Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia.

BACKGROUND: There is an increasing recognition that the pathophysiology of mental disorders could be the result of deregulation of synaptic plasticity with alterations of neurotrophins. The valine (Val)66-to-methionine (Met) variant, located in the pro brain-derived neurotrophic factor (BDNF) sequence, has been extensively studied through linkage and association approaches in several psychiatric disorders. METHODS: We performed a meta-analysis restricted to individual case-control studies in different categories of mental disorders and BDNF Val66Met polymorphism. We included data from 39 case-control studies encompassing psychiatric phenotypes: eating disorders, substance-related disorders, mood disorders, and schizophrenia, among others. RESULTS: The association of Val66Met was confined to three diagnoses: substance-related disorders, eating disorders, and schizophrenia. The Val/Met and the Met/Met genotypes increase the risk for eating disorders up to 33%, while these same genotypes confer a 21% protective effect in substance-related disorders. The homozygous carriers Met/Met showed a 19% increased risk of schizophrenia with respect to the heterozygous state. CONCLUSIONS: The study confirms the association of Val66Met to substance-related disorders, eating disorders, and schizophrenia. It remains to be determined if other variants in tight linkage disequilibrium with Val66Met could configure an extended functional haplotype that would explain observed discrepancies in risk estimations across studies.     

In comparison: 1.064 μm-1.318 μm Nd-YAG continuous wave lasers. In vitro and in vivo experiments for endoscopic tumour therapy in the gastrointestinal tract

In in vitro and animal experiments the tissue effects of the 1.318m Nd-YAG laser were compared to those of the standard 1.064m Nd-YAG laser in order to evaluate the advantages of the new wavelength with a ten times higher absorption in water for gastroenterological tumour treatment. Under irradiation parameters related to clinical endoscopic practice, the laser of the wavelength 1.318m needs for both vaporization and coagulation significantly less energy than the 1.064m laser. Since vaporization at 1.318m is always accompanied by a higher coagulation effect compared to 1.064m the risk of late necrosis and resulting perforation appears to be increased.     

Clinical symptoms in fibromyalgia are associated to catechol-O-methyltransferase (COMT) gene Val158Met polymorphism

Abstract

1.?Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. The aim of this study was to explore the frequency and clinical significance of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism in a large cohort of Turkish patients with FMS.

2.?The study included 379 FMS patients and 290 controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses.

3.?The genotype frequencies of Val158Met polymorphism showed a small difference between FMS patients and healthy controls (p?=?0.047), however, the Met/Met genotype was significantly higher in FMS patients than healthy controls (p?=?0.016). No difference was observed for allele frequencies between two groups. Stratification analysis according to clinical features for this disease reveals that weight, FMS Impact Questionnaire score, algometry and Raynaud’s syndrome, were detected to have statistically significant associations with Val158Met polymorphism (p?=?0.037, p?=?0.042, p?=?0.039 and p?=?0.033, respectively). Pain sensitivity, measured by algometry, was statistically higher in patients with Met/Met genotype than the patients with Val/Val and Val/Met genotypes (p?=?0.017).

4.?The results of this study suggested that COMT gene Val158Met polymorphism is positively associated with FMS and play a relevant role in the clinical symptoms of the disease.     

Mutaciones y variaciones estructurales en el gen catecol-O-metiltransferasa de los pacientes que exhiben dolor quirúrgico persistente crónico

ObjectivesMutations in the exon 4 of the COMT gene are associated with chronic persistent surgical pain (CPSP). Especially COMT mutated allele G472A (Val158Met) associated with CPSP patients is reported in different ethnic population. The purpose of this study is to evaluate the prevalence of genetic mutations and structural variations in exon 4 of COMT that can be related to the appearance of CPSP in patients under sternotomy.Materials and methodsOne hundred patients with American Society of Anesthesiologists (ASA) physical status grades i, ii and iii, who underwent sternotomy procedures, were selected to assess the development and magnitude of the CPSP evaluated with pain questionaries’ at the end of three months after surgery. This was correlated with COMT allele presence. The exon 4 of COMT gene (that contains the G472A allele) was studied. The polymerase chain reaction (PCR) products were sequenced and mutated sequences were deposited in GenBank®. The structural analysis of COMT was performed using ProCheck® and distortions of three-dimensional tertiary structural orientation was evaluated with root-mean-square deviation (RMSD) score.ResultsGenetic analysis carried out through PCR showed 220 bp amplicons. The 25% of patients with CPSP showed a Numeric Rating Scale (NRS) > 4 pain score. The 20% of these patients have known Val158Met mutation, 5% of patients showed novel mutations c.382C>G, c.383G>C, p.(Arg128Ala). The mutations in COMT gene contributed major structural variations in COMT leading to the formation of inactive COMT that correlates with CPSP.ConclusionThe results of the present study showed that both novel and previously reported mutations in COMT gene has strong association with CPSP.     

