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.
2.
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.
3.
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.