Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations

Background Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk. Results To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 (https://forge2.altiusinstitute.org/), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology. Conclusion In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS.

Contribution of causal factors to disease burden: how to interpret attributable fractions

What proportion of the risk in a given population is attributable to a risk factor? The population attributable fraction (PAF) answers this question. “Attributable to” is understood as “due to”, which makes PAFs closely related to the concept of potential impact or potential benefits of reducing the exposure. The PAF is a tool at the border between science and decision making. PAFs are estimated based on strong assumptions and the calculations are data intensive, making them vulnerable to gaps in knowledge and data. Current misconceptions include summing up PAFs to 100% or subtracting a PAF for a factor from 100% to deduce what proportion is left to be explained or prevented by other factors. This error is related to unrecognised multicausality or shared causal responsibility in disease aetiology. Attributable cases only capture cases in excess and should be regarded as a lower bound for aetiological cases, which cannot be estimated based on epidemiological data alone (exposure-induced cases). The population level might not be relevant to discuss prevention priorities based on PAFs, for instance when exposures concentrate in a subgroup of the population, as for occupational lung carcinogens and other workplace hazards. Alternative approaches have been proposed based on absolute rather than relative metrics, such as estimating potential gains in life expectancy that can be expected from a specific policy (prevention) or years of life lost due to a specific exposure that already happened (compensation).

Life course epidemiology and analysis

Life course epidemiology approaches disease aetiology and prevention from the perspective of risk and protective factors that influence health and disease throughout the lifespan. The integration of a life course approach to epidemiologic research is central for identifying effective policies and programmes to promote population health and health equity. This chapter will introduce life course concepts and models and analytical approaches for research on life course determinants of health. It will discuss threats to causal inference, approaches for overcoming these difficulties, and future directions in life course epidemiology. For example, in addition to expanding epidemiologic research with a life course perspective to include people with diverse life experiences, new areas of development include life course research extending beyond one human lifespan to include intergenerational and transgenerational life course research, as well as the application of innovative methods.

Small Airway Susceptibility to Chemical and Particle Injury

Small airways (SA) in humans are commonly defined as those conducting airways <2 mm in diameter. They are susceptible to particle- and chemical-induced injury and play a major role in the development of airway disease such as COPD and asthma. Susceptibility to injury can be attributed in part to structural features including airflow dynamics and tissue architecture, but recent evidence may indicate a more prominent role for cellular composition in directing toxicological responses. Animal studies support the hypothesis that inherent cellular differences across the tracheobronchial tree, including metabolic CYP450 expression in the distal conducting airways, can influence SA susceptibility to injury. Currently, there is insufficient information in humans to make similar conclusions, prompting further necessary work in this area. An understanding of why the SA are more susceptible to certain chemical and particle exposures than other airway regions is fundamental to our ability to identify hazardous materials, their properties, and accompanying exposure scenarios that compromise lung function. It is also important for the ability to develop appropriate models for toxicity testing. Moreover, it is central to our understanding of SA disease aetiology and how interventional strategies for treatment may be developed. In this review, we will document the structural and cellular airway regional differences that are likely to influence airway susceptibility to injury, including the role of secretory club cells. We will also describe recent advances in single-cell sequencing of human airways, which have provided unprecedented details of cell phenotype, likely to impact airway chemical and particle injury.

Role of cardiac magnetic resonance in stratifying the prognosis of patients with pulmonary arterial hypertension

Background Pulmonary arterial hypertension (PAH) is a rare disease characterized by a complex remodeling of heart structures. Cardiac magnetic resonance (CMR) is the gold standard for a non-invasive evaluation of right ventricle (RV) volumes and mass. Purpose To define the relationship between clinical, functional, biochemical, haemodynamic and CMR parameters and survival in patients with PAH. Methods Consecutive patients with PAH referred to our centre underwent clinical, functional, brain natriuretic peptide (BNP) plasma levels, haemodynamic and CMR evaluation. All patients were treated according to current guidelines. Univariate Cox analysis for survival was performed. Parameters with a p-value <0.1 at the univariate analysis were included in the multivariate analysis. Results One hundred forty-seven patients with PAH (mean age 49±17 years, 69% female) were included in the study. Etiology of PAH was: idiopathic/heritable (49%), associated with connective tissue disease (19%), congenital heart disease (12%), portal hypertension/HIV infection (12%) and pulmonary veno-occlusive disease (8%). Thirty-six patients died during follow-up. Parameters significantly associated with mortality at the univariate analysis were age [Hazard Ratio (95% Confidence Interval): 1.043 (1.020–1.067); p<0.001], six-minute walk test (6MWT) [HR: 0.995 (0.993–0.998); p<0.001], WHO-functional class [HR: 2.489 (1.025–6.041); p=0.044], idiopathic-heritable-congenital heart disease aetiology [HR: 0.182 (0.085–0.389); p<0.001], connective tissue disease aetiology [HR: 2.274 (1.099–4.704); p=0.027], pulmonary veno-occlusive disease aetiology [HR: 5.864 (2.328–14.773); p<0.001], right atrial pressure [HR: 1.098 (1.032–1.169); p=0.003], pulmonary artery oxygen saturation [HR: 0.947 (0.921–0.975); p<0.001], BNP levels [HR: 2.214 (1.213–4.039); p=0.010], RV wall thickness [HR: 0.633 (0.399–1.006); p=0.053], RV end diastolic volume [HR: 1.012 (1.003–1.021); p=0.007], RV end systolic volume [HR: 1.014 (1.003–1.024); p=0.011]. Parameters independently associated with mortality at the multivariate analysis were age [HR: 1.035 (1.006–1.064); p=0.018], idiopathic-heritable-congenital heart disease aetiology [HR: 0.355 (0.146–0.860); p=0.022], pulmonary veno-occlusive disease aetiology [HR: 3.129 (1.071–9.143); p=0.037], pulmonary artery oxygen saturation [HR: 0.953 (0.919–0.989); p=0.011], RV wall thickness [HR: 0.527 (0.300–0.927); p=0.026], RV end systolic volume [HR: 1.016 (1.003–1.029); p=0.014]. Conclusion RV wall thickness and RV end-systolic volume are associated with prognosis in patients with PAH independently from clinical and haemodynamic characteristics. These parameters may be used in the overall risk stratification of PAH patients. FUNDunding Acknowledgement Type of funding sources: None.

