgroundThe 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 designA 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. ResultsSignificant 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. ConclusionThis 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.

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.

Unraveling Catechol-O-Methyltransferase rs4680 SNP's Role in Patients' Response to Tramadol and Its Adverse Effects: A Pharmacogenetics Insight into Postoperative Pain Management.

Effective postoperative pain management is essential for patient well-being and an efficient healthcare system. Variations in the Catechol O-Methyltransferase (COMT) gene, specifically rs4680, play a crucial role in pain perception and opioid response. This study seeks to elucidate the impact of rs4680 polymorphism on tramadol efficacy and adverse reactions in post-surgical patients. We performed an uncontrolled cohort pharmacogenetics study in which participants underwent postoperative tramadol administration. The frequencies of rs4680 alleles were determined and the association between rs4680 genotypes and the efficacy of tramadol analgesic as pain relief, measured by the Numeric Rating Scale (NRS), was analyzed. Secondary outcomes included tramadol-induced sedation levels, opioid-induced nausea and vomiting, and other adverse effects of tramadol. Data analysis, using IBM SPSS Statistics 23, focused on pain and side effect differences across genotypes, with statistical significance set to p ≤ 0.05. The COMT (rs4680) genotype distribution exhibited a 'G' allele frequency of 41.5% and an 'A' allele frequency of 58.5%, with the AA genotype present in 44% of individuals, adhering to the Hardy-Weinberg equilibrium (p = 0.788). Patients with the AA genotype reported lower pain scores post-tramadol administration across all times examined (p < 0.001), but also experienced statistically significant (p < 0.001) higher incidences of tramadol-induced nausea, vomiting, and sedation. However, GG genotype individuals experienced poor pain relief from tramadol, requiring more supplemental analgesia. These significant findings underscore the critical role of COMT rs4680 polymorphism in response to tramadol and the necessity of a personalized approach to postoperative pain management.

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.

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

IntroductionCatechol-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. MethodsA 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. ResultsIn 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). ConclusionWithin the Chinese population, COMT gene polymorphisms could potentially serve as biomarkers for the symptoms and prognosis of TD patients.

A randomized trial of the effects of COMT inhibition on subjective response to alcohol: Moderation by baseline COMT activity and mediation of alcohol self-administration.

Poor inhibitory control and enhanced subjective response to alcohol are interrelated risk factors for alcohol use disorder (AUD) that share underlying neural substrates, including dopamine signaling in the right prefrontal cortex, a potential target for pharmacological intervention. Cortical dopamine inactivation is primarily regulated by catechol-O-methyltransferase (COMT), an enzyme with large variation in activity as a function of the COMT rs4680 (val158met) single nucleotide polymorphism. In a previous randomized, placebo-controlled trial of the COMT inhibitor tolcapone (200 mg TID) in non-treatment-seeking participants with AUD, we found that tolcapone, relative to placebo, reduced alcohol self-administration only among rs4680 val-allele homozygotes, whose COMT activity is higher than in met-allele carriers. We conducted secondary analyses of the effects of tolcapone and baseline COMT activity, as indexed by both rs4680 genotype and an enzymatic activity assay, on the subjective response to alcohol in a bar-laboratory paradigm among 60 participants in the previous trial. Tolcapone did not affect alcohol-induced stimulation or sedation more than placebo. However, baseline COMT activity moderated the effects of the drug on both outcomes, such that tolcapone-treated participants with higher baseline COMT activity had less stimulation (p = 0.008) and sedation (p = 0.053) than participants with lower baseline COMT activity and those treated with placebo. Additionally, alcohol-induced stimulation significantly mediated the interacting effects of baseline COMT activity and tolcapone on bar-laboratory self-administration. Tolcapone may reduce subjective response to alcohol more effectively among individuals with preexisting high COMT activity an effect that could account for the drug's reduction of alcohol consumption among these individuals.

