Publications by authors named "Sina A Gharib"

137 Publications

BinomiRare: A robust test for association of a rare genetic variant with a binary outcome for mixed models and any case-control proportion.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Framingham Heart Study, Framingham, MA, USA.

Whole-genome sequencing (WGS) and whole-exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g., family or household) when testing genetic associations. However, no existing tests of the association of a rare variant with a binary outcome in the presence of correlated data control the type 1 error where there are (1) few individuals harboring the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing a framework for testing rare variant association with a binary trait in individuals harboring at least one risk allele. In this framework, we estimate outcome probabilities under the null hypothesis and then use them, within the individuals with at least one risk allele, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small-vessel disease (SVD) stroke, short sleep, and venous thromboembolism (VTE), in whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program.
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http://dx.doi.org/10.1016/j.xhgg.2021.100040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321319PMC
July 2021

Admission respiratory status predicts mortality in COVID-19.

Influenza Other Respir Viruses 2021 May 24. Epub 2021 May 24.

Division of Cardiology, University of Washington, Seattle, WA, USA.

COVID-19 has significant case fatality. Glucocorticoids are the only treatment shown to improve survival, but only among patients requiring supplemental oxygen. WHO advises patients to seek medical care for "trouble breathing," but hypoxemic patients frequently have no respiratory symptoms. Our cohort study of hospitalized COVID-19 patients shows that respiratory symptoms are uncommon and not associated with mortality. By contrast, objective signs of respiratory compromise-oxygen saturation and respiratory rate-are associated with markedly elevated mortality. Our findings support expanding guidelines to include at-home assessment of oxygen saturation and respiratory rate in order to expedite life-saving treatments patients to high-risk COVID-19 patients.
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http://dx.doi.org/10.1111/irv.12869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242415PMC
May 2021

Benchmarking association analyses of continuous exposures with RNA-seq in observational studies.

Brief Bioinform 2021 May 20. Epub 2021 May 20.

Harbor-UCLA Medical Center at the Lundquist Institute, USA.

Large datasets of hundreds to thousands of individuals measuring RNA-seq in observational studies are becoming available. Many popular software packages for analysis of RNA-seq data were constructed to study differences in expression signatures in an experimental design with well-defined conditions (exposures). In contrast, observational studies may have varying levels of confounding transcript-exposure associations; further, exposure measures may vary from discrete (exposed, yes/no) to continuous (levels of exposure), with non-normal distributions of exposure. We compare popular software for gene expression-DESeq2, edgeR and limma-as well as linear regression-based analyses for studying the association of continuous exposures with RNA-seq. We developed a computation pipeline that includes transformation, filtering and generation of empirical null distribution of association P-values, and we apply the pipeline to compute empirical P-values with multiple testing correction. We employ a resampling approach that allows for assessment of false positive detection across methods, power comparison and the computation of quantile empirical P-values. The results suggest that linear regression methods are substantially faster with better control of false detections than other methods, even with the resampling method to compute empirical P-values. We provide the proposed pipeline with fast algorithms in an R package Olivia, and implemented it to study the associations of measures of sleep disordered breathing with RNA-seq in peripheral blood mononuclear cells in participants from the Multi-Ethnic Study of Atherosclerosis.
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http://dx.doi.org/10.1093/bib/bbab194DOI Listing
May 2021

Sample processing and single cell RNA-sequencing of peripheral blood immune cells from COVID-19 patients.

STAR Protoc 2021 Jun 12;2(2):100582. Epub 2021 May 12.

Computational Medicine Core at Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA 98109, USA.

Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) allows in-depth assessment of transcriptional changes in immune cells of patients with COVID-19. However, collecting, processing, and analyzing samples from patients with COVID-19 pose many challenges because blood samples may contain infectious virus, identification of immune cell subtypes can be difficult, and biological interpretation of analytical results is complex. To address these issues, we describe a protocol for sample processing, sorting, methanol fixation, and scRNA-seq analysis of PBMCs from frozen buffy coat samples from patients with COVID-19. For complete details on the use and execution of this protocol, please refer to (Yao et al., 2021).
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http://dx.doi.org/10.1016/j.xpro.2021.100582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114807PMC
June 2021

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption.

