Mapping Novel Pathways in Cardiovascular Disease Using eQTL Data: The Past, Present, and Future of Gene Expression Analysis

Genome-wide association studies (GWAS) have identified genetic variants associated with numerous cardiovascular and metabolic diseases. Newly identified polymorphisms associated with myocardial infarction, dyslipidemia, hypertension, diabetes, and insulin resistance suggest novel mechanistic pathways that underlie these and other complex diseases. Working out the connections between the polymorphisms identified in GWAS and their biological mechanisms has been especially challenging given the number of non-coding variants identified thus far. In this review, we discuss the utility of expression quantitative trait locus (eQTL) databases in the study of non-coding variants with respect to cardiovascular and metabolic phenotypes. Recent successes in using eQTL data to link variants with functional candidate genes will be reviewed, and the shortcomings of this approach will be outlined. Finally, we discuss the emerging next generation of eQTL studies that take advantage of the ability to generate induced pluripotent stem cell lines from population cohorts

Examining the benefits and barriers for the implementation of Net Zero Energy settlements

The transition of the Net Zero Energy (NZE) concept from building to settlement scale has been theoretically approached in a number of studies. This paper examines the benefits and barriers associated with the implementation of the NZE concept at a settlement scale, by adopting a comprehensive approach for the design, construction, and monitoring of NZE settlements that was developed in the EU Horizon 2020 ZERO-PLUS project and implemented in four case studies. First, the ZERO-PLUS approach is presented, followed by an analysis of associated benefits and encountered barriers. Next, the roles of different stakeholders involved in the process are identified through stakeholder analysis. Finally, new dynamics that emerge and are critical to the successful implementation of NZE settlements are discussed. The ZERO-PLUS approach leads to achieving NZE settlements with an initial cost that is on average 16% lower than the cost of a typical NZEB, while achieving a net regulated energy consumption of less than 20 kWh/m2/year and renewable energy production of more than 50 kWh/m2/year. The implementation of NZE settlements revealed two main issues: 1) the external barriers that were raised by the planning policies and regulations; and 2) the challenge of managing and integrating the needs and requirements of project stakeholders. To overcome these barriers while reaping the benefits of the approach, the management of such projects needs to focus from the outset on the establishment of a project management structure that will ensure the coordination and integration of various stakeholders. The use of a standardized collaboration protocol from the preliminary design stage is recommended to facilitate future projects. Simultaneously, regulations need to be updated towards facilitating NZE settlement implementation

Endothelial cell-specific deletion of a microRNA accelerates atherosclerosis

Background and aims: Chronic vascular endothelial inflammation predisposes to atherosclerosis; however, the cell-autonomous roles for endothelial-expressing microRNAs (miRNAs) are poorly understood in this process. MiR-181b is expressed in several cellular constituents relevant to lesion formation. The aim of this study is to examine the role of genetic deficiency of the miR-181b locus in endothelial cells during atherogenesis. Methods and Results: Using a proprotein convertase subtilisin/kexin type 9 (PCSK9)-induced atherosclerosis mouse model, we demonstrated that endothelial cell (EC)-specific deletion of miR-181a2b2 significantly promoted atherosclerotic lesion formation, cell adhesion molecule expression, and the influx of lesional macrophages in the vessel wall. Yet, endothelium deletion of miR-181a2b2 did not affect body weight, lipid metabolism, anti-inflammatory Ly6Clow or the pro-inflammatory Ly6Cinterm and Ly6Chigh fractions in circulating peripheral blood mononuclear cells (PBMCs), and pro-inflammatory or anti-inflammatory mediators in both bone marrow (BM) and PBMCs. Mechanistically, bulk RNA-seq and gene set enrichment analysis of ECs enriched from the aortic arch intima, as well as single cell RNA-seq from atherosclerotic lesions, revealed that endothelial miR-181a2b2 serves as a critical regulatory hub in controlling endothelial inflammation, cell adhesion, cell cycle, and immune response during atherosclerosis. Conclusions: Our study establishes that deficiency of a miRNA specifically in the vascular endothelium is sufficient to profoundly impact atherogenesis. Endothelial miR-181a2b2 deficiency regulates multiple key pathways related to endothelial inflammation, cell adhesion, cell cycle, and immune response involved in the development of atherosclerosis

Maintaining Blood Glucose Levels in Range (70–150 mg/dL) is Difficult in COVID-19 Compared to Non-COVID-19 ICU Patients—A Retrospective Analysis

