Polymorphisms of the ß2 adrenoreceptor gene in chronic obstructive pulmonary disease

ObjectiveChronic obstructive pulmonary disease (COPD) is associated with atherosclerosis. Previous studies including limited sample sizes have shown the prevalence of peripheral arterial occlusive disease (PAOD) among COPD patients. We sought to investigate the incidence of PAOD among COPD patients in Taiwan using a national database.MethodsCOPD patients were collected from the National Health Insurance Research Database of Taiwan from 1996 to 2010. The COPD cohort was propensity score matched according to age, sex, and comorbidities of atrial fibrillation, hypertension, diabetes, hyperlipidemia, cerebrovascular accidents, and chronic liver disease to patients without COPD (the control cohort). We evaluated the incidence of PAOD in COPD patients and the risk of PAOD associated with atrial fibrillation, hypertension, diabetes, hyperlipidemia, cerebrovascular accidents, and chronic liver disease.ResultsThe study included 51,869 COPD patients and 51,869 control patients without COPD. The incidence of PAOD was 1.23-fold higher (95% confidence interval [CI] =1.17–1.29) in the COPD group than in the non-COPD group. Moreover, COPD and atrial fibrillation alone (adjusted hazard ratio (aHR) 2.99; P=0.001), hypertension alone (aHR, 2.05; P<0.001), diabetes alone (aHR, 2.62; P<0.001) and cerebrovascular accidents alone (aHR 2.05; P<0.001), increased the risk of developing PAOD. The significant aHRs increased (from 3.7 to 4.9) when the number of comorbidities increased (from ≥1 to ≥3 comorbidities).ConclusionCOPD patients have a higher incidence and an independently higher risk of PAOD than patients without COPD. The risk of PAOD is markedly elevated in COPD patients with more comorbidities.

Chronic obstructive pulmonary disease (COPD) is characterized by a decline of lung function and symptoms such as chronic bronchitis and emphysema leading from lung tissue destruction. Increased activity of matrix metalloproteinases (MMPs) and an imbalance between MMPs and their tissue inhibitors (TIMPs) are considered as factors influencing the pathogenesis of COPD. We investigated the role of genetic polymorphism and expression level of MMP-9 and concentration of its complexes with TIMPs in the development of COPD among Polish patients. We analyzed SNP in the promoter region of MMP-9 gene (rs3918242) using PCR-RFLP method among 335 COPD patients and 309 healthy individuals. Additionally, 60 COPD patients and 61 controls were tested for copy number variants (CNV) of MMP-9 (by quantitative real-time PCR) and serum levels of MMP-9 and its complexes with TIMP1 and TIMP2 (using ELISA). All subjects were analyzed for lung function using spirometry (FEV1% and FEV1/FVC parameters). We observed that allele and genotype frequencies of the SNP rs3918242, as well as the number of gene copies, were similar in COPD patient and controls groups. Serum levels of MMP-9 and MMP-9/TIMP1 complex were significantly higher in COPD patients in comparison to controls groups, although independently of analyzed gene polymorphisms. Additionally, the significant inverse relationships between parameters of lung function (FEV1% and FEV1/FVC) and proteins level were found in ridge regression models, especially we found that FEV1% decreased when MMP-9 level increased in controls and patients with COPD group. In conclusion, we found that COPD patients were predisposed to produce more MMP-9 and MMP-9/TIMP1 complex than healthy individuals. This phenomenon is probably associated with the disease-related lung environment but not with genetic features of the MMP-9.

