Publications by authors named "Sally E Wenzel"

231 Publications

Benefits of Airway Androgen Receptor Expression in Human Asthma.

Am J Respir Crit Care Med 2021 Mar 29. Epub 2021 Mar 29.

Indiana University School of Medicine, 12250, Department of Pediatrics, Indianapolis, Indiana, United States;

RATIONALE Androgens are potentially beneficial in asthma, but androgen receptor (AR) has not been studied in human airways. OBJECTIVES To measure whether AR and its ligands are associated with human asthma outcomes. METHODS We compared AR expression to lung function, symptom scores and fractional of exhaled nitric oxide (FENO) in adults enrolled in the Severe Asthma Research Program (SARP). Further, asthma exacerbations, and emergency department (ED) visits were also evaluated in the SARP, with validation studies in the Cleveland Clinic Health System (CCHS) and the National Health and Nutrition Examination Survey (NHANES). MEASUREMENTS AND MAIN RESULTS In SARP (n=128), AR gene expression from bronchoscopic epithelial brushings was positively correlated with FEV1/FVC ratio (R2=0.135, p=0.0002) and total AQLQ score (R2=0.056, p=0.016); and was negatively associated with FENO (R2=0.178, p=9.8e-06) and NOS2 gene expression (R2=0.281, p=1.2e-10). In SARP (n=1,659), CCHS (n=32,527) and NHANES (n=2,629), women had more asthma exacerbations and ED visits than men. Levels of the AR ligand precursor dehydroepiandrosterone sulfate (DHEA-S) correlated positively with FEV1 in both women and men. CONCLUSIONS Higher AR expression in bronchial epithelial cells, and higher androgen levels, are associated with better lung function, fewer symptoms and lower FENO in human asthma. The role of androgens should be considered in asthma management.
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http://dx.doi.org/10.1164/rccm.202009-3720OCDOI Listing
March 2021

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

medRxiv 2021 Mar 20. Epub 2021 Mar 20.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.
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http://dx.doi.org/10.1101/2021.03.19.21253986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987050PMC
March 2021

Reply to: The Visible and Invisible Faces of the Iceberg of Type 2 Asthma.

Authors:
Sally E Wenzel

Am J Respir Crit Care Med 2021 Mar 17. Epub 2021 Mar 17.

University of Pittsburgh, Division of Pulmonary, Allergy and Critical Care Medicine, Pittsburgh, Pennsylvania, United States.

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http://dx.doi.org/10.1164/rccm.202102-0398LEDOI Listing
March 2021

Digital Imaging Analysis Reveals Reduced Alveolar α-Smooth Muscle Actin Expression in Severe Asthma.

Appl Immunohistochem Mol Morphol 2021 Mar 12. Epub 2021 Mar 12.

University of Pittsburgh School of Medicine Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.

Expansion of α-smooth muscle actin (α-SMA)-expressing airway smooth muscle of the large airways in asthma is well-studied. However, the contribution of α-SMA-expressing cells in the more distal alveolated parenchyma, including pericytes and myofibroblasts within the alveolar septum, to asthma pathophysiology remains relatively unexplored. The objective of this study was to evaluate α-SMA expression in the alveolated parenchyma of individuals with severe asthma (SA), compared with healthy controls or individuals with chronic obstructive pulmonary disease. Using quantitative digital image analysis and video-assisted thoracoscopic surgery lung biopsies, we show that alveolated parenchyma α-SMA expression is markedly reduced in SA in comparison to healthy controls (mean %positive pixels: 12% vs. 23%, P=0.005). Chronic obstructive pulmonary disease cases showed a similar, but trending, decrease in α-SMA positivity compared with controls (mean %positivity: 17% vs. 23%, P=0.107), which may suggest loss of α-SMA expression is a commonality of obstructive lung diseases. The SA group had similar staining for ETS-related gene protein, a specific endothelial marker, comparatively to controls (mean %positive nuclei: 34% vs. 42%, P=0.218), which suggests intact capillary endothelium and likely intact capillary-associated, α-SMA-positive pericytes. These findings suggest that the loss of α-SMA expression in SA may be because of changes in myofibroblast α-SMA expression or cell number. Further study is necessary to fully evaluate possible mechanisms and consequences of this phenomenon.
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http://dx.doi.org/10.1097/PAI.0000000000000926DOI Listing
March 2021

