ABSTRACT Thousands of genes responsible for many diseases and other common traits in humans have been detected by Genome Wide Association Studies (GWAS) in the last decade. However, candidate causal variants found so far usually explain only a small fraction of the heritability estimated by family data, the rest remaining ‘missing’. The most common explanation for this observation is that the missing heritability corresponds to variants, either rare or common, with very small effect, which pass undetected due to a lack of statistical power. We carried out a meta-analysis using data from the NHGRI-EBI GWAS Catalog in order to explore the distribution of gene effects for a set of 59 complex traits, to investigate the factors related to new gene discovery and to quantify their contributions to heritability. With the data obtained we were able to predict the expected distribution of gene effects for 16 traits and diseases including cancer and immune disorders, the missing number of genes yet to be discovered, and the additive contribution of common variants to heritability. Our results indicate that, for most traits, the additive contribution of hundreds or thousands of genes is able to explain the familiar heritability. However, for some traits, the predicted heritability is lower than the familiar one, so that part of the missing heritability cannot be explained by the contribution of common variants with additive effects, and other phenomena ( e.g . dominance or epistasis) should be invoked. AUTHOR SUMMARY The heritability of biological traits refers to the fraction of the phenotypic ( i.e. visible or diagnosable) variability that is explained by the underlying genetic variability. Despite the efforts made to find the genes responsible for complex traits and diseases, most of the heritability explained by the variants found explains only a small fraction of that measured by population and family studies. The remaining ‘missing’ heritability is usually assumed to be due to the additive effect of undetected variants. Here we carried out a meta-analysis using records from a publicly available database of genome-wide studies on humans. With these data, we were able to investigate and make inferences on the nature of heritability and the factors associated to new gene discovery. Our results indicate that increasing population sample size, as well as its diversity, enhances the discovery of new genes, but these have lower and lower effects, contributing little to heritability. We were also able to predict the distribution of gene effects for many traits and the number of variants needed to fully explain the heritability. For some traits, the additive effects of single variants yet to be discovered cannot explain the heritability, suggesting that other sources of variation are involved.
Abstract A 2-tier standardized protocol was designed to test the toxicity of microplastics to planktonic organisms. This approach uses sea urchin (Paracentrotus lividus) and copepod (Acartia clausi) larvae because they are common biological models in marine research, and standard methods for toxicity testing with regulatory applications are available. In Tier I, leachates obtained at a 100 to 1 liquid to solid ratio are tested, and toxic units are calculated using a probit dose–response model to quantify the toxicity of the plastics. In Tier II, which is conducted only if significant toxicity (> 1 toxic unit) is found in Tier I, particles less than 20 μm in size are tested at concentrations between 0.1 and 10 mg L−1, and a toxicity threshold suitable for ranking materials according to their toxicity is obtained from the 10% effect concentration (EC10) values. Results point to chemical additives as being responsible for the toxicity found in certain plastic materials. This process is suitable for both a priori identification of the hazard posed by plastic objects in the aquatic environment, and a posteriori assessment of environmental risk caused by microplastic pollution. The method also provides a quantitative procedure appropriate for ranking plastic materials according to their toxicity to aquatic organisms. Environ Toxicol Chem 2019;38:630–637. © 2018 SETAC Abstract Standard protocol for plastics’ toxicity testing including micronization of plastic objects, Tier I leachate test and calculation of toxic units (toxic units), and Tier II microparticle test and calculation of the toxicity threshold. EC10 = 10% effect concentration.
Until today, numerous studies evaluated the topic of anthocyanins and various types of cancer, regarding the anthocyanins’ preventative and inhibitory effects, underlying molecular mechanisms, and such. However, there is no targeted review available regarding the anticarcinogenic effects of dietary anthocyanins on skin cancers. If diagnosed at the early stages, the survival rate of skin cancer is quite high. Nevertheless, the metastatic form has a short prognosis. In fact, the incidence of melanoma skin cancer, the type with high mortality, has increased exponentially over the last 30 years, causing the majority of skin cancer deaths. Malignant melanoma is considered a highly destructive type of skin cancer due to its particular capacity to grow and spread faster than any other type of cancers. Plants, in general, have been used in disease treatment for a long time, and medicinal plants are commonly a part of anticancer drugs on the market. Accordingly, this work primarily aims to emphasize the most recent improvements on the anticarcinogenic effects of anthocyanins from different plant sources, with an in-depth emphasis on melanoma skin cancer. We also briefly summarized the anthocyanin chemistry, their rich dietary sources in flowers, fruits, and vegetables, as well as their associated potential health benefits. Additionally, the importance of anthocyanins in topical applications such as their use in cosmetics is also given.
