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1.
LINE-1 in Obesity and Cardiometabolic Diseases: A Systematic Review.
Lopes, LL, Bressan, J, Peluzio, MDCG, Hermsdorff, HHM
Journal of the American College of Nutrition. 2019;(5):478-484
Abstract
Epigenetic mechanisms may play an important role in the etiology of obesity and cardiometabolic diseases, by activating or silencing the related-genes. Scientific evidence has suggested that LINE-1 methylation is associated with body composition and obesity-related diseases, including insulin resistance, type 2 diabetes mellitus, and cardiovascular disease (CVD). It also has been evaluated as predictor of weight loss. The studies' results are still conflicting, and positive and negative associations have been found to LINE-1 methylation regarding adiposity and cardiometabolic markers. Overall, this review presents observational (cross-sectional and longitudinal) studies and interventions (diet, exercises, and bariatric surgery) that evaluated the relationship of the LINE-1 methylation with obesity, weight loss, dyslipidemias, hypertension, insulin resistance, CVD, and metabolic syndrome. TEACHING POINTS Epigenetic mechanisms may play an important role in the etiology of obesity and cardiometabolic diseases. Many studies have related methylation of LINE-1 with cardiometabolic diseases; however, the results are still controversial. The relationship between the etiology of chronic diseases and the methylation of LINE-1 is not fully elucidated. With advances in epigenetic studies, related mechanisms may be early biomarkers in weight change and cardiometabolic risk.
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Effect of selective BET protein inhibitor apabetalone on cardiovascular outcomes in patients with acute coronary syndrome and diabetes: Rationale, design, and baseline characteristics of the BETonMACE trial.
Ray, KK, Nicholls, SJ, Ginsberg, HD, Johansson, JO, Kalantar-Zadeh, K, Kulikowski, E, Toth, PP, Wong, N, Cummings, JL, Sweeney, M, et al
American heart journal. 2019;:72-83
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Abstract
After an acute coronary syndrome (ACS), patients with diabetes remain at high risk for additional cardiovascular events despite use of current therapies. Bromodomain and extra-terminal (BET) proteins are epigenetic modulators of inflammation, thrombogenesis, and lipoprotein metabolism implicated in atherothrombosis. The BETonMACE trial tests the hypothesis that treatment with apabetalone, a selective BET protein inhibitor, will improve cardiovascular outcomes in patients with diabetes after an ACS. DESIGN Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol (≤40 mg/dl for men, ≤45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo. Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (80%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. Assumptions include a primary event rate of 7% per annum in the placebo group and median follow-up of 1.5 years. Patients will be followed until at least 250 primary endpoint events have occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalone. SUMMARY BETonMACE will determine whether the addition of the selective BET protein inhibitor apabetalone to contemporary standard of care for ACS reduces cardiovascular morbidity and mortality in patients with type 2 diabetes. Results are expected in 2019.
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R106C TFG variant causes infantile neuroaxonal dystrophy "plus" syndrome.
Catania, A, Battini, R, Pippucci, T, Pasquariello, R, Chiapparini, ML, Seri, M, Garavaglia, B, Zorzi, G, Nardocci, N, Ghezzi, D, et al
Neurogenetics. 2018;(3):179-187
Abstract
TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient's fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking.
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High Intensity Resistance Training Methods with and without Protein Supplementation to Fight Cardiometabolic Risk in Middle-Aged Males: A Randomized Controlled Trial.
Kemmler, W, Wittke, A, Bebenek, M, Fröhlich, M, von Stengel, S
BioMed research international. 2016;:9705287
Abstract
Time-effective protocols may potentially increase people's compliance with exercise. The purpose of this paper was to compare the relative effects of 16 weeks of high intensity (resistance) training (HIT) with and without protein supplementation (HIT&P) and HVHIT (high volume/high intensity training) versus a nontraining control group on cardiometabolic risk factors. One hundred and twenty untrained males 30-50 years old were randomly assigned to 3 subgroups: (a) a HIT group; (b) a HIT&P group, and (c) a waiting-control group (phase I) that crossed over to (d) high volume/high intensity training (HVHIT) during the second study phase. HIT was defined as "single set to failure protocol" while HVHIT consistently applied two sets. Protein supplementation provided an overall intake of 1.5 g/kg/body mass. Primary study endpoint was the metabolic syndrome Z-Score (MetS-Z-Score). MetS-Z-Score significantly improved in all exercise groups (p ≤ 0.001) with no significant difference between HIT, HIT&P, and HVHIT (p ≥ 0.829). However, all the exercise groups differed significantly from the CG (p < 0.001) which deteriorated significantly (p = 0.039). In conclusion, all exercise protocols were similarly effective in improving cardiometabolic risk factors. Thus, HIT may be the best choice for people with low time budgets looking to improve their cardiometabolic health.
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The Impact of Physical Activity and Dietary Measures on the Biochemical and Anthropometric Parameters in Obese Children. Is There Any Genetic Predisposition?
