Publications by authors named "Nathan Schoettler"

16 Publications

  • Page 1 of 1

Genome-wide association study identifies TNFSF15associated with childhood asthma.

Allergy 2021 May 22. Epub 2021 May 22.

Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.

Background: Genome-wide association studies (GWASs) of asthma have identified several risk alleles and loci, but most have been conducted in individuals with European ancestry. Studies in Asians, especially children, are still lacking. We aimed to identify susceptibility loci by performing the first GWAS of asthma in Korean children with persistent asthma.

Methods: We used a discovery set of 741 children with persistent asthma as cases and 589 healthy children and 551 healthy adults as controls to perform a GWAS.We validated our GWAS findings using UK Biobank data. Wethen used the Genotype-Tissue Expression database to identify expression quantitative trait loci of candidate variants. Finally, we quantified proteins of genes associated with asthma.

Results: Variantsat the 17q12-21 locus and SNPs inCYBRD1 and TNFSF15 genes wereassociated with persistent childhood asthmaat genome-wide thresholds of significance. Four SNPsin the TNFSF15 gene were also associated with childhood-onset asthma in British white participants in the UK Biobank data. The asthma-associated rs7856856-C allele, the lead SNP, was associated with decreased TNFSF15 expression in whole blood and in arteries.Korean children with asthma had lower serum TNFSF15 levels than controls, and those with the asthma risk rs7856856-CC genotype exhibited the lowest serum TNFSF15 levels overall, especially asthmatic children.

Conclusions: Our GWAS of persistent childhood asthma with allergic sensitization identified a new susceptibility gene, TNFSF15, andreplicated associations at the 17q12-21 childhood-onset asthma locus.This novel association may be mediated by reduced expression of serum TNFSF15 and loss of suppression of angiogenesis.
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http://dx.doi.org/10.1111/all.14952DOI Listing
May 2021

A series of COVID-19 autopsies with clinical and pathologic comparisons to both seasonal and pandemic influenza.

J Pathol Clin Res 2021 May 7. Epub 2021 May 7.

Department of Pathology, University of Chicago Medical Center, Chicago, IL, USA.

Autopsies of patients who have died from COVID-19 have been crucial in delineating patterns of injury associated with SARS-CoV-2 infection. Despite their utility, comprehensive autopsy studies are somewhat lacking relative to the global burden of disease, and very few comprehensive studies contextualize the findings to other fatal viral infections. We developed a novel autopsy protocol in order to perform postmortem examinations on victims of COVID-19 and herein describe detailed clinical information, gross findings, and histologic features observed in the first 16 complete COVID-19 autopsies. We also critically evaluated the role of ancillary studies used to establish a diagnosis of COVID-19 at autopsy, including immunohistochemistry (IHC), in situ hybridization (ISH), and electron microscopy (EM). IHC and ISH targeting SARS-CoV-2 were comparable in terms of the location and number of infected cells in lung tissue; however, nonspecific staining of bacteria was seen occasionally with IHC. EM was unrevealing in blindly sampled tissues. We then compared the clinical and histologic features present in this series to six archival cases of fatal seasonal influenza and six archival cases of pandemic influenza from the fourth wave of the 'Spanish Flu' in the winter of 1920. In addition to routine histology, the inflammatory infiltrates in the lungs of COVID-19 and seasonal influenza victims were compared using quantitative IHC. Our results demonstrate that the clinical and histologic features of COVID-19 are similar to those seen in fatal cases of influenza, and the two diseases tend to overlap histologically. There was no significant difference in the composition of the inflammatory infiltrate in COVID-19 and influenza at sites of acute lung injury at the time of autopsy. Our study underscores the relatively nonspecific clinical features and pathologic changes shared between severe cases of COVID-19 and influenza, while also providing important caveats to ancillary methods of viral detection.
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http://dx.doi.org/10.1002/cjp2.220DOI Listing
May 2021

SARS-CoV-2 infection reduces Krüppel-Like Factor 2 in human lung autopsy.

bioRxiv 2021 Jan 18. Epub 2021 Jan 18.

