Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans

INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS

MicroRNA-target pairs in human renal epithelial cells treated with transforming growth factor β1: a novel role of miR-382

We reported previously an approach for identifying microRNA (miRNA)-target pairs by combining miRNA and proteomic analyses. The approach was applied in the present study to examine human renal epithelial cells treated with transforming growth factor β1 (TGFβ1), a model of epithelial–mesenchymal transition important for the development of renal interstitial fibrosis. Treatment of human renal epithelial cells with TGFβ1 resulted in upregulation of 16 miRNAs and 18 proteins and downregulation of 17 miRNAs and 16 proteins. Of the miRNAs and proteins that exhibited reciprocal changes in expression, 77 pairs met the sequence criteria for miRNA–target interactions. Knockdown of miR-382, which was up-regulated by TGFβ1, attenuated TGFβ1-induced loss of the epithelial marker E-cadherin. miR-382 was confirmed by 3′-untranslated region reporter assay to target five genes that were downregulated at the protein level by TGFβ1, including superoxide dismutase 2 (SOD2). Knockdown of miR-382 attenuated TGFβ1-induced downregulation of SOD2. Overexpression of SOD2 ameliorated TGFβ1-induced loss of the epithelial marker. The study provided experimental evidence in the form of reciprocal expression at the protein level for a large number of predicted miRNA-target pairs and discovered a novel role of miR-382 and SOD2 in the loss of epithelial characteristics induced by TGFβ1

System-wide transcriptome damage and tissue identity loss in COVID-19 patients

The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body-wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections., • Across all organs, fibroblast, and immune cell populations increase in COVID-19 patients • Organ-specific cell types and functional markers are lost in all COVID-19 tissue types • Lung compartment identity loss correlates with SARS-CoV-2 viral loads • COVID-19 uniquely disrupts co-occurrence cell type clusters (different from IAV/ARDS) , Park et al. report system-wide transcriptome damage and tissue identity loss wrought by SARS-CoV-2, influenza, and bacterial infection across multiple organs (heart, liver, lung, kidney, and lymph nodes) and provide a spatiotemporal landscape of COVID-19 in the lung

Liquid Biopsies Poorly miRror Renal Ischemia-Reperfusion Injury

Acute kidney injury (AKI) is the rapid reduction in renal function. It is often difficult to detect at an early stage. Biofluid microRNAs (miRs) have been proposed as novel biomarkers due to their regulatory role in renal pathophysiology. The goal of this study was to determine the overlap in AKI miRNA profiles in the renal cortex, urine, and plasma samples collected from a rat model of ischemia-reperfusion (IR)-induced AKI. Bilateral renal ischemia was induced by clamping the renal pedicles for 30 min, followed by reperfusion. Urine was then collected over 24 h, followed by terminal blood and tissue collection for small RNA profiling. Differentially expressed (IR vs. sham) miRs within the urine and renal cortex sample types demonstrated a strong correlation in normalized abundance regardless of injury (IR and sham: R2 = 0.8710 and 0.9716, respectively). Relatively few miRs were differentially expressed in multiple samples. Further, there were no differentially expressed miRs with clinically relevant sequence conservation common between renal cortex and urine samples. This project highlights the need for a comprehensive analysis of potential miR biomarkers, including analysis of pathological tissues and biofluids, with the goal of identifying the cellular origin of altered miRs. Analysis at earlier timepoints is needed to further evaluate clinical potential

Transcriptomic analysis identifies novel candidates in cardiorenal pathology mediated by chronic peritoneal dialysis

Abstract Peritoneal dialysis (PD) is associated with increased cardiovascular (CV) risk. Studies of PD-related CV pathology in animal models are lacking despite the clinical importance. Here we introduce the phenotypic evaluation of a rat model of cardiorenal syndrome in response to chronic PD, complemented by a rich transcriptomic dataset detailing chronic PD-induced changes in left ventricle (LV) and kidney tissues. This study aims to determine how PD alters CV parameters and risk factors while identifying pathways for potential therapeutic targets. Sprague Dawley rats underwent Sham or 5/6 nephrectomy (5/6Nx) at 10 weeks of age. Six weeks later an abdominal dialysis catheter was placed in all rats before random assignment to Control or PD (3 daily 1-h exchanges) groups for 8 days. Renal and LV pathology and transcriptomic analysis was performed. The PD regimen reduced circulating levels of BUN in 5/6Nx, indicating dialysis efficacy. PD did not alter blood pressure or cardiovascular function in Sham or 5/6Nx rats, though it attenuated cardiac hypertrophy. Importantly PD increased serum triglycerides in 5/6Nx rats. Furthermore, transcriptomic analysis revealed that PD induced numerous changed transcripts involved with inflammatory pathways, including neutrophil activation and atherosclerosis signaling. We have adapted a uremic rat model of chronic PD. Chronic PD induced transcriptomic changes related to inflammatory signaling that occur independent of 5/6Nx and augmented circulating triglycerides and predicted atherosclerosis signaling in 5/6Nx LV tissues. The changes are indicative of increased CV risk due to PD and highlight several pathways for potential therapeutic targets