Association between &lt;em&gt;RTEL1&lt;/em&gt; gene polymorphisms and COPD susceptibility in a Chinese Han population

Ding, Yipeng; Xu, Huanji; Yao, Jing; Xu, Dongchuan; He, Ping; Yi, Shengyang; Li, Quanni; Liu, Yuanshui; Wu, Cibing; Tian, Zhongjie

doi:10.2147/copd.s131246

Cited by 10 publications

(5 citation statements)

References 31 publications

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“…Of 207 proteins detected with the SOMAscan 1.3 K platform, 81 (41%) have previously been detected in BALF [ 29 ]. Using 1323 uniquely mapped SOMAscan protein identities as reference/background gave at hand that the 207 proteins detected in PEx samples are enriched 5.9 times with the proteins previously detected in supernatant from BALF samples (p < 0.0001).…”

Section: Resultsmentioning

confidence: 99%

A novel non-invasive method allowing for discovery of pathologically relevant proteins from small airways

et al. 2022

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Background There is a lack of early and precise biomarkers for personalized respiratory medicine. Breath contains an aerosol of droplet particles, which are formed from the epithelial lining fluid when the small airways close and re-open during inhalation succeeding a full expiration. These particles can be collected by impaction using the PExA® method (Particles in Exhaled Air), and are derived from an area of high clinical interest previously difficult to access, making them a potential source of biomarkers reflecting pathological processes in the small airways. Research question Our aim was to investigate if PExA method is useful for discovery of biomarkers that reflect pathology of small airways. Methods and analysis Ten healthy controls and 20 subjects with asthma, of whom 10 with small airway involvement as indicated by a high lung clearance index (LCI ≥ 2.9 z-score), were examined in a cross-sectional design, using the PExA instrument. The samples were analysed with the SOMAscan proteomics platform (SomaLogic Inc.). Results Two hundred-seven proteins were detected in up to 80% of the samples. Nine proteins showed differential abundance in subjects with asthma and high LCI as compared to healthy controls. Two of these were less abundant (ALDOA4, C4), and seven more abundant (FIGF, SERPINA1, CD93, CCL18, F10, IgM, IL1RAP). sRAGE levels were lower in ex-smokers (n = 14) than in never smokers (n = 16). Gene Ontology (GO) annotation database analyses revealed that the PEx proteome is enriched in extracellular proteins associated with extracellular exosome-vesicles and innate immunity. Conclusion The applied analytical method was reproducible and allowed identification of pathologically interesting proteins in PEx samples from asthmatic subjects with high LCI. The results suggest that PEx based proteomics is a novel and promising approach to study respiratory diseases with small airway involvement.

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Section: Resultsmentioning

confidence: 99%

A novel non-invasive method allowing for discovery of pathologically relevant proteins from small airways

et al. 2022

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“…In addition to lung structural effects, RNA-sequencing revealed that the lung genes dysregulated by the in utero SHS plus elastase treatment ( Figure 4A ) were consistent with emphysema pathogenesis ( Kneidinger et al, 2011 ). The up-regulated genes included: centrosomal protein 57 ( Cep57 ; 6.3-fold), a gene identified as part of a network module associating in utero SHS exposures with adult COPD in humans ( Kachroo et al, 2020 ); nuclear receptor coactivator 7 ( Ncoa7 ; 7.0-fold), whose expression was dysregulated in COPD lung tissue compared to non-disease tissue ( Cho et al, 2015 ); nuclear factor of activated T cells 2 ( Nfatc2 ; 7.9-fold), a transcription factor involved in T cell cytokine production, whose dysregulation has been associated with the pathogenesis of COPD exacerbation ( Singh et al, 2014 ); regulator of telomere elongation helicase 1 ( Rtel1 ; 8.6-fold), for which it was demonstrated that a single-nucleotide polymorphism in this gene was associated with COPD in a case-control study ( Ding et al, 2017 ); and leucine rich repeats and immunoglobulin like domain 2 ( Lrig2 ; 4.8-fold), for which a single-nucleotide polymorphism near this gene was associated with alterations in adjusted density of emphysematous lungs in a genome-wide association study ( Kim et al, 2019a ; Figure 4A ). We also found ( Figure 4A ) that the gene expression of wingless-type MMTV integration site family member 7B ( Wnt7b ) was down-regulated (-9.2-fold) in the in utero SHS plus adult elastase-treated female mice compared to the in utero air plus adult elastase group.…”

