MetMet Genotype Research Articles

Association study of the BDNF gene polymorphism (G196A) with overweight/obesity among women from Northwest of Iran

BackgroundObesity is a health problem defined by surplus body fat accumulation and is one of the leading causes of morbidity and mortality. Earlier studies indicated the influence of brain-derived neurotrophic factor (BDNF) molecular alterations in the development of obesity. One of these variations is the G196A single nucleotide polymorphism (Val66Met; SNP rs6265), which impairs intracellular trafficking and reduces the secretion of BDNF. In this study, we evaluated the possible association of G196A polymorphism of the BDNF gene with body mass index (BMI) among women from the Iranian Azeri Turkish ethnic group. Four hundred eighty-four women including 343 women with obesity or overweight and 141 age-sex and ethnically matched healthy controls were genotyped for G196A SNP of BDNF gene by applying polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) method. The association of this polymorphism with BMI was evaluated using analysis of covariance (ANCOVA), and the comparison of alleles and genotypes frequencies between patients (obese and/or overweight participants) and healthy controls was carried out using logistic regression models.ResultsIndividuals carrying Met-Met genotype have a significantly lower mean of BMI in comparison to those carrying non-Met/Met polymorphisms (P = 0.0138).ConclusionsIn this study, the association of the Val66Met polymorphism of the BDNF gene with BMI as an obesity trait has been confirmed among the women from the Northwest of Iran.

The role of single nucleotide polymorphism of val66met (rs6265) of the brain-derived neurotropic factor in formation of endpoints after st-segment elevation myocardial infarction

Abstract Background The single nucleotide polymorphism (SNP) Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene is a possible candidate that is associated with the development of psychopathology and combines it with cardiovascular events. Purpose To research the possible associations of single-nucleotide polymorphism of Val66Met BDNF gene with the occurrence of endpoints after 6 months of follow-up after ST segment elevation myocardial infarction (STEMI). Methods 256 acute STEMI patients after successful primary percutaneous coronary intervention (PCI) were enrolled in the study. TIMI III blood flow restoring through culprit artery was determined. The study of SNP of Val66Met (rs6265) of the BDNF gene was performed by real-time polymerase chain reaction. The emotional state of the patients and its relationship with stress were assessed with the questionnaire “Depression, Anxiety and Stress-21”. All acute STEMI patients received adjuvant treatment due to current ESC recommendations. All procedures performed in the study involving human participants were in accordance with the ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and approved by the local ethics committee. Written inform consent was obtained from each patient. The primary endpoint was combined event (follow-up major adverse cardiac events – MACEs and hospitalization) that occurred within 6-month of the discharge from the hospital. MACEs were defined as the composite of CV death, recurrent angina, newly diagnosed heart failure. Results The frequency of genotypes Val66Met gene for BDNF in STEMI patients (n=256) was the following: 66ValVal=74.2% (n=190), 66ValMet + 66MetMet – 25.8% (n=66). The 66ValMet + 66MetMet polymorphism in the BDNF gene, stress and anxiety on 10–14 days before the event, as well as reduced left ventricular ejection fraction (LVEF), were independently associated with combined 6 months clinical end point after STEMI. Severity of depression according to depression scale was more profound in individuals with 66ValMet+66MetMet polymorphysms in BDNF gene (P=0.045) than in patients with 66ValVal genotype. Univariate and multivariate linear regressions has shown that 66ValMet+66MetMet genotype in BDNF gene, anxiety and stress before event, LVEF had independent power on dependent variable entitled combined end point after 6 month observation for STEMI patients with successful revascularization (P=0.0395). Kaplan-Meier curves demonstrated that STEMI patients with 66ValVal genotype in BDNF gene had a lower accumulation of combined end point compared with acute STEMI patients with 66ValMet+66ValMet polymorphism (Cox-criterion, P=0.019; log-rang criterion, P=0.03). Conclusion The Val66Met polymorphism in BDNF gene was found as an independent predictor for combined 6-month clinical end points after acute STEMI treated primary PCI. Funding Acknowledgement Type of funding source: None

