Citations

Abstract Coronavirus disease 2019 (Covid-19) has affected millions of people and may disproportionately affect those with hypertension and diabetes. Because of inadequate methods in published systematic reviews, the prevalence of diabetes and hypertension and associated risks of poor outcomes in Covid-19 patients are unknown. We searched databases from December 1, 2019, to April 6, 2020, and selected observational peer-reviewed studies in English of patients with Covid-19. Independent reviewers extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of evidence. We included 65 (15 794 participants) observational studies at moderate to high risk of bias. Overall prevalence of diabetes and hypertension was 12% (95% confidence interval [CI], 10-15; n = 12 870; I2: 89%), and 17% (95% CI, 13-22; n = 12 709; I2: 95%), respectively. In severe Covid-19, the prevalence of diabetes and hypertension were 18% (95% CI, 16-20; n = 1099; I2: 0%) and 32% (95% CI, 16-54; n = 1078; I2: 63%), respectively. Unadjusted relative risk for intensive care unit admission and mortality were 1.96 (95% CI, 1.19-3.22; n = 8890; I2: 80%; P = .008) and 2.78 (95% CI, 1.39-5.58; n = 2058; I2: 75%; P = .0004) for diabetics; and 2.95 (95% CI, 2.18-3.99; n = 1737; I2: 0%; P < .001) and 2.39 (95% CI, 1.54-3.73; n = 3107; I2: 66%; P < .001) for hypertensives. Neither diabetes (1.50; 95% CI, 0.90-2.50; n = 1991; I2: 74%; P = .119) nor hypertension (1.48; 95% CI, 0.99-2.23; n = 2023; I2: 69%; P = .058) was associated with severe Covid-19. In conclusion, the risk of intensive care unit admission and mortality for patients with diabetes or hypertension who developed Covid-19 is increased compared with those without these comorbidities. PROSPERO registration number CRD42020176582.

Abstract Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance‐based variant filtering. PPP1R13L encodes inhibitor of apoptosis‐stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months‐9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene‐disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel‐based genetic testing for paediatric DCM.

We identified a potentially novel homozygous duplication involving the promoter region and exons 1–4 of the gene encoding type 2 cardiac ryanodine receptor ( RYR2 ) that is responsible for highly penetrant, exertion-related sudden deaths/cardiac arrests in the Amish community without an overt phenotype to suggest RYR2- mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). Homozygous RYR2 duplication (RYR2-DUP) induced pluripotent stem cell cardiomyocytes (iPSC-CMs) were generated from 2 unrelated patients. There was no difference in baseline Ca 2+ handling measurements between WT-iPSC-CM and RYR2-DUP-iPSC-CM lines. However, compared with WT-iPSC-CMs, both patient lines demonstrated a dramatic reduction in caffeine-stimulated and isoproterenol-stimulated (ISO-stimulated) Ca 2+ transient amplitude, suggesting RyR2 loss of function. There was a greater than 50% reduction in RYR2 transcript/RyR2 protein expression in both patient iPSC-CMs compared with WT. Delayed afterdepolarization was observed in the RYR2-DUP-iPSC-CMs but not in the WT-iPSC-CMs. Compared with WT-iPSC-CMs, there was significantly elevated arrhythmic activity in the RYR2-DUP-iPSC-CMs in response to ISO. Nadolol, propranolol, and flecainide reduced erratic activity by 8.5-fold, 6.8-fold, and 2.4-fold, respectively, from ISO challenge. Unlike the gain-of-function mechanism observed in RYR2- mediated CPVT, the homozygous multiexon duplication precipitated a dramatic reduction in RYR2 transcription and RyR2 protein translation, a loss of function in calcium handling, and a calcium-induced calcium release apparatus that is insensitive to catecholamines and caffeine.

Abstract Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein [LDL] and high‐density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels ( P < 5 × 10 −8 ) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

AbstractSchwann cells are the nerve ensheathing cells of the peripheral nervous system. Absence, loss and malfunction of Schwann cells or their myelin sheaths lead to peripheral neuropathies such as Charcot-Marie-Tooth disease in humans. During Schwann cell development and myelination chromatin is dramatically modified. However, impact and functional relevance of these modifications are poorly understood. Here, we analyzed histone H2B monoubiquitination as one such chromatin modification by conditionally deleting the Rnf40 subunit of the responsible E3 ligase in mice. Rnf40-deficient Schwann cells were arrested immediately before myelination or generated abnormally thin, unstable myelin, resulting in a peripheral neuropathy characterized by hypomyelination and progressive axonal degeneration. By combining sequencing techniques with functional studies we show that H2B monoubiquitination does not influence global gene expression patterns, but instead ensures selective high expression of myelin and lipid biosynthesis genes and proper repression of immaturity genes. This requires the specific recruitment of the Rnf40-containing E3 ligase by Egr2, the central transcriptional regulator of peripheral myelination, to its target genes. Our study identifies histone ubiquitination as essential for Schwann cell myelination and unravels new disease-relevant links between chromatin modifications and transcription factors in the underlying regulatory network.

AbstractCoronavirus disease 2019 (COVID-19) has affected millions of people across the world but disproportionately and severely affects persons with metabolic disorders such as obesity, diabetes mellitus, and hypertension. In this brief review, we discuss the pathways of immune dysregulation that may lead to severe COVID-19 in persons with metabolic conditions.