Acute respiratory distress syndrome (ARDS) occurred in ~12% of hospitalized COVID-19 patients in a recent New York City cohort. Pulmonary endothelial dysfunction, characterized by increased expression of inflammatory genes and increased monolayer permeability, is a major component of ARDS. Vascular leak results in parenchymal accumulation of leukocytes, protein, and extravascular water, leading to pulmonary edema, ischemia, and activation of coagulation associated with COVID-19. Endothelial inflammation further contributes to uncontrolled cytokine storm in ARDS. We have recently demonstrated that Kruppel-like factor 2 (KLF2), a transcription factor which promotes endothelial quiescence and monolayer integrity, is significantly reduced in experimental models of ARDS. Lung inflammation and high-tidal volume ventilation result in reduced KLF2, leading to pulmonary endothelial dysfunction and acute lung injury. Mechanistically, we found that KLF2 is a potent transcriptional activator of Rap guanine nucleotide exchange factor 3 (RAPGEF3) which orchestrates and maintains vascular integrity. Moreover, KLF2 regulates multiple genome-wide association study (GWAS)-implicated ARDS genes. Whether lung KLF2 is regulated by SARS-CoV-2 infection is unknown. Here we report that endothelial KLF2 is significantly reduced in human lung autopsies from COVID-19 patients, which supports that ARDS due to SARS-CoV-2 is a vascular phenotype possibly attributed to KLF2 down-regulation. We provide additional data demonstrating that KLF2 is down-regulated in SARS-CoV infection in mice.
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http://dx.doi.org/10.1101/2021.01.15.426691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814823PMC
January 2021

Transcriptional programming and T cell receptor repertoires distinguish human lung and lymph node memory T cells.

Commun Biol 2019 13;2:411. Epub 2019 Nov 13.

2Department of Human Genetics, The University of Chicago, Chicago, USA.

Antigen-specific memory T cells persist for years after exposure to a pathogen and provide effective recall responses. Many memory T cell subsets have been identified and differ in abundance throughout tissues. This study focused on CD4 and CD8 memory T cells from paired human lung and lung draining lymph node (LDLN) samples and identified substantial differences in the transcriptional landscape of these subsets, including higher expression of an array of innate immune receptors in lung T cells which were further validated by flow cytometry. Using T cell receptor analysis, we determined the clonal overlap between memory T cell subsets within the lung and within the LDLN, and this was greater than the clonal overlap observed between memory T cell subsets compared across tissues. Our results suggest that lung and LDLN memory T cells originate from different precursor pools, recognize distinct antigens and likely have separate roles in immune responses.
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http://dx.doi.org/10.1038/s42003-019-0657-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853923PMC
May 2020

Recent Advances in Severe Asthma: From Phenotypes to Personalized Medicine.

Chest 2020 03 31;157(3):516-528. Epub 2019 Oct 31.

Department of Medicine, Section of Pulmonary and Critical Care, University of Chicago, Chicago, IL.

This review focuses on recent clinical and translational discoveries in severe and uncontrolled asthma that now enable phenotyping and personalized therapies in these patients. Although asthma is common in both children and adults and typically responds to standard therapies, a subset of individuals with asthma experience severe and/or persistent symptoms despite appropriate therapies. Airflow obstruction leading to frequent symptoms requiring higher levels of controller therapy is the cardinal feature of severe asthma, but the underlying molecular mechanisms, or endotypes, are diverse and variable between individuals. Two major risk factors that contribute to severe asthma are genetics and environmental exposures that modulate immune responses, and although these often interact in complex manners that are not fully understood, certain endotypes converge in severe asthma. A number of studies have evaluated various features of patients with severe asthma and classified patients into phenotypes with clinical relevance. This phenotyping is now incorporated into clinical practice and can be used to guide advanced biological therapies that target specific molecules and inflammatory pathways that contribute to asthma pathogenesis.
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http://dx.doi.org/10.1016/j.chest.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609962PMC
March 2020

Advances in asthma and allergic disease genetics: Is bigger always better?