Nat Commun 2021 05 14;12(1):2830. Epub 2021 May 14.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.
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http://dx.doi.org/10.1038/s41467-021-22752-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121846PMC
May 2021

A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease.

Am J Physiol Lung Cell Mol Physiol 2021 Jul 28;321(1):L130-L143. Epub 2021 Apr 28.

Department of Health Sciences, University of Leicester, Leicester, United Kingdom.

Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant ( < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B () splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 (), a gene involved in regulating cell proliferation, were associated with COPD (both < 0.0001). The Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17-1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.
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http://dx.doi.org/10.1152/ajplung.00009.2021DOI Listing
July 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
April 2021

Unraveling the lung metatranscriptome in HCT.

Blood 2021 Mar;137(12):1570-1572

University of Washington.

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http://dx.doi.org/10.1182/blood.2020010539DOI Listing
March 2021

Sexually Dimorphic Relationships Among Saa3 (Serum Amyloid A3), Inflammation, and Cholesterol Metabolism Modulate Atherosclerosis in Mice.

Arterioscler Thromb Vasc Biol 2021 06 25;41(6):e299-e313. Epub 2021 Mar 25.

Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.316066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159856PMC
June 2021

Plasma epoxyeicosatrienoic acids and dihydroxyeicosatrieonic acids, insulin, glucose and risk of diabetes: The strong heart study.

EBioMedicine 2021 Apr 19;66:103279. Epub 2021 Mar 19.

Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.

Background: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid with multiple biological functions. Rodent experiments suggest EETs play a role in insulin sensitivity and diabetes, but evidence in humans is limited. To address this knowledge gap, we conducted a case-cohort study in the Strong Heart Family Study, a prospective cohort among American Indians.

Methods: We measured 4 EET species and 4 species of corresponding downstream metabolites, dihydroxyeicosatrieonic acids (DHETs), in plasma samples from 1161 participants, including 310 with type 2 diabetes. We estimated the associations of total (esterified and free) EETs and DHETs with incident diabetes risk, adjusting for known risk factors. We also examined cross-sectional associations with plasma fasting insulin and glucose in the case-cohort and in 271 participants without diabetes from the older Strong Heart Study cohort, and meta-analyzed the results from the 2 cohorts.

Findings: We observed no significant association of total EET or DHET levels with incident diabetes. In addition, plasma EETs were not associated with plasma insulin or plasma glucose. However, higher plasma 14,15-DHET was associated with lower plasma insulin and lower plasma glucose.

Interpretation: In this first prospective study of EETs and diabetes, we found no evidence for a role of total plasma EETs in diabetes. The novel associations of 14,15-DHET with insulin and glucose warrant replication and exploration of possible mechanisms.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2021.103279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010619PMC
April 2021

Pericyte-like cells undergo transcriptional reprogramming and distinct functional adaptations in acute lung injury.

FASEB J 2021 04;35(4):e21323

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.