Zlatohlávek, L, Hubáček, JA, Vrablík, M, Pejšová, H, Lánská, V, Češka, R
Central European journal of public health. 2015;:S62-6
Abstract
AIM: The aim of the study was to monitor the importance of laboratory, anthropometric and genetic determination of the presence of risk factors for atherosclerosis, obesity, dyslipidemia and components of the metabolic syndrome in obese children and the response to dietary and regimen interventions in obese children. METHODS As a part of the study, 353 paediatric patients (46% boys, 54% girls) with obesity and dyslipidemia, aged 8-16 years, participated in a one-month lifestyle intervention programme. The programme involved a reduction of energy intake and supervised exercise programme consisting of 5 exercise units per day, each 50 minutes long. Standard biochemical methods were applied, including Lp-PLA2, as were anthropometric measurements and genetic analyses. RESULTS During the reduction programme for the children there was a statistically significant decrease in all anthropometric indicators of bodyweight (p<0.001) as well as in lipid parameters and LpLPA2. Carriers of the FTO GG genotype and/or MC4R CC genotype lost significantly more body weight in comparison to non-carriers. CONCLUSION Child obesity is an important social issue. After regimen interventions, there is weight loss as well as an improvement in biochemical parameters. There are individuals with a genetic predisposition for obesity, as well as individuals with a better response to regimen interventions which could, among other things, be determined by the FTO and MC4R genotypes.
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Haplotyping strategy highlights the specificity of FTO gene association with polycystic ovary syndrome in Tunisian women population.
Ben Salem, A, Attaoua, R, Mtiraoui, N, Meddeb, S, Kacem, O, Ajina, M, Souissi, M, Poucheret, P, Normand, C, Mahjoub, T, et al
Gene. 2015;(2):166-70
Abstract
The FTO (fat mass and obesity associated) gene was associated with different metabolic disorders in populations from different origins but with great difference between African and non-African populations. North-African populations combine many genetic backgrounds, among which African, Berber and Caucasian components, which makes North-Africans a good model for studying the genetic association of FTO. In the present investigation we explored the association of FTO gene with polycystic ovary syndrome (PCOS) in a population from Tunisia (n=278). Single nucleotide polymorphisms (SNPs) used in this study were previously associated in non-African populations: rs8050136 (A/C), rs9939609 (A/T), rs9930506 (G/A), or in both African and non-African populations: rs8057044 (A/G). Genotyping was performed by allelic discrimination method on StepOne real-time PCR system or KASPar technology. Linkage disequilibrium (LD) pattern was assessed by HAPLOVIEW and reconstruction of haplotypes was performed by PHASE, while statistical analyses were performed using StatView and GoldenHelix programs. Among the 13 haplotypes in the population, three (h1, h7 and h13) were strongly associated with PCOS notably h13 (P<0.0001, OR95%CI=0.040 [0.005-0.294]) while SNPs display weaker association. Moreover the LD pattern in FTO in the Tunisian population (r(2) index) was intermediary between those of Caucasian and Africans. This highlights the need for studying the genetics of complex disorders in the North-African populations taking into-account the haplotype structure of candidate loci more than SNPs taken alone.
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Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings.
Haack, TB, Rolinski, B, Haberberger, B, Zimmermann, F, Schum, J, Strecker, V, Graf, E, Athing, U, Hoppen, T, Wittig, I, et al
Journal of inherited metabolic disease. 2013;(1):55-62
Abstract
Defects of mitochondrial oxidative phosphorylation constitute a clinical and genetic heterogeneous group of disorders affecting multiple organ systems at varying age. Biochemical analysis of biopsy material demonstrates isolated or combined deficiency of mitochondrial respiratory chain enzyme complexes. Co-occurrence of impaired activity of the pyruvate dehydrogenase complex has been rarely reported so far and is not yet fully understood. We investigated two siblings presenting with severe neonatal lactic acidosis, hypotonia, and intractable cardiomyopathy; both died within the first months of life. Muscle biopsy revealed a peculiar biochemical defect consisting of a combined deficiency of respiratory chain complexes I, II, and II+III accompanied by a defect of the pyruvate dehydrogenase complex. Joint exome analysis of both affected siblings uncovered a homozygous missense mutation in BOLA3. The causal role of the mutation was validated by lentiviral-mediated expression of the mitochondrial isoform of wildtype BOLA3 in patient fibroblasts, which lead to an increase of both residual enzyme activities and lipoic acid levels. Our results suggest that BOLA3 plays a crucial role in the biogenesis of iron-sulfur clusters necessary for proper function of respiratory chain and 2-oxoacid dehydrogenase complexes. We conclude that broad sequencing approaches combined with appropriate prioritization filters and experimental validation enable efficient molecular diagnosis and have the potential to discover new disease loci.
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FTO T/A and peroxisome proliferator-activated receptor-γ Pro12Ala polymorphisms but not ApoA1 -75 are associated with better response to lifestyle intervention in Brazilians at high cardiometabolic risk.