CircKIF4A靶向调控miR-384表达对卵巢癌SKOV3细胞增殖和凋亡的影响

Objective?To explore the effect of circKIF4A on the proliferation and apoptosis of ovarian cancer SKOV3 cells and its regulatory mechanism on miR-384. Methods?The qRT-PCR method was used to detect the expression of circKIF4A and miR-384 in ovarian cancer tissues and adjacent tissues. si-NC, si-circKIF4A, miR-NC, miR-384 mimics, si-circKIF4A and anti-miR-NC, si-circKIF4A and anti-miR-384 were transfected into SKOV3 cells respectively. The qRT-PCR method was used to detect the expression of circKIF4A and miR-384 in SKOV3 cells. MTT experiment and flow cytometry experiment were used to detect cell proliferation and apoptosis respectively. The dual luciferase reporter experiment was used to detect the targeting relationship between circKIF4A and miR-384. Results?Compared with adjacent tissues, the expression level of circKIF4A in ovarian cancer tissues was increased [(1.00±0.06), (4.28±0.32)] (t=62.915, P＜0.05), and the expression level of miR-384 was decreased [(1.00± 0.05), (0.43±0.03)] (t=61.047, P<0.05). After transfection with si-circKIF4A, the OD value of SKOV3 cells was decreased [(0.75±0.05), (0.41±0.03)] (t=17.493, P＜0.05), and the apoptosis rate was increased [(6.36±0.53)%, (23.19± 2.21)%] (t=22.216, P<0.05). After transfection of miR-384 mimics, the OD value of SKOV3 cells was decreased [(0.73±0.05), (0.47±0.04)] (t=12.182, P＜0.05), and the apoptosis rate was increased [(7.53±0.41)%, (19.11)±1.06)%] (t=30.567, P<0.05). The dual luciferase report experiment confirmed that circKIF4A could adsorb miR-384 and can act as a sponge molecule for miR-384. After co-transfection with si-circKIF4A and anti-miR-384, the OD value of SKOV3 cells was increased [(0.40±0.04), (0.65±0.03)] (t=15.000, P＜0.05), and the apoptosis rate was decreased [(25.20± 2.21)%, (10.37±0.86)%] (t=18.761, P＜0.05). Conclusion?Inhibition of circKIF4A expression could negatively regulate the expression of miR-384, thereby inhibiting the proliferation of ovarian cancer cells and inducing apoptosis.     

PARP1 rs1136410 Val762Ala contributes to an increased risk of overall cancer in the East Asian population: a meta-analysis

ObjectivesTo investigate the association between poly(ADP-ribose) polymerase 1 (PARP1) rs1136410 Val762Ala and cancer risk in Asian populations, as published findings remain controversial.MethodsThe PubMed and EMBASE databases were searched, and references of identified studies and reviews were screened, to find relevant studies. Meta-analyses were performed to evaluate the association between PARP1 rs1136410 Val762Ala and cancer risk, reported as odds ratio (OR) and 95% confidence interval (CI).ResultsA total of 24 studies with 8 926 cases and 15 295 controls were included. Overall, a significant association was found between PARP1 rs1136410 Val762Ala and cancer risk in East Asians (homozygous: OR 1.19, 95% CI 1.06, 1.35; heterozygous: OR 1.10, 95% CI 1.04, 1.17; recessive: OR 1.13, 95% CI 1.02, 1.25; dominant: OR 1.13, 95% CI 1.06, 1.19; and allele comparison: OR 1.09, 95% CI 1.03, 1.15). Stratification analyses by race and cancer type revealed similar results for gastric cancer among the Chinese population.ConclusionThe findings suggest that PARP1 rs1136410 Val762Ala may be significantly associated with an increased cancer risk in Asians, particularly the Chinese population.     

Phenotypic characterization and predictive analysis of p.Asp47Asn LDL receptor mutation associated with Familial Hypercholesterolemia in a Chilean population

BackgroundFamilial hypercholesterolemia (FH) is an inherited disorder mainly caused by mutations in the LDL receptor (LDL-R) and characterized by elevation of low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease.ObjectiveIn this study, we evaluated the clinical phenotype of the p.Asp47Asn, described as an uncertain pathogenic variant, and its effect on the structure of LDL-R and ligand interactions with apolipoproteins.Methods27 children and adolescents with suspected FH diagnosis were recruited from a pediatric endocrinology outpatient clinic. Blood samples were collected after 12 h fasting for lipid profile analysis. DNA sequencing was performed for six FH-related genes by Ion Torrent PGM platform and copy number variation by MLPA. For index cases, a familial cascade screening was done restricted to the same mutation found in the index case. In silico analysis were developed to evaluate the binding capacity of LDL-R to apolipoproteins B100 and E.ResultsLipid profile in children and adolescents demonstrated higher LDL-C levels in p.Asp47Asn carriers compared to the wild type genotype. In silico analysis predicted a reduction in the binding capacity of the ligand-binding modules LA1-2 of p.Asp47Asn LDL-R for ApoB100 and ApoE, which was not produced by local structural changes or folding defects but as a consequence of a decreased apparent affinity for both apolipoproteins.ConclusionThe clinical phenotype and the structural effects of p.Asp47Asn LDL-R mutation suggest that this variant associates to FH.     