Clinical and genetic predictors of the severity and activity of paranoid schizophrenia

Clinical symptoms, course and outcomes of paranoid schizophrenia are polymorphic. Reliable predictors of severity and activity of schizophrenic process could provide clinicians important prognostic information for adequate and timely implementation of therapeutic and rehabilitative measures. Overall, 206 patients with paranoid schizophrenia were examined. Clinical predictors were collected from hospital records and interviews. BDNF gene Val66Met polymorphism (rs6265 G>A), DRD2 gene C939T polymorphism (rs6275C>T) and 5-HTR2A gene T102C polymorphism (rs6313 T>C) were studied as potential markers of prognosis for paranoid schizophrenia. Results of research testify that the DRD2 gene C939T polymorphism and 5-HTR2A gene T102C polymorphism cannot be used as predictors of the severity and activity of paranoid schizophrenia. The MetMet genotype of BDNF gene Val66Met polymorphism can be used as marker of favorable prognosis for paranoid schizophrenia. Schizoid, epileptoid, psychasthenic and conformal accentuation of personality in the premorbid, early onset of psychosis, paranoid and hallucinatory-paranoid variants of onset predicted more expressed severity of paranoid schizophrenia. These prognostic factors can be taken into account in clinical practice.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Protective Role of Maternal P.VAL158MET Catechol-O-Methyltransferase Polymorphism against Early-Onset Preeclampsia and its Complications.

SummaryBackgroundUp until now there have been contradictory data about the association between p.Val158Met catechol-O-methyltransferase (COMT) polymorphism and risk of preeclampsia (PE). The goal of this study was to assess the potential correlation between p.Val158Met COMT polymorphism and risk of early-onset PE, risk of a severe form of early-onset PE, as well as risk of small-for-gestational-age (SGA) complicating PE.MethodsThe study included 47 early-onset PE patients and 47 control cases. Forty-seven early-onset PE patients were grouped by disease severity (33 patients with a severe form and 14 patients without severe features) and secondly by size for gestational age (12 patients with appropriate-for-gestational-age (AGA) and 35 patients with SGA size). p.Val158Met polymorphism was genotyped by PCR-RFLP analysis.ResultsAllele analysis showed significant difference in COMT allele distribution between early-onset PE and control group as well as early-onset PE SGA and controls (p=0.04057 and p=0.0411 respectively). A statistically significant distribution difference between the severe form and form without severe features of early-onset PE patients was not observed (p>0.05). The highest difference observed was in the allele recessive model where COMT MetMet genotype was associated with decreased risk of early-onset PE (OR=0.281; 95%CI = 0.092–0.7836) and PE complications including severe early-onset PE (OR= 0.304; 95%CI=0.086–0.944) and SGA early-onset PE (OR=0.284; 95%CI=0.081–0.874).ConclusionsCOMT may be used as a candidate gene for early-onset PE and its severe form and SGA complications.

DNA repair gene XRCC3 Thr241Met polymorphism and susceptibility to glioma: A case-control study.

The DNA repair gene, X-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism may be associated with a susceptibility to glioma. The present study aimed to investigate the association between the XRCC3 Thr241Met polymorphism and the potential susceptibility to gliomas. A hospital-based case-control study was conducted, which included a total of 886 patients with glioma and 886 healthy control subjects. Peripheral blood samples were extracted and the polymerase chain reaction-restriction fragment length polymorphism method was performed to analyze the genotypes. The glioma patients had a significantly higher frequency of the XRCC3 241 MetMet genotype [odds ratio (OR) = 1.62; 95% confidence interval (CI): 1.09–2.41; P=0.02] compared with the control subjects. When stratified by the grade of the glioma, the patients with stage IV glioma (according to the World Health Organization classification) had a significantly higher frequency of the XRCC3 241 MetMet genotype (OR=1.61; 95% CI: 1.06–2.44; P=0.03). When stratified by the histology of the glioma, there was no significant difference in the distribution of each genotype. The findings of the present study indicate that the XRCC3 Thr241Met polymorphism is associated with a susceptibility to glioma.