Beta cell dysfunction is suggested in patients with COVID-19 infections. Poor glycemic control in ICU is associated with poor patient outcomes. This is a single center, retrospective analysis of 562 patients in an intensive care unit from 1 March to 30 April 2020. We review the time in range (70–150 mg/dL) spent by critically ill COVID-19 patients and non-COVID-19 patients, along with the daily insulin use. Ninety-three in the COVID-19 cohort and 469 in the non-COVID-19 cohort were compared for percentage of blood glucose TIR (70–150 mg/dL) and average daily insulin use. The COVID-19 cohort spent significantly less TIR (70–150 mg/dL) compared to the non-COVID-19 cohort (44.4% vs. 68.5%). Daily average insulin use in the COVID-19 cohort was higher (8.37 units versus 6.17 units). ICU COVID-19 patients spent less time in range (70–150 mg/dL) and required higher daily insulin dose. A higher requirement for ventilator and days on ventilator was associated with a lower TIR. Mortality was lower for COVID-19 patients who achieved a higher TIR.Authors would like to acknowledge Chris C. Naum for his assistance with payment of the article processing fee

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease

Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis. Here we show that hepatic disruption of Ldlr with AAV-CRISPR results in severe hypercholesterolemia and atherosclerosis. We further demonstrate that co-disruption of Apob, whose germline loss is embryonically lethal, completely prevented disease through compensatory inhibition of hepatic LDL production. This new concept of metabolic disease modeling by somatic genome editing could be applied to many other systemic as well as liver-restricted disorders which are difficult to study by germline manipulation

Prevalence of multiple non-communicable diseases risk factors among adolescents in 140 countries:A population-based study

BACKGROUND: Modifiable non-communicable disease (NCD) risk factors are becoming increasingly common among adolescents, with clustering of these risk factors in individuals of particular concern. The aim of this study was to assess global status of clustering of common modifiable NCD risk factors among adolescents. METHODS: We used latest available data from nationally representative survey for 140 countries, namely the Global School-based Student Health Survey, the Health Behaviour in School-Aged Children and the longitudinal study of Australian Children. Weighted mean estimates of prevalence with corresponding 95% confidence intervals of nine NCD risk factors - physical inactivity, sedentary behaviour, insufficient fruits and vegetable consumption, carbonated soft drink consumption, fast food consumption, tobacco use, alcohol consumption and overweight/obesity - were calculated by country, region and sex. FINDINGS: Over 487,565 adolescents, aged 11–17 years, were included in this study. According to trend analysis, prevalence of four or more NCD risk factors increased gradually over time. Prevalence of four or more NCD risk factors was 14.8% in 2003–2007 and increased to 44% in 2013–2017, an approximately three-fold increase (44.0%). Similar trends were also observed for three and two risk factors. Large variation between countries in the prevalence of adolescents with four or more risk factors was found in all regions. The country level range was higher in the South-East Asia Region (minimum Sri Lanka = 8%, maximum Myanmar = 84%) than Western Pacific Region (minimum China = 3%, maximum Niue = 72%), European Region (minimum Sweden = 13.9%, maximum Ireland = 66.0%), African Region (minimum Senegal = 0.8%, maximum Uganda = 82.1%) and Eastern Mediterranean Region (minimum Libya = 0.2%, maximum Lebanon = 80.2%). Insufficient vegetable consumption, insufficient fruit consumption and physically inactivity were three of the four most prevalent risk factors in all regions. INTERPRETATION: Our results suggest a high prevalence of four or more NCD risk factors in adolescents globally, although variation was found between countries. Results from our study indicate that efforts to reduce adolescent NCD risk factors and the associated health burden need to be improved. These findings can assist policy makers to target the rollout of country- specific interventions. FUNDING: None

Indoor Air Quality

This is a report from the Air Quality Expert Group to the Department for Environment, Food and Rural Affairs; Scottish Government; Welsh Government; and Department of Agriculture, Environment and Rural Affairs in Northern Ireland, on indoor air quality in the UK. The information contained within this report represents a review of the understanding and evidence available at the time of writing

A TALEN Genome-Editing System for Generating Human Stem Cell-Based Disease Models

SummaryTranscription activator-like effector nucleases (TALENs) are a new class of engineered nucleases that are easier to design to cleave at desired sites in a genome than previous types of nucleases. We report here the use of TALENs to rapidly and efficiently generate mutant alleles of 15 genes in cultured somatic cells or human pluripotent stem cells, the latter for which we differentiated both the targeted lines and isogenic control lines into various metabolic cell types. We demonstrate cell-autonomous phenotypes directly linked to disease—dyslipidemia, insulin resistance, hypoglycemia, lipodystrophy, motor-neuron death, and hepatitis C infection. We found little evidence of TALEN off-target effects, but each clonal line nevertheless harbors a significant number of unique mutations. Given the speed and ease with which we were able to derive and characterize these cell lines, we anticipate TALEN-mediated genome editing of human cells becoming a mainstay for the investigation of human biology and disease

Deep learning enables genetic analysis of the human thoracic aorta

Genome-wide association analyses identify variants associated with thoracic aortic diameter. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in independent samples. Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, identifying 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests and human aortic single nucleus RNA sequencing prioritized genes including SVIL, which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (hazard ratio = 1.43 per s.d., confidence interval 1.32-1.54, P = 3.3 x 10(-20)). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI