GLCCI1 rs37973: a potential genetic predictor of therapeutic response to inhaled corticosteroids in Chinese chronic obstructive pulmonary disease patients

Lei, Yuan; Gao, Yiping; Chen, Jinkun; Li, Miao; Wu, Xiaomei; Qin, Ning; Zhao, Jianping; Xiong, Weining; Xu, Yongjian; Xie, Jungang

doi:10.1038/srep42552

Cited by 13 publications

(9 citation statements)

References 38 publications

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“…However, the prolonged lifespan of neutrophils does not enhance host immunity but contributes to bacterial persistence in the lungs of smokers and is likely to promote further pulmonary recruitment of neutrophils. Not all studies found that CSE suppressed the apoptotic course of neutrophils and that some suggest that CSE could induce apoptosis of neutrophils [49]. In the present study, we found that CSE did indeed induce apoptosis of neutrophils and that 1 mM matrine induced most neutrophils to enter early apoptosis after being incubated for 24 h in culture medium or CSE.…”

Section: Discussionsupporting

confidence: 58%

Matrine reduces cigarette smoke-induced airway neutrophilic inflammation by enhancing neutrophil apoptosis

Seow

Wang

et al. 2019

Clinical Science

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Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and will become the third largest cause of death in the world by 2030. It is well established that an exaggerated inflammatory and oxidative stress response to cigarette smoke (CS) leads to, emphysema, small airway fibrosis, mucus hypersecretion, and progressive airflow limitation. Current treatments have limited efficacy in inhibiting chronic inflammation and consequently do not reverse the pathology that initiates and drives the long-term progression of disease. In particular, there are no effective therapeutics that target neutrophilic inflammation in COPD, which is known to cause tissue damage by degranulation of a suite of proteolytic enzymes including neutrophil elastase (NE). Matrine, an alkaloid compound extracted from Sophora flavescens Ait, has well known anti-inflammatory activity. Therefore, the aim of the present study was to investigate whether matrine could inhibit CS-induced lung inflammation in mice. Matrine significantly reduced CS-induced bronchoalveolar lavage fluid (BALF) neutrophilia and NE activity in mice. The reduction in BALF neutrophils in CS-exposed mice by matrine was not due to reductions in pro-neutrophil cytokines/chemokines, but rather matrine’s ability to cause apoptosis of neutrophils, which we demonstrated ex vivo. Thus, our data suggest that matrine has anti-inflammatory actions that could be of therapeutic potential in treating CS-induced lung inflammation observed in COPD.

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Section: Discussionsupporting

confidence: 58%

Matrine reduces cigarette smoke-induced airway neutrophilic inflammation by enhancing neutrophil apoptosis

Seow

Wang

et al. 2019

Clinical Science

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“…Interestingly, studies in COPD patients, which attempted to replicate the pharmacogenetic effect of rs37973, have yielded conflicting results. Although one study of 462 Caucasians failed to identify an association [26], another study of 204 Chinese COPD patients demonstrated a significant association with ICS response [27]. The reasons behind these conflicting data for rs37973 in COPD are not clear, but may be due to differences in the underlying disease severity, sample sizes (low power), medications that were evaluated including different potencies of ICS and use of combination drugs rather than ICS monotherapy and differential follow-up times across studies.…”

Section: Discussionmentioning

confidence: 99%

The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD

Obeidat

Faiz

et al. 2019

Eur Respir J

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Inhaled corticosteroids (ICS) are widely prescribed for patients with chronic obstructive pulmonary disease (COPD), yet have variable outcomes and adverse reactions, which may be genetically determined. The primary aim of the study was to identify the genetic determinants for forced expiratory volume in 1 s (FEV1) changes related to ICS therapy.In the Lung Health Study (LHS)-2, 1116 COPD patients were randomised to the ICS triamcinolone acetonide (n=559) or placebo (n=557) with spirometry performed every 6 months for 3 years. We performed a pharmacogenomic genome-wide association study for the genotype-by-ICS treatment effect on 3 years of FEV1 changes (estimated as slope) in 802 genotyped LHS-2 participants. Replication was performed in 199 COPD patients randomised to the ICS, fluticasone or placebo.A total of five loci showed genotype-by-ICS interaction at p<5×10−6; of these, single nucleotide polymorphism (SNP) rs111720447 on chromosome 7 was replicated (discovery p=4.8×10−6, replication p=5.9×10−5) with the same direction of interaction effect. ENCODE (Encyclopedia of DNA Elements) data revealed that in glucocorticoid-treated (dexamethasone) A549 alveolar cell line, glucocorticoid receptor binding sites were located near SNP rs111720447. In stratified analyses of LHS-2, genotype at SNP rs111720447 was significantly associated with rate of FEV1 decline in patients taking ICS (C allele β 56.36 mL·year−1, 95% CI 29.96–82.76 mL·year−1) and in patients who were assigned to placebo, although the relationship was weaker and in the opposite direction to that in the ICS group (C allele β −27.57 mL·year−1, 95% CI −53.27– −1.87 mL·year−1).The study uncovered genetic factors associated with FEV1 changes related to ICS in COPD patients, which may provide new insight on the potential biology of steroid responsiveness in COPD.

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“… 27 AHR is a fundamental characteristic in asthma and also present in COPD patients and in 12%–22% of healthy subjects. 28 Compared to those without AHR, subjects with AHR are more likely to experience respiratory symptoms such as cough, phlegm, dyspnea, persistent wheeze, asthmatic attacks, and progressive airflow obstruction, and COPD patients with AHR suffer from a higher rate of FEV 1 decline, more severe air trapping, and a double increased risk of respiratory mortality. 29 – 32 We therefore suggest that AHR may be a risk factor for airway obstruction in smokers.…”

Section: Discussionmentioning

confidence: 99%

Increased matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio in smokers with airway hyperresponsiveness and accelerated lung function decline

Lo¹,

Huang²,

He³

et al. 2018

COPD

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BackgroundAirway hyperresponsiveness (AHR) is associated with airway inflammation and a rapid decline in lung function and is a predictor of future risk of COPD among smokers. Alveolar macrophages (AMs) from patients with COPD release a greater amount of matrix metalloproteinase (MMP)-9. We hypothesized that the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) is related to AHR in smokers.Patients and methodsHealthy smokers with AHR (AHR + S) or smokers without AHR (AHR − S; divided according to a methacholine challenge test) and nonsmokers without AHR (AHR − NS) were enrolled. Spirometry was performed during enrollment and repeated after 5 years. Initially, AMs recovered from bronchoalveolar lavage (BAL) fluid were cultured in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), MAPK kinase (MEK) 1/2 (the MEK of extracellular signal-regulated kinase [ERK] inhibitor, PD98059), or medium alone for 24 h. The release of MMP-9 and TIMP-1 in culture supernatants was measured by enzyme-linked immunosorbent assay.ResultsA greater reduction in forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), FEV1 (as a percentage of the predicted value [%pred]), and maximal mid-expiratory flow (MMEF) was observed among AHR + S in the 5-year period. There was a higher proportion of neutrophils and a lower proportion of AMs in BAL fluid recovered from AHR + S. Compared to AMs from AHR − NS and AHR − S, AMs from nonsmokers with AHR (AHR + NS) released more MMP-9 and less TIMP-1, with an increase in MMP-9/TIMP-1 ratios. The MMP-9/TIMP-1 ratio in smokers was positively correlated with the annual decline in FEV1%pred, FVC%pred, and MMEF%pred. Both SB203580 and PD98059 significantly reduced MMP-9, but not TIMP-1, from AMs of smokers.ConclusionAMs of AHR + NS produce excessive MMP-9 over TIMP-1, which may be a predictor of the development of airway obstruction. Inhibition of p38 MAPK and ERK suppresses the generation of MMP-9 by AMs from smokers.

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GLCCI1 rs37973: a potential genetic predictor of therapeutic response to inhaled corticosteroids in Chinese chronic obstructive pulmonary disease patients

Cited by 13 publications

References 38 publications

Matrine reduces cigarette smoke-induced airway neutrophilic inflammation by enhancing neutrophil apoptosis

Matrine reduces cigarette smoke-induced airway neutrophilic inflammation by enhancing neutrophil apoptosis

The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD

Increased matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio in smokers with airway hyperresponsiveness and accelerated lung function decline

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