Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome with a considerable case fatality rate (∼30%-40%). Health disparities exist with African descent (AD) subjects exhibiting greater mortality than European descent (ED) individuals. Myosin light chain kinase is encoded by MYLK, whose genetic variants are implicated in ARDS pathogenesis and may influence ARDS mortality. As baseline population-specific epigenetic changes, that is, cytosine modifications, have been observed between AD and ED individuals, epigenetic variations in MYLK may provide insights into ARDS disparities. We compared methylation levels of MYLK cytosine-guanine dinucleotides (CpGs) between ARDS patients and intensive care unit (ICU) controls overall and by ethnicity in a nested case-control study of 39 ARDS cases and 75 non-ARDS ICU controls. Two MYLK CpG sites (cg03892735 and cg23344121) were differentially modified between ARDS subjects and controls (P < 0.05; q < 0.25) in a logistic regression model, where no effect modification by ethnicity or age was found. One CpG site was associated with ARDS in patients aged <58 years, cg19611163 (intron 19, 20). Two CpG sites were associated with ARDS in EDs only, gene body CpG (cg01894985, intron 2, 3) and CpG (cg16212219, intron 31, 32), with higher modification levels exhibited in ARDS subjects than controls. Cis-acting modified cytosine quantitative trait loci (mQTL) were identified using linear regression between local genetic variants and modification levels for 2 ARDS-associated CpGs (cg23344121 and cg16212219). In summary, these ARDS-associated MYLK CpGs with effect modification by ethnicity and local mQTL suggest that MYLK epigenetic variation and local genetic background may contribute to health disparities observed in ARDS

Whole-Blood Mitochondrial DNA Copies Are Associated With the Prognosis of Acute Respiratory Distress Syndrome After Sepsis.

https://pubmed.ncbi.nlm.nih.gov/34557198/#:~:text=Resumen-,El%20s%C3%ADndrome%20de%20dificultad%20respiratoria%20aguda%20(SDRA)%20es%20un%20proceso,v%C3%ADnculos%20mec%C3%A1nicos%20de%20esta%20observaci%C3%B3n%20con%20la%20patogenia%20del%20SDRA.,-Palabras%20clave%3A%20SDR

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

A Transformative Approach to Academic Medicine

The University of Arizona Health Network (UAHN) was a modestly successful health care delivery organization with a vibrant academic portfolio and stable finances. By 2013, however, market forces, health care financing changes, and the burden of technology and informatics upgrades led to a compromised financial position at UAHN, a situation experienced by many academic medical centers. Concurrently, Banner Health had been interested in forming an academic partnership to enhance innovation, including the incorporation of new approaches into health care delivery, and to recruit high-quality providers to the organization. In 2015, the University of Arizona (UA) and Banner Health entered into a unique partnership known as Banner -University Medicine. The objective was to create a statewide system that provides reliable, compassionate, high-quality health care across all of its providers and facilities and to make a 30-year commitment to UA's College of Medicine in Tucson and the College of Medicine in Phoenix to support the State of Arizona's position as a first-tier research and training destination with world-class physicians. The goal of the Banner -University Medicine partnership is to create a nationally leading organization that transforms health care by delivering better care, enhanced service, and lower costs through new approaches focused on wellness. Key elements of this partnership are highlighted in this Commentary, including the unique governance structure of the Academic Management Council, the creation of the Academic Enhancement Fund to support the UA Colleges of Medicine in Tucson and Phoenix, and novel approaches to medical education, research, innovation, and care.12 month embargo; First published online August 30, 2016This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Integrating microRNAs into a system biology approach to acute lung injury

Acute lung injury (ALI), including the ventilator-induced lung injury (VILI) and the more severe acute respiratory distress syndrome (ARDS), are common and complex inflammatory lung diseases potentially affected by various genetic and non-genetic factors. Using the candidate gene approach, genetic variants associated with immune response and inflammatory pathways have been identified and implicated in ALI. Since gene expression is an intermediate phenotype that resides between DNA sequence variation and higher level cellular or whole-body phenotypes, the illustration of gene expression regulatory networks could potentially enhance understanding of disease susceptibility and the development of inflammatory lung syndromes. MicroRNAs (miRNAs) have emerged as a novel class of gene regulators which play critical roles in complex diseases including ALI. Comparisons of global miRNA profiles in animal models of ALI and VILI identified several miRNAs (e.g., miR-146a, miR-155) previously implicated in immune response and inflammatory pathways. Therefore, via regulation of target genes in these biological processes and pathways, miRNAs potentially contribute to the development of ALI. While this line of inquiry exists at a nascent stage, miRNAs have the potential to be critical components of a comprehensive model for inflammatory lung disease built by a systems biology approach that integrates genetic, genomic, proteomic, epigenetic as well environmental stimuli information. Given their particularly recognized role in regulation of immune and inflammatory responses, miRNAs also serve as novel therapeutic targets and biomarkers for ALI/ARDS or VILI, thus facilitating the realization of personalized medicine for individuals with acute inflammatory lung disease

The ARP 2/3 complex mediates endothelial barrier function and recovery

Pulmonary endothelial cell (EC) barrier dysfunction and recovery is critical to the pathophysiology of acute respiratory distress syndrome. Cytoskeletal and subsequent cell membrane dynamics play a key mechanistic role in determination of EC barrier integrity. Here, we characterizAQe the actin related protein 2/3 (Arp 2/3) complex, a regulator of peripheral branched actin polymerization, in human pulmonary EC barrier function through studies of transendothelial electrical resistance (TER), intercellular gap formation, peripheral cytoskeletal structures and lamellipodia. Compared to control, Arp 2/3 inhibition with the small molecule inhibitor CK-666 results in a reduction of baseline barrier function (1,241 +/- 53 vs 988 +/- 64 ohm; p < 0.01), S1P-induced barrier enhancement and delayed recovery of barrier function after thrombin (143 +/- 14 vs 93 +/- 6 min; p < 0.01). Functional changes of Arp 2/3 inhibition on barrier integrity are associated temporally with increased intercellular gap area at baseline (0.456 +/- 0.02 vs 0.299 +/- 0.02; p < 0.05) and thirty minutes after thrombin (0.885 +/- 0.03 vs 0.754 +/- 0.03; p < 0.05). Immunofluorescent microscopy reveals reduced lamellipodia formation after S1P and during thrombin recovery in Arp 2/3 inhibited cells. Individual lamellipodia demonstrate reduced depth following Arp 2/3 inhibition vs vehicle at baseline (1.83 +/- 0.41 vs 2.55 +/- 0.46 mm; p < 0.05) and thirty minutes after S1P treatment (1.53 +/- 0.37 vs 2.09 +/- 0.36 mm; p < 0.05). These results establish a critical role for Arp 2/3 activity in determination of pulmonary endothelial barrier function and recovery through formation of EC lamellipodia and closure of intercellular gaps.American Lung Association [RG-349765]; National Institutes of Health [HL058064, HL088144]12 month embargo; First Published February 1, 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]