Author Correction: Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Authors:
Alexander G Bick Joshua S Weinstock Satish K Nandakumar Charles P Fulco Erik L Bao Seyedeh M Zekavat Mindy D Szeto Xiaotian Liao Matthew J Leventhal Joseph Nasser Kyle Chang Cecelia Laurie Bala Bharathi Burugula Christopher J Gibson Abhishek Niroula Amy E Lin Margaret A Taub Francois Aguet Kristin Ardlie Braxton D Mitchell Kathleen C Barnes Arden Moscati Myriam Fornage Susan Redline Bruce M Psaty Edwin K Silverman Scott T Weiss Nicholette D Palmer Ramachandran S Vasan Esteban G Burchard Sharon L R Kardia Jiang He Robert C Kaplan Nicholas L Smith Donna K Arnett David A Schwartz Adolfo Correa Mariza de Andrade Xiuqing Guo Barbara A Konkle Brian Custer Juan M Peralta Hongsheng Gui Deborah A Meyers Stephen T McGarvey Ida Yii-Der Chen M Benjamin Shoemaker Patricia A Peyser Jai G Broome Stephanie M Gogarten Fei Fei Wang Quenna Wong May E Montasser Michelle Daya Eimear E Kenny Kari E North Lenore J Launer Brian E Cade Joshua C Bis Michael H Cho Jessica Lasky-Su Donald W Bowden L Adrienne Cupples Angel C Y Mak Lewis C Becker Jennifer A Smith Tanika N Kelly Stella Aslibekyan Susan R Heckbert Hemant K Tiwari Ivana V Yang John A Heit Steven A Lubitz Jill M Johnsen Joanne E Curran Sally E Wenzel Daniel E Weeks Dabeeru C Rao Dawood Darbar Jee-Young Moon Russell P Tracy Erin J Buth Nicholas Rafaels Ruth J F Loos Peter Durda Yongmei Liu Lifang Hou Jiwon Lee Priyadarshini Kachroo Barry I Freedman Daniel Levy Lawrence F Bielak James E Hixson James S Floyd Eric A Whitsel Patrick T Ellinor Marguerite R Irvin Tasha E Fingerlin Laura M Raffield Sebastian M Armasu Marsha M Wheeler Ester C Sabino John Blangero L Keoki Williams Bruce D Levy Wayne Huey-Herng Sheu Dan M Roden Eric Boerwinkle JoAnn E Manson Rasika A Mathias Pinkal Desai Kent D Taylor Andrew D Johnson Paul L Auer Charles Kooperberg Cathy C Laurie Thomas W Blackwell Albert V Smith Hongyu Zhao Ethan Lange Leslie Lange Stephen S Rich Jerome I Rotter James G Wilson Paul Scheet Jacob O Kitzman Eric S Lander Jesse M Engreitz Benjamin L Ebert Alexander P Reiner Siddhartha Jaiswal Gonçalo Abecasis Vijay G Sankaran Sekar Kathiresan Pradeep Natarajan

Nature 2021 Mar;591(7851):E27

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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http://dx.doi.org/10.1038/s41586-021-03280-1DOI Listing
March 2021

PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment.

J Allergy Clin Immunol 2021 Mar 2. Epub 2021 Mar 2.

Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.
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http://dx.doi.org/10.1016/j.jaci.2021.01.037DOI Listing
March 2021

Quantitative CT metrics are associated with longitudinal lung function decline and future asthma exacerbations: results from SARP-3.

J Allergy Clin Immunol 2021 Feb 9. Epub 2021 Feb 9.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS. Electronic address:

Background: Currently there is limited knowledge of what imaging assessments of asthma are associated with accelerated longitudinal lung function decline.

Objectives: We aimed to assess whether quantitative computerized tomography (qCT) metrics are associated with longitudinal lung function decline and morbidity in asthma.

Methods: We analyzed 205 qCT scans of adult asthma patients, and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future lung function change, future exacerbation rate, and changes in validated measurements of morbidity.

Results: Greater baseline wall area percent (WA%) (β=-0.15, 95% CI -0.26 to -0.05, P<0.01), hyperinflation% (β=-0.25, 95% CI -0.41 to -0.09, P<0.01), and Jacobian gradient measurements (cranial-caudal β=10.64, CI 3.79 to 17.49, P<0.01; posterior-anterior β=-9.14, CI -15.49 to -2.78, P<0.01) were associated with more severe future lung function decline. Additionally, greater WA% (rate ratio=1.06, CI 1.01 to 1.10, P=0.02), air-trapping% (rate ratio=1.01, CI 1.00 to 1.02, P=0.03), and lower Jacobian determinant mean (rate ratio=0.58, CI 0.41 to 0.82, P<0.01) and Jacobian determinant standard deviation (rate ratio=0.52, CI 0.32 to 0.85, P=0.01) were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires.

Conclusions: Baseline qCT measures of more severe airway remodeling, more small airways disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.
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http://dx.doi.org/10.1016/j.jaci.2021.01.029DOI Listing
February 2021

Mixed Sputum Granulocyte Longitudinal Impact on Lung Function in the Severe Asthma Research Program.

Am J Respir Crit Care Med 2021 04;203(7):882-892

College of Medicine, University of Arizona, Tucson, Arizona.

Some reports indicate longitudinal variability in sputum differential cell counts, whereas others describe stability. Highly variable sputum eosinophil percentages are associated with greater lung function loss than persistently elevated eosinophil percentages, but elevated neutrophils are linked to more severe asthma. To examine sputum granulocyte stability or variability longitudinally and associations with important clinical characteristics. The SARP III (Severe Asthma Research Program III) cohort underwent comprehensive phenotype characterization at baseline and annually over 3 years. Adult subjects with acceptable sputum levels were assigned to one of three longitudinal sputum groups: eosinophils predominantly <2%, eosinophils predominantly ≥2%, or highly variable eosinophil percentages (>2 SDs determined from independent, repeated baseline eosinophil percentages). Subjects were similarly assigned to one of three longitudinal neutrophil groups with a 50% cut point. The group with predominantly <2% sputum eosinophils had the highest lung function (prebronchodilator FEV% predicted,  < 0.01; FEV/FVC ratio,  < 0.001) at baseline and throughout 3 years compared with other eosinophil groups. Healthcare use did not differ, although the highly variable eosinophil group reported more asthma exacerbations at Year 3. Longitudinal neutrophil groups showed few differences. However, a combination of predominantly ≥2% eosinophil and ≥50% neutrophil groups resulted in the lowest prebronchodilator FEV% predicted ( = 0.049) compared with the combination with predominantly <2% eosinophils and<50% neutrophils. Subjects with predominantly ≥2% sputum eosinophils in combination with predominantly ≥50% neutrophils showed greater loss of lung function, whereas those with highly variable sputum eosinophils had greater healthcare use.
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http://dx.doi.org/10.1164/rccm.202009-3713OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017570PMC
April 2021

Defective STING expression potentiates IL-13 signaling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps.

J Allergy Clin Immunol 2020 Dec 17. Epub 2020 Dec 17.

Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: Stimulator of interferon genes (STING) activation favors effective innate immune responses against viral infections. Its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unknown.

Objective: Our aim was to explore the expression, regulation, and function of STING in CRSwNP.

Methods: STING expression in sinonasal mucosal samples was analyzed by means of quantitative RT-PCR, immunohistochemistry, flow cytometry, and Western blotting. Regulation and function of STING expression were explored by using cultured primary human nasal epithelial cells (HNECs) and cells of the line BEAS-2B in vitro.

Results: STING expression was reduced in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues. STING was predominantly expressed by epithelial cells in nasal tissue and was downregulated by IL-4 and IL-13 in a signal transducer and activator of transcription 6 (STAT6)-dependent manner. HNECs derived from eosinophilic polyps displayed compromised STING-dependent type I interferon production but heightened IL-13-induced STAT6 activation and CCL26 production as compared with HNECs from noneosinophilic polyps and control tissues, which were rescued by exogenous STING overexpression. Knocking down or overexpressing STING decreased or enhanced expression of suppressor of cytokine signaling 1 (SOCS1) in BEAS-2B cells, respectively, independent of the canonic STING pathway elements TBK1 and IRF3. Knocking down SOCS1 abolished the inhibitory effect of STING on IL-13 signaling in BEAS-2B cells. STING expression was positively correlated with SOCS1 expression but negatively correlated with CCL26 expression in nasal epithelial cells from patients with CRSwNP.