J Allergy Clin Immunol 2019 12 31;144(6):1495-1506. Epub 2019 Oct 31.

Department of Human Genetics, University of Chicago, Chicago, Ill.

This review focuses on genome-wide association studies (GWASs) of asthma and allergic diseases published between January 1, 2018, and June 30, 2019. During this time period, there were 38 GWASs reported in 19 articles, including the largest performed to date for many of these conditions. Overall, we learned that childhood-onset asthma is associated with the most independent loci compared with other defined groups of asthma and allergic disease cases; adult-onset asthma and moderate-to-severe asthma are associated with fewer genes, which are largely a subset of those associated with childhood-onset asthma. There is significant genetic overlap between asthma and allergic diseases, particularly with respect to childhood-onset asthma, which involves genes that reflect the importance of barrier function biology, and to HLA region genes, which are the most frequently associated genes overall in both groups of diseases. Although the largest GWASs in African American and Latino/Hispanic populations were reported during this period, they are still significantly underpowered compared with studies reported in populations of European ancestry, highlighting the need for larger studies, particularly in patients with childhood-onset asthma and allergic diseases, in these important populations that carry the greatest burden of disease.
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http://dx.doi.org/10.1016/j.jaci.2019.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900451PMC
December 2019

Genetic architecture of moderate-to-severe asthma mirrors that of mild asthma.

J Allergy Clin Immunol 2019 12 18;144(6):1521-1523. Epub 2019 Sep 18.

Department of Human Genetics, University of Chicago, Chicago, Ill. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.09.003DOI Listing
December 2019

Shared and distinct genetic risk factors for childhood-onset and adult-onset asthma: genome-wide and transcriptome-wide studies.

Lancet Respir Med 2019 06 27;7(6):509-522. Epub 2019 Apr 27.

Department of Medicine, The University of Chicago, Chicago, IL, USA. Electronic address:

Background: Childhood-onset and adult-onset asthma differ with respect to severity and comorbidities. Whether they also differ with respect to genetic risk factors has not been previously investigated in large samples. The goals of this study were to identify shared and distinct genetic risk loci for childhood-onset and adult-onset asthma, and to identify the genes that might mediate the effects of associated variation.

Methods: We did genome-wide and transcriptome-wide studies, using data from the UK Biobank, in individuals with asthma, including adults with childhood-onset asthma (onset before 12 years of age), adults with adult-onset asthma (onset between 26 and 65 years of age), and adults without asthma (controls; aged older than 38 years). We did genome-wide association studies (GWAS) for childhood-onset asthma and adult-onset asthma each compared with shared controls, and for age of asthma onset in all asthma cases, with a genome-wide significance threshold of p<5 × 10. Enrichment studies determined the tissues in which genes at GWAS loci were most highly expressed, and PrediXcan, a transcriptome-wide gene-based test, was used to identify candidate risk genes.

Findings: Of 376 358 British white individuals from the UK Biobank, we included 37 846 with self-reports of doctor-diagnosed asthma: 9433 adults with childhood-onset asthma; 21 564 adults with adult-onset asthma; and an additional 6849 young adults with asthma with onset between 12 and 25 years of age. For the first and second GWAS analyses, 318 237 individuals older than 38 years without asthma were used as controls. We detected 61 independent asthma loci: 23 were childhood-onset specific, one was adult-onset specific, and 37 were shared. 19 loci were associated with age of asthma onset. The most significant asthma-associated locus was at 17q12 (odds ratio 1·406, 95% CI 1·365-1·448; p=1·45 × 10) in the childhood-onset GWAS. Genes at the childhood onset-specific loci were most highly expressed in skin, blood, and small intestine; genes at the adult onset-specific loci were most highly expressed in lung, blood, small intestine, and spleen. PrediXcan identified 113 unique candidate genes at 22 of the 61 GWAS loci. Single-nucleotide polymorphism-based heritability estimates were more than three times larger for childhood-onset asthma (0·327) than for adult-onset disease (0·098). The onset of disease in childhood was associated with additional genes with relatively large effect sizes, with the largest odds ratio observed at the FLG locus at 1q21.3 (1·970, 95% CI 1·823-2·129).