Association of Catechol-O-Methyl-Transferase and Estrogen Receptors polymorphism with Severity of Temporomandibular Disorder in Iranian Patients

Background: There are many studies which strongly suggest that the pathophysiology of Temporomandibular joint Disorder (TMD) may also be influenced by genetic conditions. The current study was aimed to evaluate the hypothesis that the polymorphism of estrogen receptor genes, estrogen receptor 1 and 2 (ESR1 and ESR2), and the gene Catechol -O-Methyl-Transferase (COMT) could be Predisposing factor for TMD. Methods: In this case-control study, blood sample were taken from 100 TMD diagnosed patients based on Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and 103 healthy individuals as the control group. Tetra ARMS-PCR method was used to amplify and identify COMT rs4680, ESR1 rs1643821, and ESR2 rs1676303 gene polymorphism. Results: ESR1 genotype AA and GA showed significantly increase probability (OR= 4.80, OR=2.98, respectively) of TMD. ESR2 T/T homozygosity was associated with decreased risk for TMD (OR=0.41). The relationship between COMT and TMD was not statistically significant (p&gt;00.05). The relationship between the severity of TMD and ESR1 was significant (p=0.003). According to the inheritance pattern the COMT and ESR1 gene, in the dominant pattern can be susceptible to TMD and in ESR2 gene, in the recessive pattern can be protective to TMD. Conclusion: It seems that SNPs of ESR1 rs1643821 has a susceptible role and ESR2 rs1676303 has a protective role against TMD. Also, we add evidences that various genotype of COMT rs4680 were not statistically different between case and control, but allele A in the dominant inherence pattern can be susceptible to TMD.

Genotypic and Haplotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Gene Polymorphisms with Particular Clinical Symptoms in Schizophrenia.

Catechol-O-methyl transferase (COMT) gene variants are involved in different neuropsychiatric disorders and cognitive impairments, associated with altered dopamine function. This study investigated the genotypic and haplotypic association of COMT rs4680 and rs4618 polymorphisms with the severity of cognitive and other clinical symptoms in 544 male and 385 female subjects with schizophrenia. COMT rs4818 G carriers were more frequent in male patients with mild abstract thinking difficulties, compared to CC homozygotes or C allele carriers. Male carriers of COMT rs4680 A allele had worse abstract thinking (N5) scores than GG carriers, whereas AA homozygotes were more frequent in male subjects with lower scores on the intensity of the somatic concern (G1) item, compared to G carriers. Male carriers of COMT rs4818-rs4680 GA haplotype had the highest scores on the G1 item (somatic concern), whereas GG haplotype carriers had the lowest scores on G2 (anxiety) and G6 (depression) items. COMT GG haplotype was less frequent in female patients with severe disturbance of volition (G13 item) compared to the group with mild symptoms, while CG haplotype was more frequent in female patients with severe then mild symptoms. These findings suggest the sex-specific genotypic and haplotypic association of COMT variants with a severity of cognitive and other clinical symptoms of schizophrenia.

Early life adversity and cardiovascular responses to repeated stress among adolescents: Moderating role of COMT gene rs4680 polymorphism

BackgroundEarly life adversity (ELA) increases the risk of cardiovascular diseases through dysregulation of cardiovascular stress responses manifested by either exaggerated or blunted reactivity. The catechol-O-methyltransferase (COMT) gene rs4680 polymorphism has been identified in gene–environment interaction (G×E) studies to explain individual differences in the effects of ELA on physiological stress responses. However, little is known about whether ELA interacts with COMT gene rs4680 polymorphism to affect cardiovascular responses to repeated stress exposures. ObjectiveThe current study examined the associations between ELA and cardiovascular responses to repeated stress exposures, and the moderating role of COMT rs4680 polymorphism in these associations. MethodsThe childhood trauma questionnaire (CTQ) was administered to 359 junior school students who underwent a two-successive stress exposures protocol with continuous cardiovascular monitoring [heart rate (HR) and systolic and diastolic blood pressure (SBP, DBP)] across four laboratory phases, and their saliva samples for deoxyribonucleic acid (DNA) genotyping were collected. ResultsELA was associated with blunted HR reactivity to the first and second stress exposures, blunted SBP reactivity to the first stress exposure, and attenuated SBP habituation to repeated stress exposures. Moreover, COMT rs4680 moderated these associations, such that the associations between ELA and blunted HR, SBP, and DBP reactivity to the first stress and disrupted DBP habituation to repeated stress exposures only existed in GA/AA genotype carriers but not in GG genotype carriers. ConclusionsThese findings suggest that the A allele of COMT rs4680 is vulnerable to the negative effects of ELA on the developmental dysregulation of stress physiological systems.