Conclusions: Reduced STING expression caused by the type 2 milieu not only impairs STING-dependent type I interferon production but also amplifies IL-13 signaling by decreasing SOCS1 expression in nasal epithelial cells in eosinophilic CRSwNP.
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http://dx.doi.org/10.1016/j.jaci.2020.12.623DOI Listing
December 2020

Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics to Improve Outcomes.

Authors:
Sally E Wenzel

Am J Respir Crit Care Med 2021 04;203(7):809-821

Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh Asthma and Environmental Lung Health Institute at UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania.

Evaluation and effective management of asthma, and in particular severe asthma, remains at the core of pulmonary practice. Over the last 20-30 years, there has been increasing appreciation that "severe asthma" encompasses multiple different subgroups or phenotypes, each with differing presentations. Using clinical phenotyping, in combination with rapidly advancing molecular tools and targeted monoclonal antibodies (human knockouts), the understanding of these phenotypes, and our ability to treat them, have greatly advanced. Type-2 (T2)-high and -low severe asthmas are now easily identified. Fractional exhaled nitric oxide and blood eosinophil counts can be routinely employed in clinical settings to identify these phenotypes and predict responses to specific therapies, meeting the initial goals of precision medicine. Integration of molecular signals, biomarkers, and clinical responses to targeted therapies has enabled identification of critical molecular pathways and, in certain phenotypes, advanced them to near-endotype status. Despite these advances, little guidance is available to determine which class of biologic is appropriate for a given patient, and current "breakthrough" therapies remain expensive and even inaccessible to many patients. Many of the most severe asthmas, with and without T2-biomarker elevations, remain poorly understood and treated. Nevertheless, conceptual understanding of "the severe asthmas" has evolved dramatically in a mere 25 years, leading to dramatic improvements in the lives of many.
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http://dx.doi.org/10.1164/rccm.202009-3631CIDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017568PMC
April 2021

Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate-to-Severe Asthma.

Am J Respir Crit Care Med 2021 04;203(7):841-852

Divisions of Pulmonary and Critical Care and of Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts.

It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function. To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline. Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV% predicted. Categories of participant FEV slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline. Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models ( < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3-1.8), when adjusted for baseline FEV, exacerbation history, blood eosinophils and body mass index. Failure to improve the post-bronchodilator FEV after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.
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http://dx.doi.org/10.1164/rccm.202002-0454OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017577PMC
April 2021

The emerging role of quantitative imaging in asthma.

Br J Radiol 2020 Dec 3:20201133. Epub 2020 Dec 3.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS, USA.

Quantitative imaging of the lung has proved to be a valuable tool that has improved our understanding of asthma. CT, MRI, and positron emission tomography have all been utilized in asthma with each modality having its own distinct advantages and disadvantages. Research has now demonstrated that quantitative imaging plays a valuable role in characterizing asthma phenotypes and endotypes, as well as potentially predicting future asthma morbidity. Nonetheless, future research is needed in order to minimize radiation exposure, standardize reporting, and further delineate how imaging can predict longitudinal outcomes. With future work, quantitative imaging may make its way into the clinical care of asthma and change our practice.
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http://dx.doi.org/10.1259/bjr.20201133DOI Listing
December 2020

Exploration of plasma interleukin-27 levels in asthma patients and the correlation with lung function.

Respir Med 2020 12 29;175:106208. Epub 2020 Oct 29.

Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Respiratory Diseases, National Ministry of Health of the People's Republic of China and National Clinical Research Center for Respiratory Disease, Wuhan, China. Electronic address:

Background: IL-27 attenuates allergic inflammation and improves lung function in mouse models of allergic asthma. However, plasma IL-27 levels of asthma patients and the association with clinical features remain poorly understood.

Methods: This study examined plasma IL-27 protein expression in untreated asthma patients and controls, analyzed its correlation with Th2 inflammation and lung function, and evaluated the effect of corticosteroids on IL-27 expression.

