ORCID Profile
0000-0002-4907-1657
Current Organisation
Brigham and Women's Hospital
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Publisher: Springer Science and Business Media LLC
Date: 20-05-2019
DOI: 10.1038/S41588-019-0438-3
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: BMJ
Date: 24-08-2020
DOI: 10.1136/THORAXJNL-2019-214487
Abstract: The anti-inflammatory pneumoprotein club cell secretory protein-16 (CC-16) is associated with the clinical expression of chronic obstructive pulmonary disease (COPD). We aimed to determine if there is a causal effect of serum CC-16 level on the risk of having COPD and/or its progression using Mendelian randomisation (MR) analysis. We performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study (LHS), n=3850 and ECLIPSE, n=1702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) as instrumental variables in MR analysis to identify a causal effect of serum CC-16 on ‘COPD risk’ (ie, case status in the International COPD Genetics Consortium/UK-Biobank dataset n=35 735 COPD cases, n=222 076 controls) and ‘COPD progression’ (ie, annual change in forced expiratory volume in 1 s in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1111 lung tissue s les from the Lung Expression Quantitative Trait Locus Study. We identified seven SNPs independently associated (p ×10 –8 ) with serum CC-16 levels six of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (MR estimate (SE) −0.11 (0.04), p=0.008) and progression (LHS only, MR estimate (SE) 7.40 (3.28), p=0.02). Five of the SNPs were also associated with gene expression in lung tissue (at false discovery rate .1) of several genes, including the CC-16-encoding gene SCGB1A1 . We have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on the risk of having COPD and its progression, the biological basis of which warrants further investigation.
Publisher: American Thoracic Society
Date: 2019
Publisher: European Respiratory Society (ERS)
Date: 03-02-2022
DOI: 10.1183/13993003.01814-2021
Abstract: Interstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis however, it is not known if ILA are associated with decreased mean telomere length (MTL). Telomere length was measured with quantitative PCR in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) and Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) cohorts and Southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL Cox proportional hazards models were used to assess the association between MTL and mortality. In all three cohorts, ILA were associated with decreased MTL. In the COPDGene and AGES-Reykjavik cohorts, after adjustment there was greater than twofold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (OR 2.2, 95% CI 1.5–3.4, p=0.0001, and OR 2.6, 95% CI 1.4–4.9, p=0.003, respectively). In the FHS, those with ILA had shorter telomeres than those without ILA (−767 bp, 95% CI 76–1584 bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR 1.3, 95% CI 1.1–1.6, p=0.01) in COPDGene, the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death when comparing the shortest quartile of telomere length in COPDGene and AGES-Reykjavik (HR 0.82, 95% CI 0.4–1.7, p=0.6, and HR 1.2, 95% CI 0.6–2.2, p=0.5, respectively). ILA are associated with decreased MTL.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
Publisher: Springer Science and Business Media LLC
Date: 06-02-2017
DOI: 10.1038/NG.3752
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-07-2022
Abstract: Genome-wide association studies (GWAS) have identified dozens of loci associated with chronic obstructive pulmonary disease (COPD) susceptibility however, the function of associated genes in the cell type(s) affected in disease remains poorly understood, partly due to a lack of cell models that recapitulate human alveolar biology. Here, we apply CRISPR interference to interrogate the function of nine genes implicated in COPD by GWAS in induced pluripotent stem cell–derived type 2 alveolar epithelial cells (iAT2s). We find that multiple genes implicated by GWAS affect iAT2 function, including differentiation potential, maturation, and/or proliferation. Detailed characterization of the GWAS gene DSP demonstrates that it regulates iAT2 cell-cell junctions, proliferation, mitochondrial function, and response to cigarette smoke–induced injury. Our approach thus elucidates the biological function, as well as disease-relevant consequences of dysfunction, of genes implicated in COPD by GWAS in type 2 alveolar epithelial cells.
Publisher: Springer Science and Business Media LLC
Date: 06-02-2017
DOI: 10.1038/NG.3787
No related grants have been discovered for Michael Cho.