We previously reported on the role of pericyte-like cells as functional sentinel immune cells in lung injury. However, much about the biological role of pericytes in lung injury remains unknown. Lung pericyte-like cells are well-positioned to sense disruption to the epithelial barrier and coordinate local inflammatory responses due to their anatomic niche within the alveoli. In this report, we characterized transcriptional responses and functional changes in pericyte-like cells following activation by alveolar components from injured and uninjured lungs in a mouse model of acute lung injury (ALI). Purified pericyte-like cells from lung digests using PDGFRβ as a selection marker were expanded in culture as previously described (1). We induced sterile acute lung injury in mice with recombinant human Fas ligand (rhFasL) instillation followed by mechanical ventilation (1). We then collected bronchoalveolar lavage fluid (BALF) from injured and uninjured mice. Purified pericyte-like cells in culture were exposed to growth media only (control), BALF from uninjured mice, and BALF from injured mice for 6 and 24 hours. RNA collected from these treatment conditions were processed for RNAseq. Targets of interest identified by pathway analysis were validated using in vitro and in vivo assays. We observed robust global transcriptional changes in pericyte-like cells following treatment with uninjured and injured BALF at 6 hours, but this response persisted for 24 hours only after exposure to injured BALF. Functional enrichment analysis of pericytes treated with injured BALF revealed the activation of pro-inflammatory, cell migration, and angiogenesis-related pathways, whereas processes associated with tissue development and cell differentiation were down-regulated. We validated select upregulated targets in the inflammatory, angiogenic, and cell migratory pathways using functional biological assays in vitro and in vivo. We conclude that lung pericyte-like cells are highly responsive to alveolar compartment content from both uninjured and injured lungs, but injured BALF elicits a more sustained response. The inflammatory, angiogenic, and migratory changes exhibited by activated pericyte-like cells underscore the phenotypic plasticity of these specialized stromal cells in the setting of acute lung injury.
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http://dx.doi.org/10.1096/fj.201903192RRDOI Listing
April 2021

Cell-Type-Specific Immune Dysregulation in Severely Ill COVID-19 Patients.

Cell Rep 2021 01 16;34(1):108590. Epub 2020 Dec 16.

Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address:

Recent studies have demonstrated immunologic dysfunction in severely ill coronavirus disease 2019 (COVID-19) patients. We use single-cell RNA sequencing (scRNA-seq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMCs) from healthy (n = 3) and COVID-19 patients with moderate disease (n = 5), acute respiratory distress syndrome (ARDS, n = 6), or recovering from ARDS (n = 6). Our data reveal transcriptomic profiles indicative of defective antigen presentation and interferon (IFN) responsiveness in monocytes from ARDS patients, which contrasts with higher responsiveness to IFN signaling in lymphocytes. Furthermore, genes involved in cytotoxic activity are suppressed in both natural killer (NK) and CD8 T lymphocytes, and B cell activation is deficient, which is consistent with delayed viral clearance in severely ill COVID-19 patients. Our study demonstrates that COVID-19 patients with ARDS have a state of immune imbalance in which dysregulation of both innate and adaptive immune responses may be contributing to a more severe disease course.
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http://dx.doi.org/10.1016/j.celrep.2020.108590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744012PMC
January 2021

Matrix Metalloproteinase-12 Is Required for Granuloma Progression.

Front Immunol 2020 18;11:553949. Epub 2020 Sep 18.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Brody School of Medicine- East Carolina University, Greenville, NC, United States.

Background: Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation.

Methods: C57BL/6 (wildtype) and KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1).

Results: Pulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and KO mice. In contrast, by 60 days after MWCNT instillation, KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days.

Conclusions: The striking reduction of granuloma formation at day 60 in KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis.
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http://dx.doi.org/10.3389/fimmu.2020.553949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531023PMC
April 2021

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Nat Commun 2020 10 14;11(1):5182. Epub 2020 Oct 14.

The Institute for Translational Genomics and Population Sciences, The Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
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http://dx.doi.org/10.1038/s41467-020-18334-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598941PMC
October 2020

CFTR Modulator Therapy Enhances Peripheral Blood Monocyte Contributions to Immune Responses in People With Cystic Fibrosis.

Front Pharmacol 2020 13;11:1219. Epub 2020 Aug 13.

Center for Lung Biology, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, United States.

Background: CFTR modulators decrease some etiologies of CF airway inflammation; however, data indicate that non-resolving airway infection and inflammation persist in individuals with CF and chronic bacterial infections. Thus, identification of therapies that diminish airway inflammation without allowing unrestrained bacterial growth remains a critical research goal. Novel strategies for combatting deleterious airway inflammation in the CFTR modulator era require better understanding of cellular contributions to chronic CF airway disease, and how inflammatory cells change after initiation of CFTR modulator therapy. Peripheral blood monocytes, which traffic to the CF airway, can develop both pro-inflammatory and inflammation-resolving phenotypes, represent intriguing cellular targets for focused therapies. This therapeutic approach, however, requires a more detailed knowledge of CF monocyte cellular programming and phenotypes.

Material And Methods: In order to characterize the inflammatory phenotype of CF monocytes, and how these cells change after initiation of CFTR modulator therapy, we studied adults (n=10) with CF, chronic airway infections, and the mutations before and 7 days after initiation of ivacaftor. Transcriptomes of freshly isolated blood monocytes were interrogated by RNA-sequencing (RNA-seq) followed by pathway-based analyses. Plasma concentrations of cytokines and chemokines were evaluated by multiplex ELISA.

Results: RNAseq identified approximately 50 monocyte genes for which basal expression was significantly changed in all 10 subjects after 7 days of ivacaftor. Of these, the majority were increased in expression post ivacaftor, including many genes traditionally associated with enhanced inflammation and immune responses. Pathway analyses confirmed that transcriptional programs were overwhelmingly up-regulated in monocytes after 7 days of ivacaftor, including biological modules associated with immunity, cell cycle, oxidative phosphorylation, and the unfolded protein response. Ivacaftor increased plasma concentrations of CXCL2, a neutrophil chemokine secreted by monocytes and macrophages, and CCL2, a monocyte chemokine.

Conclusions: Our results demonstrate that ivacaftor causes acute changes in blood monocyte transcriptional profiles and plasma chemokines, and suggest that increased monocyte inflammatory signals and changes in myeloid cell trafficking may contribute to changes in airway inflammation in people taking CFTR modulators. To our knowledge, this is the first report investigating the transcriptomic response of circulating blood monocytes in CF subjects treated with a CFTR modulator.
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http://dx.doi.org/10.3389/fphar.2020.01219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461946PMC
August 2020

Alveolar CCN1 is associated with mechanical stretch and acute respiratory distress syndrome severity.

Am J Physiol Lung Cell Mol Physiol 2020 11 16;319(5):L825-L832. Epub 2020 Sep 16.

Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, Washington.

The cellular communication network factor 1 (CCN1) is a matricellular protein that can modulate multiple tissue responses, including inflammation and repair. We have previously shown that adenoviral overexpression of is sufficient to cause acute lung injury in mice. We hypothesized that CCN1 is present in the airspaces of lungs during the acute phase of lung injury, and higher concentrations are associated with acute respiratory distress syndrome (ARDS) severity. We tested this hypothesis by measuring ) CCN1 in bronchoalveolar lavage fluid (BALF) and lung homogenates from mice subjected to ventilation-induced lung injury (VILI), ) gene expression and protein levels in MLE-12 cells (alveolar epithelial cell line) subjected to mechanical stretch, and ) CCN1 in BALF from mechanically ventilated humans with and without ARDS. BALF CCN1 concentrations and whole lung CCN1 protein levels were significantly increased in mice with VILI ( = 6) versus noninjured controls ( = 6). gene expression and CCN1 protein levels were increased in MLE-12 cells cultured under stretch conditions. Subjects with ARDS ( = 77) had higher BALF CCN1 levels compared with mechanically ventilated subjects without ARDS ( = 45) ( < 0.05). In subjects with ARDS, BALF CCN1 concentrations were associated with higher total protein, sRAGE, and worse [Formula: see text]/[Formula: see text] ratios (all < 0.05). CCN1 is present in the lungs of mice and humans during the acute inflammatory phase of lung injury, and concentrations are higher in patients with increased markers of severity. Alveolar epithelial cells may be an important source of CCN1 under mechanical stretch conditions.
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http://dx.doi.org/10.1152/ajplung.00073.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789974PMC
November 2020

Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture.

Circ Res 2020 09 30;127(8):997-1022. Epub 2020 Jul 30.

Departments of Medicine (T.V., J.H.H., N.A., K.F., J.H., S.A.G., D.A.D.), University of Washington, Seattle.