Results: Plasma IL-27 levels were lower in untreated asthma patients compared to controls. Plasma IL-27 levels were inversely correlated with sputum IL-5 mRNA expression in Th2 group. The Th2IL-27 subgroup suffered from the highest airway hyperresponsiveness (AHR) and the worst pulmonary function. The patients in Th2IL-27 subgroup were less likely to be atopic and had the worst improvement of symptoms after four weeks of standard treatment. In vitro, dexamethasone could decrease the expression of IL-27 in THP-1 cell line. The majority of asthma patients had further decreased IL-27 levels after standard treatment, whereas patients with sustained high levels of IL-27 post-treatment had more blood neutrophils at baseline compared with those without.

Conclusions: The results indicate that low levels of IL-27 in peripheral blood are closely related to Th2 inflammation and lung function of asthma patients. Low IL-27 levels in combination with high Th2 inflammation identify an asthma phenotype with high AHR and substantial response to corticosteroids. Understanding of this interaction could help to elucidate the inherent inflammation heterogeneity of asthma.
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http://dx.doi.org/10.1016/j.rmed.2020.106208DOI Listing
December 2020

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Authors:
Alexander G Bick Joshua S Weinstock Satish K Nandakumar Charles P Fulco Erik L Bao Seyedeh M Zekavat Mindy D Szeto Xiaotian Liao Matthew J Leventhal Joseph Nasser Kyle Chang Cecelia Laurie Bala Bharathi Burugula Christopher J Gibson Amy E Lin Margaret A Taub Francois Aguet Kristin Ardlie Braxton D Mitchell Kathleen C Barnes Arden Moscati Myriam Fornage Susan Redline Bruce M Psaty Edwin K Silverman Scott T Weiss Nicholette D Palmer Ramachandran S Vasan Esteban G Burchard Sharon L R Kardia Jiang He Robert C Kaplan Nicholas L Smith Donna K Arnett David A Schwartz Adolfo Correa Mariza de Andrade Xiuqing Guo Barbara A Konkle Brian Custer Juan M Peralta Hongsheng Gui Deborah A Meyers Stephen T McGarvey Ida Yii-Der Chen M Benjamin Shoemaker Patricia A Peyser Jai G Broome Stephanie M Gogarten Fei Fei Wang Quenna Wong May E Montasser Michelle Daya Eimear E Kenny Kari E North Lenore J Launer Brian E Cade Joshua C Bis Michael H Cho Jessica Lasky-Su Donald W Bowden L Adrienne Cupples Angel C Y Mak Lewis C Becker Jennifer A Smith Tanika N Kelly Stella Aslibekyan Susan R Heckbert Hemant K Tiwari Ivana V Yang John A Heit Steven A Lubitz Jill M Johnsen Joanne E Curran Sally E Wenzel Daniel E Weeks Dabeeru C Rao Dawood Darbar Jee-Young Moon Russell P Tracy Erin J Buth Nicholas Rafaels Ruth J F Loos Peter Durda Yongmei Liu Lifang Hou Jiwon Lee Priyadarshini Kachroo Barry I Freedman Daniel Levy Lawrence F Bielak James E Hixson James S Floyd Eric A Whitsel Patrick T Ellinor Marguerite R Irvin Tasha E Fingerlin Laura M Raffield Sebastian M Armasu Marsha M Wheeler Ester C Sabino John Blangero L Keoki Williams Bruce D Levy Wayne Huey-Herng Sheu Dan M Roden Eric Boerwinkle JoAnn E Manson Rasika A Mathias Pinkal Desai Kent D Taylor Andrew D Johnson Paul L Auer Charles Kooperberg Cathy C Laurie Thomas W Blackwell Albert V Smith Hongyu Zhao Ethan Lange Leslie Lange Stephen S Rich Jerome I Rotter James G Wilson Paul Scheet Jacob O Kitzman Eric S Lander Jesse M Engreitz Benjamin L Ebert Alexander P Reiner Siddhartha Jaiswal Gonçalo Abecasis Vijay G Sankaran Sekar Kathiresan Pradeep Natarajan

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations.

J Biopharm Stat 2020 11 17;30(6):1026-1037. Epub 2020 Sep 17.

University of Chicago, Chicago, IL.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients' biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.
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http://dx.doi.org/10.1080/10543406.2020.1821705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954787PMC
November 2020

Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways.

J Allergy Clin Immunol 2021 Mar 11;147(3):894-909. Epub 2020 Aug 11.

Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz.

Background: The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium.

Objectives: We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program.

Methods: Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed.

