Emerging genetics of COPD

Berndt, Annerose; Leme, Adriana S.; Shapiro, Steven D.

doi:10.1002/emmm.201100627

Cited by 73 publications

(56 citation statements)

References 101 publications

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“…Similarly, population studies indicate an association of SNPs near IL1RL1 on chromosome 2 and IL33 on chromosome 9 with the development of asthma (65)(66)(67), but to our knowledge, no similar associations have been reported for COPD thus far (68). Moreover, the present results suggest that environmental agents (i.e., viral infection) may alter IL-33 expression, making it likely that epigenetic approaches may be more informative than studies of gene sequence in identifying a basis for COPD-related differences in airway epithelial cells.…”

Section: Methodsmentioning

confidence: 69%

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

Byers

Alexander‐Brett²,

Patel³

et al. 2013

J. Clin. Invest.

280

255

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Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13-dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production.

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Section: Methodsmentioning

confidence: 69%

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

Byers

Alexander‐Brett²,

Patel³

et al. 2013

J. Clin. Invest.

280

255

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“…Unfortunately, few studies have successfully unraveled the genetic predisposition and pathogenetic mechanisms for COPD 25. Dysregulation of miRNAs has been reported to be involved in the pathogenesis of pulmonary diseases, including COPD 26.…”

Section: Discussionmentioning

confidence: 99%

Peripheral leukocyte microRNAs as novel biomarkers for COPD

Wang¹,

Xu²,

Liu³

et al. 2017

COPD

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COPD is a multifactorial disease caused by environmental determinants as well as genetic risk factors. The prevalence and mortality of COPD continue to increase, and underdiagnosis of COPD remains a critical issue. Previous reports investigated promising microRNAs (miRNAs) to reveal the molecular mechanism for the development of COPD; however, diagnostic and therapeutic markers for COPD have not yet been found. For this study, 20 representative COPD patients were separated into four groups based on increasing severity (A, B, C, and D) and compared to six healthy controls. Small RNA profiles of peripheral leukocytes were differentially expressed miRNAs (analyzed via next-generation sequencing) were validated via quantitative reverse transcriptase-polymerase chain reaction. Compared to healthy controls, 19 differentially expressed miRNAs were found in COPD patients. For all COPD groups, miR-3177-3p was downregulated, while 17 miRNAs were upregulated. Furthermore, the results revealed 21 differentially expressed miRNAs, of which miR-183-5p was continually downregulated from A to B to D. Between respective bronchodilator reversibility positive and negative groups of COPD different groups (A, B, C, and D), 10 miRNAs were differentially expressed, while miR-100-5p was upregulated in the negative groups. In conclusion, miR-106b-5p, miR-125a-5p, miR-183-5p, and miR-100-5p are central for the development of COPD. The severity of COPD was attenuated by miR-106b-5p, thus suggesting this miRNA as potential target for disease treatment.

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“…However, only a fraction (∼20%) of smokers develop COPD, and some families have an increased risk to COPD, suggesting that host factors, likely inherited, modulate the risk for COPD from smoking [2]. Consistent with this concept, genome-wide association studies (GWAS), and candidate gene studies have identified COPD risk loci [3]–[5]. However, despite convincing evidence that inherited genetic variation conveys an increased risk of COPD in smokers, the relationship between these loci and the disordered biology of specific cell types within the lung is unclear.…”

Section: Introductionmentioning

confidence: 95%

Smoking Dysregulates the Human Airway Basal Cell Transcriptome at COPD Risk Locus 19q13.2

et al. 2014

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Genome-wide association studies (GWAS) and candidate gene studies have identified a number of risk loci associated with the smoking-related disease COPD, a disorder that originates in the airway epithelium. Since airway basal cell (BC) stem/progenitor cells exhibit the earliest abnormalities associated with smoking (hyperplasia, squamous metaplasia), we hypothesized that smoker BC have a dysregulated transcriptome, enriched, in part, at known GWAS/candidate gene loci. Massive parallel RNA sequencing was used to compare the transcriptome of BC purified from the airway epithelium of healthy nonsmokers (n = 10) and healthy smokers (n = 7). The chromosomal location of the differentially expressed genes was compared to loci identified by GWAS to confer risk for COPD. Smoker BC have 676 genes differentially expressed compared to nonsmoker BC, dominated by smoking up-regulation. Strikingly, 166 (25%) of these genes are located on chromosome 19, with 13 localized to 19q13.2 (p<10−4 compared to chance), including 4 genes (NFKBIB, LTBP4, EGLN2 and TGFB1) associated with risk for COPD. These observations provide the first direct connection between known genetic risks for smoking-related lung disease and airway BC, the population of lung cells that undergo the earliest changes associated with smoking.

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Emerging genetics of COPD

Cited by 73 publications

References 101 publications

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

Long-term IL-33–producing epithelial progenitor cells in chronic obstructive lung disease

Peripheral leukocyte microRNAs as novel biomarkers for COPD

Smoking Dysregulates the Human Airway Basal Cell Transcriptome at COPD Risk Locus 19q13.2

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