Rationale: Plaque rupture is the proximate cause of most myocardial infarctions and many strokes. However, the molecular mechanisms that precipitate plaque rupture are unknown.

Objective: By applying proteomic and bioinformatic approaches in mouse models of protease-induced plaque rupture and in ruptured human plaques, we aimed to illuminate biochemical pathways through which proteolysis causes plaque rupture and identify substrates that are cleaved in ruptured plaques.

Methods And Results: We performed shotgun proteomics analyses of aortas of transgenic mice with macrophage-specific overexpression of urokinase (SR-uPA mice) and of SR-uPA bone marrow transplant recipients, and we used bioinformatic tools to evaluate protein abundance and functional category enrichment in these aortas. In parallel, we performed shotgun proteomics and bioinformatics studies on extracts of ruptured and stable areas of freshly harvested human carotid plaques. We also applied a separate protein-analysis method (protein topography and migration analysis platform) to attempt to identify substrates and proteolytic fragments in mouse and human plaque extracts. Approximately 10% of extracted aortic proteins were reproducibly altered in SR-uPA aortas. Proteases, inflammatory signaling molecules, as well as proteins involved with cell adhesion, the cytoskeleton, and apoptosis, were increased. ECM (Extracellular matrix) proteins, including basement-membrane proteins, were decreased. Approximately 40% of proteins were altered in ruptured versus stable areas of human carotid plaques, including many of the same functional categories that were altered in SR-uPA aortas. Collagens were minimally altered in SR-uPA aortas and ruptured human plaques; however, several basement-membrane proteins were reduced in both SR-uPA aortas and ruptured human plaques. Protein topography and migration analysis platform did not detect robust increases in proteolytic fragments of ECM proteins in either setting.

Conclusions: Parallel studies of SR-uPA mouse aortas and human plaques identify mechanisms that connect proteolysis with plaque rupture, including inflammation, basement-membrane protein loss, and apoptosis. Basement-membrane protein loss is a prominent feature of ruptured human plaques, suggesting a major role for basement-membrane proteins in maintaining plaque stability.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508285PMC
September 2020

Cell type-specific immune dysregulation in severely ill COVID-19 patients.

medRxiv 2020 Jul 24. Epub 2020 Jul 24.

Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Coronavirus disease 2019 (COVID-19) has quickly become the most serious pandemic since the 1918 flu pandemic. In extreme situations, patients develop a dysregulated inflammatory lung injury called acute respiratory distress syndrome (ARDS) that causes progressive respiratory failure requiring mechanical ventilatory support. Recent studies have demonstrated immunologic dysfunction in severely ill COVID-19 patients. To further delineate the dysregulated immune response driving more severe clinical course from SARS-CoV-2 infection, we used single-cell RNA sequencing (scRNAseq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) from hospitalized COVID-19 patients having mild disease (n = 5), developing ARDS (n = 6), and recovering from ARDS (n = 6). Our data demonstrated an overwhelming inflammatory response with select immunodeficiencies within various immune populations in ARDS patients. Specifically, their monocytes had defects in antigen presentation and deficiencies in interferon responsiveness that contrasted the higher interferon signals in lymphocytes. Furthermore, cytotoxic activity was suppressed in both NK and CD8 lymphocytes whereas B cell activation was deficient, which is consistent with the delayed viral clearance in severely ill COVID-19 patients. Finally, we identified altered signaling pathways in the severe group that suggests immunosenescence and immunometabolic changes could be contributing to the dysfunctional immune response. Our study demonstrates that COVID-19 patients with ARDS have an immunologically distinct response when compared to those with a more innocuous disease course and show a state of immune imbalance in which deficiencies in both the innate and adaptive immune response may be contributing to a more severe disease course in COVID-19.
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http://dx.doi.org/10.1101/2020.07.23.20161182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386732PMC
July 2020

Genetic variation implicates plasma angiopoietin-2 in the development of acute kidney injury sub-phenotypes.

BMC Nephrol 2020 07 17;21(1):284. Epub 2020 Jul 17.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, 325 9th Avenue, Seattle, WA, 98104, USA.