Curti, ML, Rogero, MM, Baltar, VT, Barros, CR, Siqueira-Catania, A, Ferreira, SR
Metabolic syndrome and related disorders. 2013;(3):169-76
Abstract
BACKGROUND The role of obesity-related polymorphisms on weight loss and inflammatory responses to interventions is unclear. We investigated associations of certain polymorphisms with response to a lifestyle intervention. METHODS This 9-month intervention on diet and physical activity included 180 Brazilians at high cardiometabolic risk, genotyped for the fat mass and obesity-associated (FTO) T/A, peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala, and ApoA1 -75G/A polymorphisms. Changes in metabolic and inflammatory variables were analyzed according to these polymorphisms. RESULTS The intervention resulted in lower energy intake and higher physical activity. Anthropometric measurements, 2-hr plasma glucose, insulin, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) improved significantly for the total sample, and these benefits were similar among genotypes. Only variant allele carriers of FTO T/A decreased fasting plasma glucose after intervention (99.9±1.3 to 95.6±1.4 mg/dL, P=0.021). Mean blood pressure reduced after intervention in variant allele carriers of the PPARγ Pro12Ala (109.4±2.1 to 101.3±2.1 mmHg, P<0.001). Improvement in lipid variables was not significant after adjustment for medication. Only the reference genotype of PPARγ Pro12Ala increased apolipoprotein A1 (ApoA1) after intervention (134.3±2.4 to 140.6±2.3 mg/dL, P<0.001). Only variant allele carriers of FTO reduced C-reactive protein (CRP) concentration (0.366±0.031 to 0.286±0.029 mg/dL, P=0.023). CONCLUSION In Brazilian individuals, the FTO T/A polymorphism induces a favorable impact on inflammatory status and glucose metabolism. The reference genotype of PPARγ Pro12Ala seems to favor a better lipid profile, while the variant allele decreases blood pressure. Our data did not support benefits of the variant allele of ApoA1 -75G/A polymorphism. Further studies are needed to direct lifestyle intervention to subsets of individuals at cardiometabolic risk.
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Common variant (rs9939609) in the FTO gene is associated with metabolic syndrome.
Zhou, D, Liu, H, Zhou, M, Wang, S, Zhang, J, Liao, L, He, F
Molecular biology reports. 2012;(6):6555-61
Abstract
Recent genome-wide association studies have showed that common variant (rs9939609) in fat mass and obesity associated (FTO) gene was significantly associated with type 2 diabetes through an effect on human body mass index/obesity. Further studies have suggested that this variant was also involved in the development of metabolic syndrome (MetS). However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association between rs9939609 polymorphism and the risk of MetS. Published literature from PubMed, EMBASE and other databases were searched. All studies assessing the association between rs9939609 polymorphism and the risk of MetS were identified. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed-effects model. Thirteen studies (8,370 cases and 23,156 controls) using NCEP ATPIII criteria for MetS were pooled with a meta-analysis. The overall result showed that there was a statistically significant association between rs9939609 polymorphism and MetS risk (OR = 1.11, 95% CI = 1.06-1.17). Subgroup analysis based on ethnicity showed that effect size was only statistically significant in Europeans (OR = 1.11, 95% CI = 1.05-1.16). Eight studies (1,256 cases and 2,551 controls) using IDF criteria for MetS were pooled with a meta-analysis. The overall analysis suggested that rs9939609 polymorphism was significantly associated with MetS risk (OR = 1.32, 95% CI = 1.13-1.54). Subgroup analysis stratified by ethnicity suggested that effect size was only statistically significant in Asians (OR = 1.33, 95% CI = 1.10-1.61). Our results suggested that FTO rs9939609 polymorphism was significantly associated with the increased risk of MetS in European and Asian populations. Mechanistic investigation is also needed to clarify the effect of FTO gene in the predisposition to MetS.
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Genetic variants in FTO associated with metabolic syndrome: a meta- and gene-based analysis.
Wang, H, Dong, S, Xu, H, Qian, J, Yang, J
Molecular biology reports. 2012;(5):5691-8
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Abstract
The objective of this study was to examine the effect of genetic variants in fat mass and obesity associated (FTO) gene on metabolic syndrome (MetS). A systematic literature search was performed and random-effects meta-analysis was used to evaluate genetic variants in FTO with MetS. A gene-based analysis was conducted to investigate the cumulative effects of genetic polymorphisms in FTO. A total of 18 studies from 13 published papers were included in our analysis. Random-effects meta-analysis yielded an estimated odds ratio of 1.19 (95% CI 1.12-1.27; P = 1.38 × 10(-7)) for rs9939609, 1.19 (95% CI 1.05-1.35; P = 0.008) for rs8050136, and 1.89 (95% CI 1.20-2.96; P = 0.006) for rs1421085. The gene-based analysis indicated that FTO is strongly associated with MetS (P < 10(-5)). This association remains after excluding rs9939609, a SNP that was frequently reported to have strong association with obesity and MetS. In this study, we concluded that the FTO gene may play a critical role in leading to MetS. Targeting this gene may provide novel therapeutic strategies for the prevention and treatment of metabolic syndrome.