Results: Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10 
Conclusions: By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized subjects with asthma, we show that SNPs in GSDMB associated with asthma severity, exacerbations, and GSDMB expression levels. Furthermore, its expression levels correlated with asthma exacerbations and antiviral pathways. Thus, GSDMB is a functional gene for both asthma susceptibility and severity.
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http://dx.doi.org/10.1016/j.jaci.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876167PMC
March 2021

Automated quantification of COVID-19 severity and progression using chest CT images.

Eur Radiol 2021 Jan 13;31(1):436-446. Epub 2020 Aug 13.

Department of Radiology, Xi'an Jiaotong University The First Affiliated Hospital, Xi'an, Shaanxi, China.

Objective: To develop and test computer software to detect, quantify, and monitor progression of pneumonia associated with COVID-19 using chest CT scans.

Methods: One hundred twenty chest CT scans from subjects with lung infiltrates were used for training deep learning algorithms to segment lung regions and vessels. Seventy-two serial scans from 24 COVID-19 subjects were used to develop and test algorithms to detect and quantify the presence and progression of infiltrates associated with COVID-19. The algorithm included (1) automated lung boundary and vessel segmentation, (2) registration of the lung boundary between serial scans, (3) computerized identification of the pneumonitis regions, and (4) assessment of disease progression. Agreement between radiologist manually delineated regions and computer-detected regions was assessed using the Dice coefficient. Serial scans were registered and used to generate a heatmap visualizing the change between scans. Two radiologists, using a five-point Likert scale, subjectively rated heatmap accuracy in representing progression.

Results: There was strong agreement between computer detection and the manual delineation of pneumonic regions with a Dice coefficient of 81% (CI 76-86%). In detecting large pneumonia regions (> 200 mm), the algorithm had a sensitivity of 95% (CI 94-97%) and specificity of 84% (CI 81-86%). Radiologists rated 95% (CI 72 to 99) of heatmaps at least "acceptable" for representing disease progression.

Conclusion: The preliminary results suggested the feasibility of using computer software to detect and quantify pneumonic regions associated with COVID-19 and to generate heatmaps that can be used to visualize and assess progression.

Key Points: • Both computer vision and deep learning technology were used to develop computer software to quantify the presence and progression of pneumonia associated with COVID-19 depicted on CT images. • The computer software was tested using both quantitative experiments and subjective assessment. • The computer software has the potential to assist in the detection of the pneumonic regions, monitor disease progression, and assess treatment efficacy related to COVID-19.
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http://dx.doi.org/10.1007/s00330-020-07156-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755837PMC
January 2021

Interleukin-22 Inhibits Respiratory Syncytial Virus Production by Blocking Virus-Mediated Subversion of Cellular Autophagy.

iScience 2020 Jul 10;23(7):101256. Epub 2020 Jun 10.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, MUH 628 NW, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address:

Respiratory syncytial virus (RSV) infection can cause severe bronchiolitis in infants requiring hospitalization, whereas the elderly and immunocompromised are prone to RSV-induced pneumonia. RSV primarily infects lung epithelial cells. Given that no vaccine against RSV is currently available, we tested the ability of the epithelial-barrier protective cytokine interleukin-22 (IL-22) to control RSV production. When used in a therapeutic modality, IL-22 efficiently blunted RSV production from infected human airway and alveolar epithelial cells and IL-22 administration drastically reduced virus titer in the lungs of infected newborn mice. RSV infection resulted in increased expression of LC3B, a key component of the cellular autophagic machinery, and knockdown of LC3B ablated virus production. RSV subverted LC3B with evidence of co-localization and caused a significant reduction in autophagic flux, both reversed by IL-22 treatment. Our findings inform a previously unrecognized anti-viral effect of IL-22 that can be harnessed to prevent RSV-induced severe respiratory disease.
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http://dx.doi.org/10.1016/j.isci.2020.101256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317237PMC
July 2020

Expression of SARS-CoV-2 receptor ACE2 and coincident host response signature varies by asthma inflammatory phenotype.

J Allergy Clin Immunol 2020 08 10;146(2):315-324.e7. Epub 2020 Jun 10.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Department of Environmental Medicine and Occupational Health, Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Electronic address:

Background: More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019.

Objective: We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection.

Methods: Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2-correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets.

Results: Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes.