Background: We previously identified two acute kidney injury (AKI) sub-phenotypes (AKI-SP1 and AKI-SP2) with different risk of poor clinical outcomes and response to vasopressor therapy. Plasma biomarkers of endothelial dysfunction (tumor necrosis factor receptor-1, angiopoietin-1 and 2) differentiated the AKI sub-phenotypes. However, it is unknown whether these biomarkers are simply markers or causal mediators in the development of AKI sub-phenotypes.

Methods: We tested for associations between single-nucleotide polymorphisms within the Angiopoietin-1, Angiopoietin-2, and Tumor Necrosis Factor Receptor 1A genes and AKI- SP2 in 421 critically ill subjects of European ancestry. Top performing single-nucleotide polymorphisms (FDR < 0.05) were tested for cis-biomarker expression and whether genetic risk for AKI-SP2 is mediated through circulating biomarkers. We also completed in vitro studies using human kidney microvascular endothelial cells. Finally, we calculated the renal clearance of plasma biomarkers using 20 different timed urine collections.

Results: A genetic variant, rs2920656C > T, near ANGPT2 was associated with reduced risk of AKI-SP2 (odds ratio, 0.45; 95% CI, 0.31-0.66; adjusted FDR = 0.003) and decreased plasma angiopoietin-2 (p = 0.002). Causal inference analysis showed that for each minor allele (T) the risk of developing AKI-SP2 decreases by 16%. Plasma angiopoietin-2 mediated 41.5% of the rs2920656 related risk for AKI-SP2. Human kidney microvascular endothelial cells carrying the T allele of rs2920656 produced numerically lower levels of angiopoietin-2 although this was not statistically significant (p = 0.07). Finally, analyses demonstrated that angiopoietin-2 is minimally renally cleared in critically ill subjects.

Conclusion: Genetic mediation analysis provides supportive evidence that angiopoietin-2 plays a causal role in risk for AKI-SP2.
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http://dx.doi.org/10.1186/s12882-020-01935-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368773PMC
July 2020

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.

Lancet Respir Med 2020 07;8(7):696-708

Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.

Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0·7 and FEV <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.

Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.

Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.

Funding: US National Institutes of Health, Wellcome Trust.
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http://dx.doi.org/10.1016/S2213-2600(20)30101-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429152PMC
July 2020

Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality.

Circ Genom Precis Med 2020 08 11;13(4):e002766. Epub 2020 Jun 11.

The Cardiovascular Health Research Unit, University of Washington, Seattle, WA (S.A.G., N.S., J.A.B., C.M.S.).

Background: DNA methylation patterns associated with habitual diet have not been well studied.

Methods: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality.

Results: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected <1.6×10). Hypermethylation of cg18181703 () was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (=5.7×10). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR <4.5×10). For example, hypermethylation of cg11250194 () was associated with lower triglyceride concentrations (MR, =1.5×10).and hypermethylation of cg02079413 (; ) was associated with body mass index (corrected MR, =1×10).

Conclusions: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.
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http://dx.doi.org/10.1161/CIRCGEN.119.002766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442697PMC
August 2020

Low oxygen saturation during sleep reduces CD1D and RAB20 expressions that are reversed by CPAP therapy.

EBioMedicine 2020 Jun 5;56:102803. Epub 2020 Jun 5.

Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA.

Background: Sleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment.

Methods: In two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses.

Findings: Twenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT).

Interpretation: Low oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.
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http://dx.doi.org/10.1016/j.ebiom.2020.102803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276515PMC
June 2020

Higher Epoxyeicosatrienoic Acids in Cardiomyocytes-Specific CYP2J2 Transgenic Mice Are Associated with Improved Myocardial Remodeling.

Biomedicines 2020 May 30;8(6). Epub 2020 May 30.

Department of Medicinal Chemistry, University of Washington, Box 357610, Seattle, WA 98195, USA.