Chronic obstructive pulmonary disease (COPD) is common in patients with aortic aneurysms. Severe COPD is associated with an increased risk of aneurysm rupture and perioperative complications. This study assesses the outcomes of COPD and non-COPD patients after fenestrated-branched endovascular aortic aneurysm repair (FBEVAR). A single institution, retrospective study of FBEVAR patients between 2011 and 2020 compared outcomes between COPD and non-COPD patients. COPD patients were stratified by Global Initiative for Chronic Obstructive Lung Disease criteria and oxygen dependence. Outcome measures included 30-day mortality, pulmonary complications, major adverse events (MAE), and mid-term survival. 387 patients (71% male, age 72 years, interquartile range [68-79]) underwent FBEVAR. 181 patients (47%) had COPD. Smoking history was more frequent in COPD patients (P = .022). Among COPD patients, 20.4% were oxygen-dependent. Technical success, defined as successful delivery of the main aortic endograft and all intended side branches, was 98.4%. 30-day mortality (P = .83) and MAE rates (P = .87) were similar between groups. While not statistically significant, COPD patients had more frequent pulmonary complications (6.1% vs. 2.4%, P = .13) and were more frequently discharged on oxygen (P = .002). There were no differences in intensive care unit or hospital length of stay between groups (P = .29; P = .85, respectively). 5-year survival was similar between groups (P = .10). Oxygen-dependent COPD and severe-very severe COPD were associated with decreased mid-term survival (Hazard Ratio 2.39, P = .048). FBEVAR is safe and effective for treating complex aortic pathology in COPD patients, including oxygen-dependent patients. Patients with more severe COPD were more frequently discharged on oxygen. Mid-term survival was slightly reduced in patients with oxygen-dependent and severe-very severe COPD. Level 3, non-randomized controlled cohort/follow-up study.

Background Chronic obstructive pulmonary disease (COPD) is one of the most important causes of morbidity and mortality worldwide, characterized by persistent and progressive airflow limitations. The etiology seems to be an interaction between genetic and environmental factors. Objectives We aim in this present study to evaluate the role of Cytochrome P450 1A1 (CYP1A1 MspI) (3801 T/C) gene polymorphism in the development of Chronic Obstructive Pulmonary Disease ( COPD) by PCR-RFLP. Subjects and Methods Our study was performed on 50 subjects ( 35 COPD patients &amp; 15 control ). Pulmonary function test was performed for patient group,DNA extraction was done and polymorphism was assayed for all participants by polymerase chain reaction-restriction fraction length polymorphism ( PCR-RFLP). Results We found that smoking rate among COPD patients was significantly higher than the control group ( P value = 0.003). The genotypic distribution of the single nucleotide polymorphisms (SNP) 3801 T/C did not differ significantly between patients and healthy controls (P value = 0.78).As regards disease severity , the genotype distribution was found to be significantly different between GOLD 1&amp;2 and Gold 3&amp;4 groups. Combined TC +CC alleles was found in 6 patients ( 100%) of Gold 3&amp;4 ( P value&amp;lt;0.001) Conclusion Our study demonstrated that there is no relation between CYP1A1 gene polymorphism and development of COPD.It shows significant relation between COPD development and smoking, it also shows significant relation between MSPI gene polymorphism and disease severity regarding Gold staging and decline in lung function.

Case-finding and improving patient outcomes for chronic obstructive pulmonary disease in primary care: the BLISS research programme including cluster RCT

Introduction: Little is known about protease, anti-protease markers in chronic obstructive pulmonary disease (COPD) patients. Objectives: The objective of present study was to identify and try to correlate serum markers of protease and anti-protease with pulmonary functions in different stages of patients with COPD and to determine the ratio of neutrophil elastase/alpha-1-antitrypsin in different stages of COPD patients. Methods: This prospective observational study was carried out in patients with stable COPD. Activities of serum alpha-1-antitrypsin and neutrophil elastase were measured in 220 stable COPD patients and in 60 healthy controls by ELISA method. 220 COPD patients were divided into 4 stages according to severity: stage I, II, III and IV. Results: An increase in serum neutrophil elastase and neutrophil elastase/alpha-1-antitrypsin ratio was observed in COPD patients with the advancement of the stage. In contrast to that, decreased activity of alpha-1-antitrypsin in serum was observed in different stages of COPD and is correlated positively with lung function parameters. Conclusion: From these findings we conclude that as the severity increases there is decrease in alpha-1-antitrypsin resulting in concomitant increase in neutrophil elastase activity causing imbalance between protease-antiprotease in COPD patients and this imbalance is associated with impairment of lung function. The neutrophil elastase/ α-1-antitrypsin ratio can tell us the severity of the chronic obstructive pulmonary disease it may be in terms of increased fibrosis of the lung. Though the magnitude of neutrophil elatase/alpha-1-antitrypsin ratio is minute, still it can be a good marker of pulmonary function in term of severity of the COPD.

Allele distribution at a highly polymorphic minisatellite adjacent to the c-Hras1 gene as well as deletions of microsatellite markers, D3S966, D3S1298, D9S171, and a microsatellite within p53 gene, were examined in bronchial epithelium specimens obtained from 53 chronic obstructive pulmonary disease (COPD) patients and healthy donors. A higher frequency of rare Hras1minisatellite alleles in COPD patients than in the individuals without pulmonary pathology (6.6% versus 2.2%; P < 0.05) was shown. This difference was most pronounced in the group of ten COPD patients with idiopathic pulmonary fibrosis. Three of these patients had rare Hras1 minisatellite allele (P < 0.02 in comparison with healthy controls). Alterations in at least one of the microsatellite markers (deletions or microsatellite instability) were detected in bronchial epithelium samples obtained from: 4 of 10 COPD patients with pneumofibrosis (40%); 15 of 43 COPD patients (34.9%) without pneumofibrosis; and 8 of 20 tobacco smokers (40%) without pulmonary pathology. These defects were not observed in the analogous samples obtained from healthy nonsmoking individuals. No statistically significant differences were revealed between COPD patients and healthy smokers upon comparison of both the total number of molecular defects and the number of defects in the individual chromosomal loci. The total number of molecular defects revealed in bronchial epithelium samples from the individuals of two groups examined correlated with the intensity of exposure to tobacco smoke carcinogens (r = 0.28; P < 0.05). These findings suggest that rare alleles at theHras1 locus may be associated with hereditary predisposition to COPD and the development of pneumofibrosis, while mutations in microsatellite markers result from exposure to tobacco smoke carcinogens and are not associated with the appearance of these pathologies.

Background: Cardiovascular diseases associated with chronic obstructive pulmonary disease (COPD) account for 50% of COPD deaths. Autonomic dysfunction and poor pulmonary function increase the cardiovascular risk in COPD patients. Severity of COPD can be assessed by forced expiratory volume in 1 s. Autonomic balance can be assessed by heart rate variability (HRV). There are variations in the reports of COPD patients regarding the level or onset of dysfunction is a sympathetic or parasympathetic system in them. Aims and Objectives: In our study, we intended to assess HRV parameters such as, total power (TP), high frequency normalized units (HFnu), low frequency normalized units (LFnu), LF/HF ratio, mean HR, root mean square of the successive differences (RMSSD), NN50, and pNN50 among different stages of COPD and also to identify the association of these HRV parameters with disease severity. Materials and Methods: It is a cross-sectional study done on (n = 130) male stable COPD patients. Anthropometric parameters, HRV parameters, and pulmonary function test were assessed. Later, based on the Global Initiative for Chronic Obstructive Lung Disease stage criteria (mild, moderate, severe, and very severe), they were divided into four subgroups. Data were analyzed by SPSS 19.0 version software. Kruskal–Wallis test was used to find a statistical difference between the groups. Correlations between the variables were done using Spearman correlation test. Results: LF/HF ratio (2 ± 0.5) was increased when compared to reference value reported by the previous studies. TP, HFnu, and RMSSD levels were significantly decreased in very severe, severe, and moderate COPD patients when compared to mild COPD patients. The mean HR, LFnu, and LF/HF ratio levels were significantly increased in very severe, severe, and moderate COPD patients when compared to mild COPD patients. TP, HFnu, and RMSSD levels negatively correlated with disease severity and mean HR, LFnu, and LF/HF ratio positively correlated with disease severity. Conclusion: We have noted that cardiac autonomic dysfunction in the form of increased sympathetic and reduced parasympathetic activity occurs in COPD patients and the association was more prominent when the disease severity increased.

Bacground: Chronic obstructive pulmonary disease (COPD) is a prevalent chronic inflammatory disorder of the airways. A fundamental aspect of airway remodeling in COPD, following prolonged inflammation, involves specific molecular and phenotypic alterations in airway basal cells (BCs). Preliminary large-scale single-cell analyses of COPD patients have revealed an enrichment of CAVIN2+ BCs. We aim to investigate the mechanistic role of CAVIN2+ BCs in COPD. By doing so, it seeks to offer novel theoretical foundations and potential therapeutic targets for COPD intervention. Methods: This research integrates single-cell data from multiple studies involving lung tissues from COPD patients. After data integration, cell clustering and subgroup identification were performed. Lung tissues and BCs from COPD patients and healthy controls were then collected for further analysis. Using in situ multicolor immunofluorescence, the CAVIN2+ BCs subgroup was identified. Additionally, cell culture and animal experiments were conducted to explore the influence of CAVIN2 on BC proliferation and differentiation. In vitro, CAVIN2 was either overexpressed or knocked out, and its impact on BC proliferation and differentiation was assessed using CCK-8 assays, migration assays, and air-liquid interface differentiation experiments. In vivo, BC differentiation was evaluated through subcutaneous tumor formation in nude mice, with genetic modifications either overexpressing or knocking out CAVIN2. Results: Analysis of large-scale single-cell data revealed a significant enrichment of CAVIN2+ BCs in the airways of COPD patients. Both gene and protein expression levels of CAVIN2 were markedly elevated in COPD patients compared to healthy controls. Further investigations suggested that the AREG/EGFR signaling pathway plays a pivotal role in the interaction between macrophages and CAVIN2+ BCs, influencing the process of airway remodeling in COPD. In situ multicolor immunohistochemistry of lung tissues from COPD and control groups confirmed a higher proportion of CAVIN2+ BCs in COPD airways. In vitro experiments, including CCK-8 and Transwell assays, demonstrated that knocking out CAVIN2 promoted the proliferation and migration of airway basal stem cells, while its overexpression inhibited these processes. Similarly, air-liquid interface differentiation and in vivo differentiation experiments revealed that overexpression of CAVIN2 significantly suppressed BC differentiation. Conclusion: CAVIN2+ BCs play a crucial role in airway remodeling during COPD progression. This study provides new insights into the pathological mechanisms of COPD and lays a theoretical foundation for future COPD therapies targeting stem cell regulation.

To investigate the correlations between lipid ratio/oxidative stress status in chronic obstructive pulmonary disease (COPD) patients and pulmonary hypertension as well as the prognosis. Methods: A total of 120 patients with COPD were randomly selected and served as the COPD group and 30 healthy persons were selected as the control group. The ratios of low density lipoprotein (LDL)/high-density lipoprotein (HDL), triglyceride (TG)/HDL and total cholesterol (TC)/HDL were measured. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) level in the control group and COPD patients were detected. Pulmonary hypertension incidence and 3-year survival rate for COPD patients were statistically analyzed. Spearman rank correlation method was used to analyze relationship between lipid ratio /oxidative stress status and pulmonary hypertension. Results: Compared with control group, the ratios of LDL/HDL, TG/HDL and TC/HDL, and the serum MDA level in the COPD group were increased, while the serum SOD and T-AOC level in the COPD group were decreased; compared with stable period, lipid ratios and MDA levels in the acute period were elevated, while serum SOD and T-AOC levels were reduced (P<0.05). Pulmonary hypertension incidence and 3-year survival rates in the COPD group were 56.67% and 81.67% respectively; the lipid ratios and serum MDA levels in COPD patients with pulmonary hypertension were elevated compared with that in COPD patients without pulmonary hypertension; the serum SOD and T-AOC levels in COPD patients with pulmonary hypertension were reduced compared with that in patients without pulmonary hypertension (P<0.05). Spearman rank correlation analysis showed that ratios of LDL/HDL, TG/HDL and TC/HDL, and the serum MDA levels in COPD patients were positively correlated with 3-years pulmonary hypertension incidence (r=0.752, 0.748, 0.752, 0.748; P<0.05), and negatively correlated with 3-years survival rate (r=-0.722, -0.751, -0.736, -0.748; P<0.05); serum SOD and T-AOC levels in COPD patients were negatively correlated with 3-years pulmonary hypertension (r=-0.711, -0.734; P<0.05), and positively correlated with 3-year survival rate (r=0.726, 0.733; P<0.05). Conclusion: Blood lipid ratio and oxidative stress levels in COPD patients are elevated while antioxidant abilities were attenuated. The lipid ratio and oxidative stress status in COPD patients is closely related to the prognosis of pulmonary hypertension. Therefore, blood lipid ratio and oxidative stress status may be used in evaluation of pulmonary hypertension and prognosis for COPD patients.

BackgroundAlthough chronic inflammation, oxidative stress, airway remodeling, and protease-antiprotease imbalance have been implicated in chronic obstructive pulmonary disease (COPD), the exact pathogenesis is still obscure. Gene transcription and post-transcriptional regulation have been taken into account as key regulators of COPD occurrence and development. Identifying the hub genes and constructing biological regulatory networks at the post-transcriptional level will help extend current knowledge on COPD pathogenesis and develop potential drugs.MethodsAll lung tissues from non-smokers (n = 6), smokers without COPD (smokers, n = 7), and smokers with COPD (COPD, n = 7) were collected to detect messenger RNA (mRNA), microRNA (miRNA), circular RNA (circRNA), and long non-coding RNA (lncRNA) expression and identify the hub genes. Biological regulatory networks were constructed at the post-transcriptional level, including the RNA-binding protein (RBP)-hub gene interaction network and the competitive endogenous RNA (ceRNA) network. In addition, we assessed the composition and abundance of immune cells in COPD lung tissue and predicted potential therapeutic drugs for COPD. Finally, the hub genes were confirmed at both the RNA and protein levels.ResultsAmong the 20 participants, a total of 121169 mRNA transcripts, 1871 miRNA transcripts, 4244 circRNA transcripts, and 122130 lncRNA transcripts were detected. There were differences in the expression of 1561 mRNAs, 48 miRNAs, 33 circRNAs, and 545 lncRNAs between smokers and non-smokers, as well as 1289 mRNAs, 69 miRNAs, 32 circRNAs, and 433 lncRNAs between smokers and COPD patients. 18 hub genes were identified in COPD. TGF-β signaling and Wnt/β-catenin signaling may be involved in the development of COPD. Furthermore, the circRNA/lncRNA-miRNA-mRNA ceRNA networks and the RBP-hub gene interaction network were also constructed. Analysis of the immune cell infiltration level revealed that M2 macrophages and activated NK cells were increased in COPD lung tissues. Finally, we identified that the ITK inhibitor and oxybutynin chloride may be effective in treating COPD.ConclusionsWe identified several novel hub genes involved in COPD pathogenesis. TGF-β signaling and Wnt/β-catenin signaling were the most dysregulated pathways in COPD patients. Our study constructed post-transcriptional biological regulatory networks and predicted small-molecule drugs for the treatment of COPD, which enhanced the existing understanding of COPD pathogenesis and suggested an innovative direction for the therapeutic intervention of the disease.

Asthma and chronic obstructive pulmonary disease (COPD) are heterogenetic diseases and exhibit many similarities. Dutch hypothesis proposed that these two diseases may have common genetic origins. This study aims to investigate whether asthma and COPD share a common genetic background in Chinese patients. In this case-control study, single nucleotide polymorphisms (SNPs) were genotyped using SNaPshot. Haplotype disease analysis and haplotype phenotype analysis were applied to assess the relationship between three polymorphisms of the FCER2 gene and the risk of COPD/asthma. Additionally, associations between polymorphisms of the FCER2 gene and phenotypes were analyzed. We detected ten SNPs of seven genes (FCER1A, FCGR2A, FCGR2B, CHI3L1, ADRB2, STAT6, and FCER2) expressed by airway epithelial cells. We detected genotypes and allele distributions in 251 COPD patients, 597 asthma patients, and 632 healthy controls. A significant difference was found in the FCER2 gene (rs28364072) between COPD patients and controls (P=0.009). Significant differences were observed in the genotype and allele distributions of rs1801274 (FCGR2A), rs12368672 (STAT6), and rs2228137 (FCER2) between asthma patients and controls (P=0.004, 0.007 and 0.010, respectively). Notably, polymorphisms of FCER2 gene were associated with the risk of both COPD (P=0.009 for rs28364072) and asthma (P=0.01 for rs2228137). Haplotype analysis revealed that haplotype T-G-T (alleles of rs28364072, rs2228137, and rs3760687, respectively) was significantly associated with a higher risk of asthma [odds ratios (OR) =2.25, 95% confidence interval (CI): 1.26-4.01, P=0.006]. Further analysis showed that the C-A-C haplotype and C-G-T haplotype were associated with increased blood eosinophils in either COPD or asthma patients (P=0.034, and P<0.001, respectively). Moreover, haplotypes C-A-C, C-G-C, and T-G-C showed significant associations with serum IgE levels in asthma patients (P=0.002, 0.041, and 0.004, respectively). Our data suggest that the FCER2 gene might associate with predisposition to asthma and COPD, while FCER2 haplotypes were associated with pulmonary function measurements and blood eosinophils counts in both diseases. Our findings support the common genetic basis for asthma and COPD, suggesting a potential therapeutic target for the two diseases.

Introduction:Chronic obstructive pulmonary disease (COPD) is an important non-communicable disease worldwide with a rising global incidence. COPD is associated with multiple co-morbidities. Patients with COPD are at increased risk of atherosclerosis and other cardiovascular events. Cardiovascular diseases are an important cause of morbidity and mortality in COPD. The present case-control study was designed to assess the relationship between sub-clinical atherosclerotic vascular diseases with COPD.Methods:It was a prospective case-control blinded observational study. There were 142 COPD patients and 124 age-and sex-matched controls without COPD and cardiovascular diseases. Frequency of sub-clinical atherosclerosis was assessed by the carotid B-mode duplex ultrasonography assessment of carotid wall intima medial thickness (IMT). Plaque was defined as IMT of more than 1.2 mm.Results:Prevalence of carotid plaqing was significantly higher amongst patients of COPD (38.7%) compared to controls (13.7%, odds ratio 3.9, P < 0.0001). Multinomial logistic regression analysis revealed COPD as an independent predictor of carotid plaqing (r = 0.85, P < 0.023).Conclusion:The frequency of carotid plaqing is high in COPD patients. Carotid plaqing may be due to shared risk factors or the presence of low-grade systemic inflammation. Presence of increased CIMT and carotid plaqing in COPD patients identifies early atherosclerotic changes and future cardiovascular risk. Hence screening of CIMT should be a part of cardiovascular assessment in patients with COPD.

BackgroundDepression is a common and mostly undertreated problem in patients with chronic diseases. However, population-based studies on the association between chronic obstructive pulmonary disease (COPD) and subsequent depression are limited in Asian populations. This study evaluated the incidence and risk factors of depression for patients with COPD in Taiwan.MethodsUsing the claims data from the National Health Insurance of Taiwan, we identified 38,010 COPD patients newly diagnosed in 2000–2004 and 38,010 subjects without COPD frequency, matched by sex, age and index date. The incidence rate and hazard ratio for depression were estimated by the end of 2008.ResultsThe incidence rate of depression was 1.88 folds higher in the COPD cohort than in the non-COPD cohort (12.2 versus 6.47 per 1,000 person-years, p < 0.0001). The depression risk was the greatest within the first year following COPD diagnosis and tended to decline with follow-up time. Among COPD patients, multivariate analysis showed that younger women and low-income patients were at higher risk of depression. Hospitalization and comorbidities such as hypertension, arthritis, cancer, and heart disease were also significant predictors for depression risk.ConclusionThis population-based cohort study demonstrated a strong relationship between COPD and subsequent depression. These findings could assist healthcare providers to pinpoint individuals with a higher predisposition to having depression, which could then facilitate the provision of culturally appropriate rehabilitation within the first year after the diagnosis of COPD.

Proteinase-activated receptor-1 (PAR-1) plays a key role in mediating the interplay between coagulation and inflammation in response to injury. The aim of this study was to investigate the role of the promoter single-nucleotide polymorphism (SNP) rs2227744G>A in modulating PAR-1/F2R gene expression in the context of chronic obstructive pulmonary disease (COPD) and COPD exacerbations. The function of the rs2227744G>A SNP was investigated by using reporter gene assays. The frequency of the polymorphism in the UK population was assessed by genotyping 8,579 healthy individuals from the Whitehall II and English Longitudinal Study of Ageing cohorts. The rs2227744G>A SNP was genotyped in a carefully phenotyped cohort of 203 COPD cases and matched controls. The results were further replicated in two different COPD cohorts. The minor allele of the rs2227744G>A polymorphism was found to increase F2R expression by 2.6-fold (P < 0.001). The rs2227744G>A SNP was not significantly associated with COPD, or with lung function, in all cohorts. The minor allele of the SNP was found to be associated with protection from frequent exacerbations (P = 0.04) in the cohort of COPD patients for which exacerbation frequency was available. Considering exacerbations as a continuous variable, the presence of the minor allele was associated with a significantly lower COPD exacerbation rate (3.03 vs. 1.98 exacerbations/year, Mann-Whitney U-test P = 0.04). Taken together, these data do not support a role for the rs2227744G>A F2R polymorphism in the development of COPD but suggest a protective role for this polymorphism from frequent exacerbations. Studies in separate cohorts to replicate these findings are warranted.