Conclusions: ACE2 expression is linked to upregulation of viral response genes in a subset of type 2-low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell-activating factors may therefore be of benefit in a subset of patients.
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http://dx.doi.org/10.1016/j.jaci.2020.05.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283064PMC
August 2020

PEBP1 acts as a rheostat between prosurvival autophagy and ferroptotic death in asthmatic epithelial cells.

Proc Natl Acad Sci U S A 2020 06 8;117(25):14376-14385. Epub 2020 Jun 8.

Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260;

Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway epithelial cells (HAECs) generate proferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamines (HpETE-PEs) as proximate death signals. Production of 15-HpETE-PE depends on activation of 15-lipoxygenase-1 (15LO1) in complex with PE-binding protein-1 (PEBP1). We hypothesized that cellular membrane damage induced by these proferroptotic phospholipids triggers compensatory prosurvival pathways, and in particular autophagic pathways, to prevent cell elimination through programmed death. We discovered that PEBP1 is pivotal to driving dynamic interactions with both proferroptotic 15LO1 and the autophagic protein microtubule-associated light chain-3 (LC3). Further, the 15LO1-PEBP1-generated ferroptotic phospholipid, 15-HpETE-PE, promoted LC3-I lipidation to stimulate autophagy. This concurrent activation of autophagy protects cells from ferroptotic death and release of mitochondrial DNA. Similar findings are observed in Type 2 Hi asthma, where high levels of both 15LO1-PEBP1 and LC3-II are seen in HAECs, in association with low bronchoalveolar lavage fluid mitochondrial DNA and more severe disease. The concomitant activation of ferroptosis and autophagy by 15LO1-PEBP1 complexes and their hydroperoxy-phospholipids reveals a pathobiologic pathway relevant to asthma and amenable to therapeutic targeting.
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http://dx.doi.org/10.1073/pnas.1921618117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321965PMC
June 2020

Evidence for Exacerbation-Prone Asthma and Predictive Biomarkers of Exacerbation Frequency.

Am J Respir Crit Care Med 2020 10;202(7):973-982

Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine, Madison, Wisconsin.

Cross-sectional studies suggest an exacerbation-prone asthma (EPA) phenotype and the utility of blood eosinophils and plasma IL-6 as predictive biomarkers. To prospectively test for EPA phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers. Three-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research Program-3. Transition models were used to assess uninformed and informed probabilities of exacerbation in year 3. Binomial regression models were used to assess eosinophils and IL-6 as predictive biomarkers. Eighty-three participants (21%) had ≥1 exacerbation in each year (EPA) and 168 participants (41%) had no exacerbation in any year (exacerbation-resistant asthma). The uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. Compared with exacerbation-resistant asthma, EPA was characterized by lower FEV and a higher prevalence of obesity, hypertension, and diabetes. High-plasma IL-6 occurred in EPA, and the incident rate ratio for exacerbation increased 10% for each 1-pg/μl increase in baseline IL-6 level. Although high blood eosinophils did not occur in EPA, the incident rate ratio for exacerbations increased 9% for each 100-cell/μl increase in baseline eosinophil number. Longitudinal analysis confirms an EPA phenotype characterized by features of metabolic dysfunction. Blood measures of IL-6, but not eosinophils, were significantly associated with EPA, and IL-6 and eosinophils predicted exacerbations in the sample as a whole.
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http://dx.doi.org/10.1164/rccm.201909-1813OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528796PMC
October 2020

ACE2, TMPRSS2, and furin gene expression in the airways of people with asthma-implications for COVID-19.

J Allergy Clin Immunol 2020 07 22;146(1):208-211. Epub 2020 May 22.

National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (Respiratory theme) and College of Life Sciences, University of Leicester, Leicester, United Kingdom.

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http://dx.doi.org/10.1016/j.jaci.2020.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243787PMC
July 2020

COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids.

Am J Respir Crit Care Med 2020 07;202(1):83-90

Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, California.