Paediatric Idiopathic Intracranial Hypertension (IIH)—A Review

Paediatric idiopathic intracranial hypertension (IIH), is a rare but important differential diagnosis in children presenting with papilloedema. It is characterised by raised intracranial pressure in the absence of an identifiable secondary structural or systemic cause and is, therefore, a diagnosis of exclusion. In the adult population, there is a strong predilection for the disease to occur in female patients who are obese. This association is also seen in paediatric patients with IIH but primarily in the post-pubertal cohort. In younger pre-pubertal children, this is not the case, possibly reflecting a different underlying disease aetiology and pathogenesis. Untreated IIH in children can cause significant morbidity from sight loss, chronic headaches, and the psychological effects of ongoing regular hospital monitoring, interventions, and medication. The ultimate goal in the management of paediatric IIH is to protect the optic nerve from papilloedema-induced optic neuropathy and thus preserve vision, whilst reducing the morbidity from other symptoms of IIH, in particular chronic headaches. In this review, we will outline the typical work-up and diagnostic process for paediatric patients with suspected IIH and how we manage these patients.

Zebrafish as a Model for the Study of Lipid-Lowering Drug-Induced Myopathies

Drug-induced myopathies are classified as acquired myopathies caused by exogenous factors. These pathological conditions develop in patients without muscle disease and are triggered by a variety of medicaments, including lipid-lowering drugs (LLDs) such as statins, fibrates, and ezetimibe. Here we summarise the current knowledge gained via studies conducted using various models, such as cell lines and mammalian models, and compare them with the results obtained in zebrafish (Danio rerio) studies. Zebrafish have proven to be an excellent research tool for studying dyslipidaemias as a model of these pathological conditions. This system enables in-vivo characterization of drug and gene candidates to further the understanding of disease aetiology and develop new therapeutic strategies. Our review also considers important environmental issues arising from the indiscriminate use of LLDs worldwide. The widespread use and importance of drugs such as statins and fibrates justify the need for the meticulous study of their mechanism of action and the side effects they cause.

Development and uptake of an online systematic review platform: the early years of the CAMARADES Systematic Review Facility (SyRF)

Preclinical research is a vital step in the drug discovery pipeline and more generally in helping to better understand human disease aetiology and its management. Systematic reviews (SRs) can be powerful in summarising and appraising this evidence concerning a specific research question, to highlight areas of improvements, areas for further research and areas where evidence may be sufficient to take forward to other research domains, for instance clinical trial. Guidance and tools for preclinical research synthesis remain limited despite their clear utility. We aimed to create an online end-to-end platform primarily for conducting SRs of preclinical studies, that was flexible enough to support a wide variety of experimental designs, was adaptable to different research questions, would allow users to adopt emerging automated tools and support them during their review process using best practice. In this article, we introduce the Systematic Review Facility (https://syrf.org.uk), which was launched in 2016 and designed to support primarily preclinical SRs from small independent projects to large, crowdsourced projects. We discuss the architecture of the app and its features, including the opportunity to collaborate easily, to efficiently manage projects, to screen and annotate studies for important features (metadata), to extract outcome data into a secure database, and tailor these steps to each project. We introduce how we are working to leverage the use of automation tools and allow the integration of these services to accelerate and automate steps in the systematic review workflow.

Cervical lymphadenitis as a result of (Hijab) pin prick in north of Jordan

Introduction. Cervical lymph nodes are lymph nodes found in the neck. Hijab is a head cover worn by some Muslim women in the presence of any adult male outside of their immediate family, which usually covers the head, neck and chest. It is strictly forbidden to Muslim woman to unveil any single hair of her head, so they use many pins around the head to fix their Hijab. Often, while using pins they are self-pricked. Aim. The main aim of our work is to reveal a new cause of lymphadenopathy, which is not known till now. Material and methods. Retrospective study during the past five years among seventy-five female outpatients, visited our Oral and Maxillofacial clinic in dental department. Our data was collected according to medical history of patients; all female patients with cervical lymphadenopathy were using (A hijab). Results. Data collected of 75 female patients. Lymphadenopathy causes were various. Most of these causes resulted from nonspecific lymphadenitis (67 patients), 4 tuberculosis, 2 lymphoma, 2 cat scratch disease. Aetiology of 67 nonspecific lymphadenitis was 40 patients of dental cause, 10 of sore throat, 7 of acne vulgaris, 3 of mild facial injuries, and 7 of (Hijab pin pricks). Conclusion. Hijab pin prick cervical lymphadenitis in Islamic communities is not uncommon and, unexplained cervical lymphadenitis should be considered as potential cause.