High prevalence of polymorphisms of angiotensin-converting enzyme (I/D) and endothelial nitric oxide synthase (Glu298Asp) in patients with systemic sclerosis

PURPOSE: Systemic sclerosis is characterized by progressive microvascular occlusion and fibrosis and by an imbalance in the fibrinolytic system. In vivo and in vitro studies suggest that the renin-angiotensin system partly regulates vascular fibrinolytic balance. Angiotensin II increases the production and secretion of plasminogen activator inhibitor-1, while angiotensin-converting enzyme (ACE) contributes to reduced production of tissue plasminogen activator and endothelial nitric oxide synthesis by bradykinin degradation. The aim of our study was to investigate the effects of ACE insertion/deletion (I/D) and endothelial nitric oxide synthase (eNOS) Glu298Asp (G894-->T) and T-786-->C polymorphisms in patients with systemic sclerosis. SUBJECTS AND METHODS: We studied 73 consecutive patients (47 with limited and 26 with diffuse cutaneous systemic sclerosis) and 112 control subjects. ACE I/D and eNOS polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The ACE I/D and the eNOS G894-->T polymorphisms were more common in patients than in controls (for the ACE D allele: odds ratio [OR] = 3.4; 95% confidence interval [CI]: 1.5 to 7.9; P = 0.003; for the eNOS T allele: OR = 1.9; 95% CI: 1.0 to 3.4; P = 0.04). There was no association between the eNOS T-786-->C polymorphism and systemic sclerosis. CONCLUSIONS: Our findings of an increased risk of systemic sclerosis in ACE D and eNOS 894T allele carriers suggest that these polymorphisms may contribute to the pathogenesis of the disease.     

环氧合酶-2-1195G/A和锰超氧化物歧化酶9Ala/Val基因多态性与高脂饮食的交互作用及其与溃疡性结肠炎的关系

目的 探讨环氧合酶-2-1195G/A(COX-2-1195G/A)和锰超氧化物歧化酶9Ala/Val(MnSOD9Ala/Val)基因多态性与高脂饮食的交互作用及其与溃疡性结肠炎(UC)的关系。方法 采用病例-对照研究的方法,以750例UC患者及750例健康对照者的外周血白细胞为样本,采用聚合酶链反应(PCR)技术分析COX-2-1195G/A和MnSOD9Ala/Val基因多态性。结果 UC组和对照组COX-2-1195G/A(A/A)基因型的分布频率分别为49.07%和21.20%,MnSOD9Ala/Val(V/V)基因型的分布频率分别为50.13%和22.40%,差异均有统计学意义(P均＜0.01)。COX-2-1195G/A(A/A)基因型(OR=3.5808,95%CI=1.8062～5.3478)和MnSOD9Ala/Val(V/V)基因型(OR=3.4828,95%CI=1.9137～5.5496)者患UC的风险均显著增加。基因突变的协同分析结果显示,COX-2-1195G/A(A/A)/MnSOD9Ala/Val(V/V)基因型者在UC组和对照组中的分布频率分别为40.67%和8.40%,差异有统计学意义(P＜0.01),COX-2-1195G/A(A/A)/MnSOD9Ala/Val(V/V)基因型者患UC的风险显著增加(OR=7.5655,95%CI=4.1849～11.2037)。UC组高脂饮食率显著高于对照组(49.73%比20.13%,P＜0.01),高脂饮食与COX-2-1195G/A(A/A)(γ=11.81821)和 MnSOD9Ala/Val(V/V)(γ=9.0107)基因型均有交互作用。结论 COX-2-1195G/A(A/A)和MnSOD9Ala/Val(V/V)基因型及高脂饮食是UC的易患因素,基因多态性与高脂饮食的交互作用增加了UC的发病风险。     

Glutathione S-transferase P1 and lung function in patients with alpha1-antitrypsin deficiency and COPD

BACKGROUND: The glutathione S-transferase P1 (GSTP1) gene is involved in detoxification of electrophilic substances of tobacco smoke. A polymorphism at nucleotide 315 of this gene alters its enzymatic activity. OBJECTIVE: We analyzed the association between the variability in the GSTP1 gene and impairment in lung function in smokers with and without alpha(1)-antitrypsin (AAT) deficiency and COPD.Population and method: The study population consisted of 99 patients with smoking-related COPD and 69 patients with AAT deficiency; 198 healthy volunteers provided the frequency of the different polymorphisms in the general population. GSTP1 genotyping was performed by a real-time polymerase chain reaction amplification assay. RESULTS: The frequency (0.28) of the 105Val polymorphism was identical in COPD patients and the general population. However, the frequency was significantly increased (0.44) in patients with AAT deficiency (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.17 to 3.72 compared to control subjects; and OR, 2.41; 95% CI, 1.27 to 4.59 compared to COPD). FEV(1) percentage of predicted was significantly impaired in AAT-deficient carriers of 105Val. This effect was not observed in COPD patients. CONCLUSIONS: These findings suggest that the frequency of the GSTP1 105Val polymorphism is increased in patients with AAT deficiency. Globally, GSTP1 genotypes, age, and tobacco smoking explained 41% of total FEV(1) percentage of predicted variability in patients with AAT deficiency. The modulatory role of GSTP1 in lung disease has only been observed in smokers lacking AAT.