Effects of Acute Caffeine Intake on Insulin-Like Growth Factor-1 Responses to Total Sleep Deprivation: Interactions with COMT Polymorphism – A Randomized, Crossover Study

Introduction: Genes encoding catechol-O-methyl-transferase (COMT) and adenosine A2A receptor (ADORA2A) have been shown to influence cognitive performances and responses to caffeine intake during prolonged wakefulness. The rs4680 single-nucleotide polymorphism (SNP) of COMT differentiates on memory score and circulating levels of the neurotrophic factor IGF-1. This study aimed to determine the kinetics of IGF-1, testosterone, and cortisol concentrations during prolonged wakefulness under caffeine or placebo intake in 37 healthy participants, and to analyze whether the responses are dependent on COMT rs4680 or ADORA2A rs5751876 SNPs. Methods: In caffeine (2.5 mg/kg, twice over 24 h) or placebo-controlled condition, blood sampling was performed at 1 h (08:00, baseline), 11 h, 13 h, 25 h (08:00 next day), 35 h, and 37 h of prolonged wakefulness, and at 08:00 after one night of recovery sleep, to assess hormonal concentrations. Genotyping was performed on blood cells. Results: Results indicated a significant increase in IGF-1 levels after 25, 35, and 37 h of prolonged wakefulness in the placebo condition, in subjects carrying the homozygous COMT A/A genotype only (expressed in absolute values [±SEM]: 118 ± 8, 121 ± 10, and 121 ± 10 vs. 105 ± 7 ng/mL for A/A, 127 ± 11, 128 ± 12, and 129 ± 13 vs. 120 ± 11 ng/mL for G/G, and 106 ± 9, 110 ± 10, and 106 ± 10 vs. 101 ± 8 ng/mL for G/A, after 25, 35, and 37 h of wakefulness versus 1 h; p < 0.05, condition X time X SNP). Acute caffeine intake exerted a COMT genotype-dependent reducing effect on IGF-1 kinetic response (104 ± 26, 107 ± 27, and 106 ± 26 vs. 100 ± 25 ng/mL for A/A genotype, at 25, 35, and 37 h of wakefulness vs. 1 h; p < 0.05 condition X time X SNP), plus on resting levels after overnight recovery (102 ± 5 vs. 113 ± 6 ng/mL) (p < 0.05, condition X SNP). Testosterone and cortisol concentrations decreased during wakefulness, and caffeine alleviated the testosterone reduction, unrelated to the COMT polymorphism. No significant main effect of the ADORA2A SNP was shown regardless of hormonal responses. Conclusion: Our results indicated that the COMT polymorphism interaction is important in determining the IGF-1 neurotrophic response to sleep deprivation with caffeine intake (NCT03859882).

COMT rs4680 and DRD2 rs6275 variants and their association with YMRS scores in children with early-onset bipolar disorder

Background and objectivesBipolar disorder (BD) is a clinical status with at least one manic, hypomanic or mixed attacks. Genetic factors take part significantly in early-onset BD (EOBD). Dopamine receptors (DRD) act in neurological mechanisms like motivation, learning, memory, and, control of neuroendocrine signaling. DRD2 receptor has been reported to influence the stability of DRD2 transcript. Catechol-O-Methyl transferase (COMT) inactivates catecholamines and Val158Met variation on COMT has effects on COMT activity. This study aims to explore DRD2 and COMT variants in the clinical development of EOBD. MethodsIn this case-control study, 102 EOBD patients and 168 healthy control subjects were used. DRD2 rs6275 and COMT Val158Met variations were detected by real-time polymerase chain reaction (RT-PCR). Young Mania Rating Scale (YMRS) was utilized to determine the EOBD severity. ResultsFor DRD2 rs6275 and COMT Val158Met polymorphisms, no significant relationship was observed in the genotype and allele frequencies between patient and control groups. Nevertheless, TT genotype carriers of DRD2 rs6275 polymorphism demonstrated significantly increased YMRS scores when compared with CC and CT genotype carriers (p = 0.039). Nevertheless, no significant difference was observed between COMT Val158Met genotypes and YMRS scores. ConclusionsWe suggest that the DRD2 rs6275 TT variant can be associated with symptom severity in children with EOBD and can have a clinical significance in EOBD pathogenesis. However, these results need to be confirmed with larger samples of patient and control groups.