Elevated epoxyeicosatrienoic acids (EETs) are known to be cardioprotective during ischemia-reperfusion injury in cardiomyocyte-specific overexpressing cytochrome P450 2J2 (CYP2J2) transgenic (Tr) mice. Using the same Tr mice, we measured changes in cardiac and erythrocyte membranes EETs following myocardial infarction (MI) to determine if they can serve as reporters for cardiac events. Cardiac function was also assessed in Tr vs. wild-type (WT) mice in correlation with EET changes two weeks following MI. Tr mice (N = 25, 16 female, nine male) had significantly higher cardiac and EETs compared to their WT counterparts (N=25, 18 female, seven male). Total cardiac EETs in Tr mice were positively correlated with total EETs in erythrocyte membrane, but there was no correlation with EETs or in WT mice. Following MI, and EETs were elevated in the erythrocyte membrane and cardiac tissue in Tr mice, accounting for the improved cardiac outcomes observed. Tr mice showed significantly better myocardial remodeling following MI, evidenced by higher % fractional shortening, smaller infarct size, lower reactive oxygen species (ROS) formation, reduced fibrosis and apoptosis, and lower pulmonary edema. A positive correlation between total cardiac EETs and total erythrocyte membrane EETs in a Tr mouse model suggests that erythrocyte EETs may be used as predictive markers for cardiac events. All EET regioisomers displayed similar trends following acute MI; however, the magnitude of change for each regioisomer was markedly different, warranting measurement of each individually.
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http://dx.doi.org/10.3390/biomedicines8060144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344501PMC
May 2020

CYP2J2 Modulates Diverse Transcriptional Programs in Adult Human Cardiomyocytes.

Sci Rep 2020 03 24;10(1):5329. Epub 2020 Mar 24.

Cardiovascular Health Research Unit, Department of Medicine, Seattle, WA, USA.

CYP2J2, a member of the Cytochrome P450 family of enzymes, is the most abundant epoxygenase in the heart and has multifunctional properties including bioactivation of arachidonic acid to epoxyeicosatrienoic acids, which, in turn, have been implicated in mediating several cardiovascular conditions. Using a proteomic approach, we found that CYP2J2 expression is lower in cardiac tissue from patients with cardiomyopathy compared to controls. In order to better elucidate the complex role played by CYP2J2 in cardiac cells, we performed targeted silencing of CYP2J2 expression in human adult ventricular cardiomyocytes and interrogated whole genome transcriptional responses. We found that knockdown of CYP2J2 elicits widespread alterations in gene expression of ventricular cardiomyocytes and leads to the activation of a diverse repertoire of programs, including those involved in ion channel signaling, development, extracellular matrix, and metabolism. Several members of the differentially up-regulated ion channel module have well-known pathogenetic roles in cardiac dysrhythmias. By leveraging causal network and upstream regulator analysis, we identified several candidate drivers of the observed transcriptional response to CYP2J2 silencing; these master regulators have been implicated in aberrant cardiac remodeling, heart failure, and myocyte injury and repair. Collectively, our study demonstrates that CYP2J2 plays a central and multifaceted role in cardiomyocyte homeostasis and provides a framework for identifying critical regulators and pathways influenced by this gene in cardiovascular health and disease.
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http://dx.doi.org/10.1038/s41598-020-62174-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093536PMC
March 2020

Hematopoietic Cell-Expressed Endothelial Nitric Oxide Protects the Liver From Insulin Resistance.

Arterioscler Thromb Vasc Biol 2020 03 30;40(3):670-681. Epub 2020 Jan 30.

From the Department of Medicine, University of Washington, Seattle (B.P.D., R.M., T.K., S.A.G., T.V., T.W., K.D.O., K.E.B., A.C., F.K.).