Effect of BDNF Val66Met Polymorphism on Normal Variability of Executive Functions

Associations of BDNF Val66Met polymorphism with such components of executive functions as verbal fluency, working memory, attention set shifting, and response inhibition were evaluated. A total of 401 healthy volunteers were genotyped. The effect of polymorphism on working memory during the counting test was detected. The test performance in heterozygotic carriers was much worse than in homozygotic ones. Individuals with the MetMet genotype demonstrated the best results, presumably due to molecular mechanisms compensating for the neuropeptide secretion deficiency.

Catechol O-methyltransferase and monoamine oxidase A genotypes, and plasma catecholamine metabolites in bipolar and schizophrenic patients

Metabolites of dopamine and norepinephrine measured in the plasma have long been associated with symptomatic severity and response to treatment in schizophrenic, bipolar and other psychiatric patients. Plasma concentrations of catecholamine metabolites are genetically regulated. The genes encoding enzymes that are involved in the synthesis and degradation of these monoamines are candidate targets for this genetic regulation. We have studied the relationship between the Val158Met polymorphism in catechol O-methyltransferase gene, variable tandem repeat polymorphisms in the monoamine oxidase A gene promoter, and plasma concentrations of 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid in healthy control subjects as well as in untreated schizophrenic and bipolar patients. We found that the Val158Met substitution in catechol O-methyltransferase gene influences the plasma concentrations of homovanillic and 3,4-dihydroxyphenylacetic acids. Although higher concentrations of plasma homovanillic acid were found in the high-activity ValVal genotype, this mutation did not affect the plasma concentration of 3-methoxy-4-hydroxyphenylglycol. 3,4-dihydroxyphenylacetic acid concentrations were higher in the low-activity MetMet genotype. Interestingly, plasma values 3-methoxy-4-hydroxyphenylglycol were greater in schizophrenic patients and in bipolar patients than in healthy controls. Our results are compatible with the previously reported effect of the Val158Met polymorphism on catechol O-methyltransferase enzymatic activity. Thus, our results suggest that this polymorphism, alone or associated with other polymorphisms, could have an important role in the genetic control of monoamine concentration and its metabolites.

COMT Genotype Influences the Effect of Alcohol on Blood Pressure: Results From the COMBINE Study

Heavy drinking can cause chronic hypertension, possibly due to effects on the autonomic nervous system. Catechol- O-methyltransferase (COMT) inactivates catecholamines, and a G to A substitution in codon 108 in the soluble COMT mRNA (or codon 158 in the membrane-bound form) substitutes methionine for valine and alters enzyme activity. We evaluated the association of COMT genotype at this locus with blood pressure (BP) in 839 alcohol-dependent individuals before and during participation in an alcoholism treatment trial. Hierarchical linear models were used to account for within-subject correlation on repeated BP measurements, and findings were adjusted for age, gender, ethnicity, alcohol use, body mass index, current smoking, hypertension history, and study site. Relative to those with the val-val genotype, those with the met-met genotype had higher adjusted systolic (+4.9 mm Hg, P < 0.01) and diastolic (+3.2 mm Hg, P < 0.01) BP at baseline. Those with the val-met genotype did not significantly differ from the val-val genotype. Changes in BP between baseline and 4 weeks of alcohol treatment also differed by genotype. Relative to the val-val genotype, the met-met genotype had a greater reduction in adjusted systolic pressure (-3.9 mm Hg, P < 0.01) and diastolic pressure (-2.8 mm Hg, P < 0.01). Corresponding relative reductions for the val-met genotype were -2.2 mm Hg systolic (P = 0.070) and -1.5 mm Hg diastolic (P < 0.05). Findings suggest that alcohol-induced BP elevation may be related to the effects of catecholamines and their genetically determined inactivation.