Interpretation: Genetic risk factors for adult-onset asthma are largely a subset of the genetic risk for childhood-onset asthma but with overall smaller effects, suggesting a greater role for non-genetic risk factors in adult-onset asthma. Combined with gene expression and tissue enrichment patterns, we suggest that the establishment of disease in children is driven more by dysregulated allergy and epithelial barrier function genes, whereas the cause of adult-onset asthma is more lung-centred and environmentally determined, but with immune-mediated mechanisms driving disease progression in both children and adults.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/S2213-2600(19)30055-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534440PMC
June 2019

Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet 2018 09;50(9):1343

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41588-018-0197-6DOI Listing
September 2018

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet 2018 08 16;50(8):1072-1080. Epub 2018 Jul 16.

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.
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http://dx.doi.org/10.1038/s41588-018-0157-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068780PMC
August 2018

A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle.

J Allergy Clin Immunol 2018 09 4;142(3):749-764.e3. Epub 2018 Jan 4.

Department of Human Genetics, University of Chicago, Chicago, Ill. Electronic address:

Chromosome 17q12-21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12-21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus.
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http://dx.doi.org/10.1016/j.jaci.2017.12.974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172038PMC
September 2018

B cell receptor light chain repertoires show signs of selection with differences between groups of healthy individuals and SLE patients.

Mol Immunol 2012 Jul 18;51(3-4):273-82. Epub 2012 Apr 18.

Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, IL 60637, USA.

We have developed a microarray to study the expression of L-chain V genes (V(L) genes) in healthy and SLE patient peripheral κ- and λ-sorted B cells. In all repertoires tested, one V(L) gene accounts for over 10% of all gene V(L) expression, consistent with positive selection acting on L-chains. While a few V(L) genes were highly expressed in all individuals, most V(L) genes were expressed at different levels. Some V(L) genes (5 out of a total of 78) were not detected. We attribute their absence from the repertoire to negative selection. Positive selection and negative selection were also found in SLE repertoires, but expression of V(L) genes was different; the differences point to less regulation of V(L) gene repertoires in SLE. Our data shows that V(L) gene expression is variable and supports a model where the L-chain repertoire is generated by both positive and negative selection on L-chains.
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http://dx.doi.org/10.1016/j.molimm.2012.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264353PMC
July 2012

Angiogenesis inhibitors for the treatment of chronic autoimmune inflammatory arthritis.

Curr Opin Investig Drugs 2009 May;10(5):425-33

University of Chicago, Pritzker School of Medicine, Gwen Knapp Center for Lupus and Immunology Research, Chicago, IL 60637, USA.

Angiogenesis, the formation of new blood vessels, is closely linked with both the initiation and progression of rheumatoid arthritis (RA). Rheumatoid joints contain elevated levels of proangiogenic molecules, such as VEGF, basic FGF, hypoxia-inducible factor 1 and angiopoietins. Increased angiogenesis is also associated with malignancies and proliferative retinopathies, and targeting this process therapeutically has proven beneficial in treating several of these diseases including colorectal, kidney and lung cancer. Adapting such a therapeutic strategy to the treatment of RA may prove beneficial, as data from preclinical studies have demonstrated that angiogenesis inhibitors reduce pannus formation, inflammation and joint erosion. New therapies that inhibit angiogenesis by blocking VEGFR tyrosine kinase signaling, integrin interactions, microtubule formation and endothelial cell proliferation may be applicable to the treatment of RA. There are several angiogenesis inhibitors that have been approved by the FDA or are currently being assessed in clinical trials which are safe for use in humans, although their effects on RA remain untested. This review discusses the potential of angiogenesis inhibition in the context of treating RA.
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May 2009

Involution of collagen-induced arthritis with an angiogenesis inhibitor, PPI-2458.