Objective: Mice genetically deficient in endothelial nitric oxide synthase (Nos3) have fasting hyperinsulinemia and hepatic insulin resistance, indicating the importance of Nos3 (nitric oxide synthase) in maintaining metabolic homeostasis. Although the current paradigm holds that these metabolic effects are derived specifically from the expression of Nos3 in the endothelium, it has been established that bone marrow-derived cells also express Nos3. The aim of this study was to investigate whether bone marrow-derived cell Nos3 is important in maintaining metabolic homeostasis. Approach and Results: To test the hypothesis that bone marrow-derived cell Nos3 contributes to metabolic homeostasis, we generated chimeric male mice deficient or competent for Nos3 expression in circulating blood cells. These mice were placed on a low-fat diet for 5 weeks, a time period which is known to induce hepatic insulin resistance in global Nos3-deficient mice but not in wild-type C57Bl/6 mice. Surprisingly, we found that the absence of Nos3 in the bone marrow-derived component is associated with hepatic insulin resistance and that restoration of Nos3 in the bone marrow-derived component in global Nos3-deficient mice is sufficient to restore hepatic insulin sensitivity. Furthermore, we found that overexpression of Nos3 in bone marrow-derived component in wild-type mice attenuates the development of hepatic insulin resistance during high-fat feeding. Finally, compared with wild-type macrophages, the loss of macrophage Nos3 is associated with increased inflammatory responses to lipopolysaccharides and reduced anti-inflammatory responses to IL-4, a macrophage phenotype associated with the development of hepatic and systemic insulin resistance.

Conclusions: These results would suggest that the metabolic and hepatic consequences of high-fat feeding are mediated by loss of Nos3/nitric oxide actions in bone marrow-derived cells, not in endothelial cells.
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http://dx.doi.org/10.1161/ATVBAHA.119.313648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047596PMC
March 2020

Obstructive sleep apnea and CPAP therapy alter distinct transcriptional programs in subcutaneous fat tissue.

Sleep 2020 06;43(6)

Center for Sleep and Cardiovascular Outcomes Research, University of Pittsburgh, Pittsburgh, PA.

Obstructive sleep apnea (OSA) has been linked to dysregulated metabolic states, and treatment of sleep apnea may improve these conditions. Subcutaneous adipose tissue is a readily samplable fat depot that plays an important role in regulating metabolism. However, neither the pathophysiologic consequences of OSA nor the effects of continuous positive airway pressure (CPAP) in altering this compartment's molecular pathways are understood. This study aimed to systematically identify subcutaneous adipose tissue transcriptional programs modulated in OSA and in response to its effective treatment with CPAP. Two subject groups were investigated: Study Group 1 was comprised of 10 OSA and 8 controls; Study Group 2 included 24 individuals with OSA studied at baseline and following CPAP. For each subject, genome-wide gene expression measurement of subcutaneous fat was performed. Differentially activated pathways elicited by OSA (Group 1) and in response to its treatment (Group 2) were determined using network and Gene Set Enrichment Analysis (GSEA). In Group 2, treatment of OSA with CPAP improved apnea-hypopnea index, daytime sleepiness, and blood pressure, but not anthropometric measures. In Group 1, GSEA revealed many up-regulated gene sets in OSA subjects, most of which were involved in immuno-inflammatory (e.g. interferon-γ signaling), transcription, and metabolic processes such as adipogenesis. Unexpectedly, CPAP therapy in Group 2 subjects was also associated with up-regulation of several immune pathways as well as cholesterol biosynthesis. Collectively, our findings demonstrate that OSA alters distinct inflammatory and metabolic programs in subcutaneous fat, but these transcriptional signatures are not reversed with short-term effective therapy.
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http://dx.doi.org/10.1093/sleep/zsz314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294406PMC
June 2020

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Nat Commun 2019 11 12;10(1):5121. Epub 2019 Nov 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
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http://dx.doi.org/10.1038/s41467-019-12958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851116PMC
November 2019

Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.

Am J Hum Genet 2019 11 24;105(5):1057-1068. Epub 2019 Oct 24.

Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA 98101, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.

Average arterial oxyhemoglobin saturation during sleep (AvSpOS) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpOS variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.
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http://dx.doi.org/10.1016/j.ajhg.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849112PMC
November 2019
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