Gender divergent effect of COMT gene rs4680 polymorphism on the association between executive dysfunction and psychotic-like experiences

AimPremorbid cognitive impairments are observed prior to the onset of schizophrenia. Catechol-O-methyltransferase (COMT) rs4680 is associated with psychosis and plays a crucial role in the development of the executive function. In addition, genetic COMT variations and gender affect its enzymatic activity. Therefore, the aim of this study was to evaluate the impact of COMT rs4680 on the relationship between executive dysfunction and psychotic-like experiences (PLEs) in college students, with the additional investigation of the gender difference. MethodsA total of 463 students provided biological samples for DNA analysis and the COMT gene rs4680 polymorphism was discriminated by the improved multiplex ligase detection reaction method. They also completed the Prodromal Questionnaire and the Dysexecutive Questionnaire. ResultsExecutive dysfunction significantly predicted positive PLEs in the total, male and female population (β = 0.515, 0.508 and 0.512, p < 0.001). The results of moderated analysis revealed that COMT rs4680 recessive genetic model (‘AA genotype’ versus ‘G carrier’) moderated the relationship between executive dysfunction and psychotic-like experience in the total and females (p = 0.002 and p <0.001, respectively), but not in males. ConclusionThese findings revealed a female-specific effect of COMT rs4680 on the relationship between executive dysfunction and PLEs in young adults.

No Association between Genetic Variants of the COMT and OPRM1 Genes and Pain Perception among Patients Undergoing Total Hip or Knee Arthroplasty for Primary Osteoarthritis.

Each year approximately 1 million total hip replacements are performed worldwide. The most common indications to choose this procedure are rest pain and pain after activity as well as functional limitations influencing daily activities. Experimental pain is highly variable by individuals, which is partly due to genetics. The aim of the study was to investigate a possible association of the catechol-O-methyltransferase (COMT) and μ-opioid receptor (OPRM1) genotypes with pain perception in patients undergoing total hip replacement and total knee replacement taking into account aspects such as age, sex and diabetes. The study included 207 patients (119 females, 88 males, median age 65 years, range 33–77) that qualified for surgical treatment (total hip replacement and knee arthroplasty) due to osteoarthritis. Pain sensitivity measurement was performed using a standard algometer. The genomic DNA was extracted from the buccal cells.. Single locus analysis was conducted using a general linear model. In the study group, we did not find statistically significant genetic associations between variants of COMT and OPRM1 and pain thresholds/pain tolerance. The analysis of subjective pain perception using the visual analog scale did not show any relationship between the OPRM1 rs1799971A>G variant and COMT rs4680, rs4633, rs4818 and rs6269.

Associations between the COMT rs4680 Gene Polymorphism and Personality Dimensions and Anxiety in Patients with a Diagnosis of Other Stimulants Dependence.

Background: Research on the hypodopaminergic hypothesis of addictions showed that hypodopaminergic activity in males predicted the number of drugs used and is associated with drug-seeking behavior. Variant alleles may cause hypodopaminergic functioning as a result of the reduced density of dopamine receptors, decreased response to dopamine, increased dopamine clearance or metabolism in the reward system. The catechol-O-methyltransferase (COMT) is involved in the metabolism of dopamine. Personality traits may mediate the genetic predisposition to substance use disorders additively by various motivations associated with reward-seeking and regulating negative emotions, and also relate to self-control and environment selection. The aim of the study: The aim of this study was to investigate the association of the rs4680 polymorphism of COMT with personality dimensions and anxiety in patients addicted to stimulants other than cocaine (F15 according to WHO ICD-10 nomenclature) in the case of examined patients amphetamine. Methods: The study was conducted among patients addicted to stimulants other than cocaine (amphetamine). The study group included 247 patients addicted to stimulants (amphetamine) and the control group comprised 280 healthy male volunteers. The real-time PCR method was used to carry out genetic tests; personality dimensions were assessed using the standardized NEO-FFI and state and trait anxiety were assessed with STAI. All analyses were performed using STATISTICA 13. Results: The results of the 2 × 3 factorial ANOVA showed a statistically significant effect of the combined factor COMT rs4680 genotype on the group of patients diagnosed with other stimulants dependence/control (F2,252 = 3.11, p = 0.0465, η2 = 0.024). Additionally, we observed that the results of the 2 × 3 factorial ANOVA showed a statistically significant influence of the combined factor COMT rs4680 on the genotype in the group of patients diagnosis with other stimulants dependence/control (F2,252 = 6.16, p = 0.0024, η2 = 0.047). Conclusions: In our research, the polymorphism G/G COMT rs4680 genotype was associated with higher scores of STAI traits and STAI states in the patients dependent on amphetamine. In the control group we observed no such interactions.