Section: Discussionmentioning

confidence: 99%

Mmp12 Is Upregulated by in utero Second-Hand Smoke Exposures and Is a Key Factor Contributing to Aggravated Lung Responses in Adult Emphysema, Asthma, and Lung Cancer Mouse Models

et al. 2021

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Matrix metalloproteinase-12 (Mmp12) is upregulated by cigarette smoke (CS) and plays a critical role in extracellular matrix remodeling, a key mechanism involved in physiological repair processes, and in the pathogenesis of emphysema, asthma, and lung cancer. While cigarette smoking is associated with the development of chronic obstructive pulmonary diseases (COPD) and lung cancer, in utero exposures to CS and second-hand smoke (SHS) are associated with asthma development in the offspring. SHS is an indoor air pollutant that causes known adverse health effects; however, the mechanisms by which in utero SHS exposures predispose to adult lung diseases, including COPD, asthma, and lung cancer, are poorly understood. In this study, we tested the hypothesis that in utero SHS exposure aggravates adult-induced emphysema, asthma, and lung cancer.Methods: Pregnant BALB/c mice were exposed from gestational days 6–19 to either 3 or 10mg/m3 of SHS or filtered air. At 10, 11, 16, or 17weeks of age, female offspring were treated with either saline for controls, elastase to induce emphysema, house-dust mite (HDM) to initiate asthma, or urethane to promote lung cancer. At sacrifice, specific disease-related lung responses including lung function, inflammation, gene, and protein expression were assessed.Results: In the elastase-induced emphysema model, in utero SHS-exposed mice had significantly enlarged airspaces and up-regulated expression of Mmp12 (10.3-fold compared to air-elastase controls). In the HDM-induced asthma model, in utero exposures to SHS produced eosinophilic lung inflammation and potentiated Mmp12 gene expression (5.7-fold compared to air-HDM controls). In the lung cancer model, in utero exposures to SHS significantly increased the number of intrapulmonary metastases at 58weeks of age and up-regulated Mmp12 (9.3-fold compared to air-urethane controls). In all lung disease models, Mmp12 upregulation was supported at the protein level.Conclusion: Our findings revealed that in utero SHS exposures exacerbate lung responses to adult-induced emphysema, asthma, and lung cancer. Our data show that MMP12 is up-regulated at the gene and protein levels in three distinct adult lung disease models following in utero SHS exposures, suggesting that MMP12 is central to in utero SHS-aggravated lung responses.

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“…In our study, we investigated six SNPs in RTEL1: rs6089953, rs6010620, rs6010621, rs2297440, rs4809324, and rs2297441. Among these SNPs, Ding Y et al, (Ding et al, 2017) reported the presence of rs4809324 was associated with increasing the COPD risk. The presence of rs2297441 was found to be associated with Crohn's disease in Canadian children (Amre et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of the relation of telomere length‐related gene (RTEL1) and coronary heart disease risk

Zhong

et al. 2019

Molec Gen & Gen Med

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Background Regulator of telomere elongation helicase 1 ( RTEL1 ), a telomere length‐related gene, is closely linked to cancer and age‐related diseases. The aim of this study was to investigate the association between genetic polymorphisms in the RTEL1 gene and coronary heart disease (CHD) risk. Methods In this case–control study, which includes samples from 596 CHD patients and 603 healthy controls, five SNPs in RTEL1 were selected. The genotypes were studied using the Agena MassARRAY platform, and the statistical analyses were performed using the chi‐square and Fisher's exact tests, genetic model analysis, and haplotype analysis. Results In the allele model, using the chi‐square test, we found that the patients with the “G” allele of rs6010620 and the “C” allele of rs4809324 in the RTEL1 gene showed a decreased risk of CHD once the results were adjusted for age and gender. In the genetic model, logistic regression analyses revealed that the rs6010620 polymorphism conferred a decreased risk of CHD in the codominant model (OR = 0.52, 95% CI: 0.31–0.88, p = 0.007 for the “G/G” genotype) and the recessive model (OR = 0.49, 95% CI: 0.30–0.80, p = 0.004 for the “G/G” genotype). In addition, the haplotype “G rs6010620 T rs6010621 T rs4809324 ” of RTEL1 was associated with a 0.03‐fold decreased risk of CHD once the results were adjusted for age and gender (OR = 0.03, 95% CI: 0.01–0.12, p < 0.001). Conclusion Our findings have demonstrated that the genetic variants of RTEL1 may have a protective role against CHD risk.

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Association between <em>RTEL1</em> gene polymorphisms and COPD susceptibility in a Chinese Han population

Cited by 10 publications

References 31 publications

A novel non-invasive method allowing for discovery of pathologically relevant proteins from small airways

A novel non-invasive method allowing for discovery of pathologically relevant proteins from small airways

Mmp12 Is Upregulated by in utero Second-Hand Smoke Exposures and Is a Key Factor Contributing to Aggravated Lung Responses in Adult Emphysema, Asthma, and Lung Cancer Mouse Models

Genetic analysis of the relation of telomere length‐related gene (RTEL1) and coronary heart disease risk

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