Sleep and COMT Polymorphism in ADHD Children: Preliminary Actigraphic Data

To examine whether COMT (catechol-O-methyltransferase) polymorphism modulates aspects of sleep in children diagnosed with attention-deficit/hyperactivity disorder (ADHD). Nightly sleep actigraphic recordings during a double-blind, placebo-controlled, crossover clinical study (1 week of 0.5 mg/kg MPH; 1 week of placebo) were obtained for 34 children, 7.4 to 12 years old, diagnosed with ADHD (DSM-IV). Diagnosis was generated by the Diagnostic Interview Schedule for Children and was confirmed by multidisciplinary consensus. Children who were Val allele carriers had poorer sleep continuity compared with children with the Met-Met genotype while receiving a placebo and while receiving methylphenidate. The findings of the present study support the hypothesis that sleep disturbances in children with ADHD are related to the underlying pathophysiology of the disorder.

BDNF Val66Met Polymorphism Is Associated with Body Mass Index in Healthy Adults

Although recent studies suggest a possible relationship between the brain-derived neurotrophic factor Val66Met polymorphism and eating disorders, no study has examined the possibility that the Met-Met genotype is associated with a lower body mass index (BMI) in healthy individuals. We examined this possibility in 481 adults (age range 18–82 years) without significant medical or psychiatric history. After adjusting for gender, analysis of covariance showed that persons with the Met-Met genotype had a lower BMI than those with the Val-Met/Val-Val genotypes (22.28 ± 3.77 vs. 24.72 ± 4.81). A similar, though nonsignificant, trend emerged when comparing all three genotypes separately. These findings suggest a possible relationship between Val66Met polymorphism and BMI in healthy adults. Further work is needed to clarify possible mechanisms for this relationship.

Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health

Catechol-O-methyltransferase plays a central role in the metabolism of biogenic amines such as norepinephrine, dopamine and serotonin. Functional studies have demonstrated a dose relationship between ValMet genotypes and catechol-O-methyltransferase activity. Compared with the ValVal genotype, the ValMet and MetMet genotypes result in two- and four-fold reductions in catechol-O-methyltransferase activity, respectively. Two recent reports have observed the association between the MetMet genotype and risk of anxiety in adult populations. We examined the association between the ValMet genotypes and propensity to anxiety across adolescence. Participants were drawn from an eight-wave study of the mental and behavioural health of over 2000 young Australians followed from 14 to 24 years of age (Victorian Adolescent Health Cohort Study, 1992 to present). DNA was received from 962 participants using a cheek swab collection method. The odds of reporting persistent episodic anxiety (phobic avoidance, panic attacks) were doubled among carriers of the MetMet genotype (odds ratio 2.0, 95% confidence interval 1.1-3.4, P=0.014). A dose relationship between additional copies of the Met allele and persistent episodic anxiety was also observed (1.5, 1.1-1.94, P=0.007). Stratification by sex showed that the risk effect of the Met allele was among females only. No association was observed for measures of neuroticism, persistent generalized anxiety, or a composite measure of psychiatric distress. These data replicate previous findings suggesting association between the ValMet polymorphism and specific expressions of anxiety among females.

CatecholO-Methyltransferase Polymorphism and Eye Tracking in Schizophrenia: A Preliminary Report

This study examined associations between functional polymorphism (Val(108/158) Met) in the catechol O-methyltransferase (COMT) gene and eye tracking measures in schizophrenia. Predictive pursuit and closed-loop gains of 62 patients with schizophrenia and 53 healthy comparison subjects with Val-Val, Val-Met, and Met-Met genotypes were compared. There was a significant diagnosis-by-genotype interaction: patients with the Met-Met genotype showed poor predictive pursuit. The Met-Met genotype in healthy subjects was associated with significantly higher predictive pursuit gain values than the Val-Val genotype in healthy subjects. The COMT genotype explained about 10% of the variance in each group's predictive pursuit performance. These preliminary data suggest that the COMT gene is associated with predictive eye tracking performance in healthy subjects. Predictive pursuit abnormality in schizophrenia is not attributable to the Val allele. These findings suggest a complex interaction with other etiological factors (e.g., another gene), and/or with prefrontal cortical dopaminergic activity.