Objective: Previous ambulatory blood pressure (BP) monitoring (ABPM) outcome investigations relied upon only a single, low-reproducible 24 h ABPM assessment per participant done at study inclusion. This approach precluded the opportunity to explore the potential reduction in cardiovascular disease (CVD) risk associated with modification of prognostic ABPM-derived parameters by hypertension therapy. The Hygia Project, a research network presently composed of 292 investigators of 40 clinical sites, was specifically designed to investigate, among other primary objectives, whether specific treatment-induced changes in ABPM-derived parameters reduce risk of CVD events. Design and method: This study involved 18,078 persons, 9,769 men/8,309 women, 59.1 ± 14.3 years of age, with baseline BP ranging, according to ABPM criteria, from normotension to hypertension. At inclusion and at every scheduled clinic visit for ABPM (at least annually) during follow-up, BP was assessed at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h. During ABPM, participants kept a diary listing the times of going to bed at night and awakening in the morning. The primary CVD-outcome was the composite of CVD death, myocardial infarction, coronary revascularization, heart failure, and stroke. Results: During a median 5.1-year follow-up, we documented 1,209 events for the primary CVD-outcome. Analyses of therapy-induced changes in clinic and ambulatory BP during follow-up revealed progressive decrease in sleep-time systolic BP (SBP) (adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, cigarette smoking, HDL-cholesterol, hypertension treatment-time, and previous CVD event) was the most significant prognostic marker of CVD event-free survival (hazard ratio 0.73 [95%CI 0.65–0.83] per SD decrease in asleep SBP mean, P < 0.001), independent of changes in office SBP (0.96 [0.87–1.06], P = 0.414) or awake SBP mean (0.92 [0.78–1.09], P = 0.326). Only the progressive increase in the sleep-time relative SBP decline was a marker of survival jointly with diminishing asleep SBP (0.87 [0.77–0.99], P = 0.035). Conclusions: Treatment-induced decrease of asleep SBP mean and increase of sleep-time SBP decline towards more normal dipper BP patterning, two novel hypertension therapeutic targets requiring proper patient evaluation by ABPM, are the most significant independent predictors of reduced CVD morbidity and mortality.
Time of ingestion of hypertension medications can affect circadian patterns of BP, but whether this translates into an effect on clinical outcomes is unknown. Here, in an open-label trial, we randomly assigned 661 patients with CKD either to take all prescribed hypertension medications upon awakening or to take at least one of them at bedtime. We measured 48-hour ambulatory BP at baseline and 3 months after any adjustment in treatment or, at the least, annually. After a median follow-up of 5.4 years, patients who took at least one BP-lowering medication at bedtime had an adjusted risk for total cardiovascular events (a composite of death, myocardial infarction, angina pectoris, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke) that was approximately one-third that of patients who took all medications upon awakening (adjusted HR 0.31; 95% CI 0.21 to 0.46; P < 0.001). Bedtime dosing demonstrated a similar significant reduction in risk for a composite outcome of cardiovascular death, myocardial infarction, and stroke (adjusted HR 0.28; 95% CI 0.13 to 0.61; P < 0.001). Furthermore, patients on bedtime treatment had a significantly lower mean sleep-time BP and a greater proportion demonstrated control of their ambulatory BP (56% versus 45%, P = 0.003). Each 5-mmHg decrease in mean sleep-time systolic BP was associated with a 14% reduction in the risk for cardiovascular events during follow-up (P < 0.001). In conclusion, among patients with CKD and hypertension, taking at least one antihypertensive medication at bedtime improves control of BP and reduces the risk for cardiovascular events.