J Pharmacol Exp Ther 2009 May 13;329(2):615-24. Epub 2009 Feb 13.

Division of Rheumatology, UCLA School of Medicine, Los Angeles, CA 90095-1670, USA.

Pannus formation, in both rheumatoid arthritis (RA) and collagen-induced arthritis (CIA), is angiogenesis-dependent. PPI-2458 [(1R)-1-carbamoyl-2-methyl]-carbamic acid-(3R,3S,5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)oxiranyl]-1-oxaspiro(2*5)oct-6-yl ester], a new fumagillin derivative known to inhibit methionine aminopeptidase 2 (MetAP-2) and endothelial proliferation at the late G(1) phase, was evaluated in CIA rats to study its potential to involute synovitis. Arthritic syngeneic LOU rats received either a vehicle control or various dosages of oral, intravenous, or subcutaneous PPI-2458. Plasma samples were analyzed to determine a pharmacokinetic profile of PPI-2458, and whole blood was evaluated by flow cytometry to assess the effect on lymphocyte subsets. At 15 mg/kg i.v., 30 mg/kg s.c., or 100 mg/kg p.o., there was a significant reduction in clinical severity scores (p < 0.001) and blinded radiographic scores (p < 0.001) compared with vehicle control groups. Structural damage was virtually eliminated with PPI-2458. Continuous inhibition of MetAP-2 was needed to maintain benefits, although pannus involution could be achieved with the inhibitor when escape flares occurred. Pharmacokinetic analysis after a single p.o. dose showed a rapid T(max) value of 15 min followed by biphasic elimination (t(1/2), approximately 20 min and t(1/2), approximately 5 h) and an estimated oral bioavailability of approximately 15%. Flow cytometry revealed a dose-dependent decrease in white blood cells and lymphocytes manifested as decreases in circulating CD3+ T cells and natural killer cells. PPI-2458, however, did not seem to be immunosuppressive, as determined by delayed-type hypersensitivity or IgG antibody assays. These studies indicate that the MetAP-2 inhibitor PPI-2458 can regress established CIA and that angiogenic mechanisms might be important targets in the treatment of other pannus-mediated diseases such as RA.
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http://dx.doi.org/10.1124/jpet.108.148478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672877PMC
May 2009

Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor.

Clin Immunol 2007 Sep 29;124(3):244-57. Epub 2007 May 29.

Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., San Francisco, CA 94080, USA.

Spleen tyrosine kinase (Syk), a key mediator of immunoreceptor signaling in inflammatory cells, is essential for immune complex-mediated signal transduction initiated by activated receptors for immunoglobulin G. In collagen-induced arthritis, R788/R406, a novel and potent small molecule Syk inhibitor suppressed clinical arthritis, bone erosions, pannus formation, and synovitis. Serum anti-collagen type II antibody levels were unaltered, while the half-life of exogenous antibody was extended when co-administered with R406. Expression of the targeted kinase (Syk) in synovial tissue correlated with the joint level of inflammatory cell infiltrates and was virtually undetectable in treated rats. Syk inhibition suppressed synovial cytokines and cartilage oligomeric matrix protein (COMP) in serum, suggesting a sensitive and reliable biomarker for R406 activity. These results highlight the role of activating Fcgamma receptors in inflammatory synovitis and suggest that interruption of the signaling cascade with a novel Syk inhibitor may be a useful addition to immunosuppressive disease-modifying anti-rheumatic drugs currently used in the treatment of human autoimmune diseases such as rheumatoid arthritis.
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http://dx.doi.org/10.1016/j.clim.2007.03.543DOI Listing
September 2007