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 (angiotensin-converting enzyme 2), and TMPRSS2 (transmembrane protease serine 2) mediate viral infection of host cells. We reasoned that differences in ACE2 or TMPRSS2 gene expression in sputum cells among patients with asthma may identify subgroups at risk for COVID-19 morbidity. To determine the relationship between demographic features and sputum ACE2 and TMPRSS2 gene expression in asthma.: We analyzed gene expression for ACE2 and TMPRSS2, and for ICAM-1 (intercellular adhesion molecule 1) (rhinovirus receptor as a comparator) in sputum cells from 330 participants in SARP-3 (Severe Asthma Research Program-3) and 79 healthy control subjects. Gene expression of ACE2 was lower than TMPRSS2, and expression levels of both genes were similar in asthma and health. Among patients with asthma, male sex, African American race, and history of diabetes mellitus were associated with higher expression of ACE2 and TMPRSS2. Use of inhaled corticosteroids (ICS) was associated with lower expression of ACE2 and TMPRSS2, but treatment with triamcinolone acetonide did not decrease expression of either gene. These findings differed from those for ICAM-1, where gene expression was increased in asthma and less consistent differences were observed related to sex, race, and use of ICS. Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID-19 outcomes. The lower expression of ACE2 and TMPRSS2 with ICS use warrants prospective study of ICS use as a predictor of decreased susceptibility to SARS-CoV-2 infection and decreased COVID-19 morbidity.
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http://dx.doi.org/10.1164/rccm.202003-0821OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328313PMC
July 2020

Distinct associations of sputum and oral microbiota with atopic, immunologic, and clinical features in mild asthma.

J Allergy Clin Immunol 2020 11 13;146(5):1016-1026. Epub 2020 Apr 13.

Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, University of Michigan, Ann Arbor, Mich. Electronic address:

Background: Whether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown.

Objective: We sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma.

Methods: Bacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines.

Results: Sputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders.

Conclusions: Novel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.
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http://dx.doi.org/10.1016/j.jaci.2020.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554083PMC
November 2020

Intersection of biology and therapeutics: type 2 targeted therapeutics for adult asthma.

Lancet 2020 02;395(10221):371-383

Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.
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http://dx.doi.org/10.1016/S0140-6736(19)33005-3DOI Listing
February 2020

genotype identifies glucocorticoid responsiveness in severe asthma.

Proc Natl Acad Sci U S A 2020 01 13;117(4):2187-2193. Epub 2020 Jan 13.

Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195;

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive (1245A) allele limits conversion, whereas the adrenal permissive (1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEVPP). (1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEVPP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined ( = 318). Validation was performed in a second cohort (SARP I&II; = 184). DHEA-sulfate is associated with FEVPP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEVPP compared with noGC patients (54.3% vs. 75.1%; < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEVPP difference in GC vs. noGC patients (73.4% vs. 78.9%; = 0.39). Results were independently confirmed: FEVPP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 ( < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 ( = 0.92). The adrenal restrictive (1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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http://dx.doi.org/10.1073/pnas.1918819117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995013PMC
January 2020

Are We Meeting the Promise of Endotypes and Precision Medicine in Asthma?

Physiol Rev 2020 07 9;100(3):983-1017. Epub 2020 Jan 9.

Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; Pulmonary Allergy Critical Care Medicine, Departments of Medicine and of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Pediatrics, Emory University, Atlanta, Georgia.

While the term has long been known to describe heterogeneous groupings of patients, only recently have data evolved which enable a molecular understanding of the clinical differences. The evolution of transcriptomics (and other 'omics platforms) and improved statistical analyses in combination with large clinical cohorts opened the door for molecular characterization of pathobiologic processes associated with a range of asthma patients. When linked with data from animal models and clinical trials of targeted biologic therapies, emerging distinctions arose between patients with and without elevations in type 2 immune and inflammatory pathways, leading to the confirmation of a broad categorization of type 2-Hi asthma. Differences in the ratios, sources, and location of type 2 cytokines and their relation to additional immune pathway activation appear to distinguish several different (sub)molecular phenotypes, and perhaps endotypes of type 2-Hi asthma, which respond differently to broad and targeted anti-inflammatory therapies. Asthma in the absence of type 2 inflammation is much less well defined, without clear biomarkers, but is generally linked with poor responses to corticosteroids. Integration of "big data" from large cohorts, over time, using machine learning approaches, combined with validation and iterative learning in animal (and human) model systems is needed to identify the biomarkers and tightly defined molecular phenotypes/endotypes required to fulfill the promise of precision medicine.
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http://dx.doi.org/10.1152/physrev.00023.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474260PMC
July 2020