Dutch Hypothesis Research Articles

Polymorphisms in the FCER2 gene have associations with asthma and chronic obstructive pulmonary 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.

Asthma versus chronic obstructive pulmonary disease, the Dutch versus British hypothesis, and role of interleukin-5.

Asthma and COPD represent heterogeneous disorders with broad ranging impact on patients and health systems. This review focuses on evidence for early attempts at understanding their pathogenesis by the British and Dutch hypotheses. It also addresses the role of eosinophils, IL-5, and biologics targeting these pathways in asthma and COPD. Among asthma and COPD patients, clusters exist based on phenotypic and biologic markers allowing for further understanding of endotypes. Recent studies suggest the role of eosinophils and optimal therapies for each condition may be different. Although patients with ACOS or overlap symptoms may be an exception, overall there appears to be more evidence supporting that asthma and COPD are distinct processes. Targeting eosinophils with anti-IL-5 therapy appears to be an exciting pathway in the properly selected patient with asthma and recent data also supports its use in COPD.

Asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) have striking differences but the similarities are also striking. Some scientists consider them as different expression of same disease. Some COPD patients show reversibility; on the other hand, asthma, a basically reversible disease, may lose its reversible nature by the process of airway remodeling and thereby blurring their differences. Although both are inflammatory diseases, they differ in the nature of inflammation and spectrum of inflammatory mediators. Clinically, most physicians can differentiate between two diseases, but the overlap also is widely recognized. The question remains whether any physiological test, among plethora available, can definitely differentiate asthma from COPD. Apart from overlap between asthma and COPD, it is now a well-established fact that asthma is a risk factor for the development of COPD. Only future can say, “whether Dutch or British hypothesis is right.”

Dutch Hypothesis and British Hypothesis in Bronchial Asthma and Chronic Obstructive Pulmonary Disease (COPD)

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are obstructive pulmonary diseases with airway inflammation. Both diseases have similar pathologies such as airflow limitation, inflammation and airway hyperresponsiveness. These findings provide molecular levels molecular support for both points of view in the British/Dutch hypothesis controversy regarding the relationship between bronchial asthma and COPD. Both diseases are often complicated, and a new concept such as Asthma COPD Overlap Syndrome (ACOS) is proposed.

Clinical approaches towards asthma and chronic obstructive pulmonary disease based on the heterogeneity of disease pathogenesis.

Asthma and chronic obstructive pulmonary disease (COPD) are each heterogeneous disease classifications that include several clinical and pathophysiological phenotypes. This heterogeneity complicates characterization of each disease and, in some cases, hinders the selection of appropriate treatment. Therefore, in recent years, emphasis has been placed on improving our understanding of the various phenotypes of asthma and of COPD and identifying biomarkers for each phenotype. Likewise, the concept of the endotype has been gaining acceptance; an endotype is a disease subtype that is defined by unique or distinctive functional or pathophysiological mechanisms. Endotypes of asthma or COPD may be primarily characterized by increased susceptibility to type 2 inflammation, increased susceptibility to viral infections, bacterial colonization or impaired lung development. The 'Dutch hypothesis' is as follows: gene variants underlying particular endotypes interact with detrimental environmental stimuli (e.g. smoking, viral infection and air pollution) and contribute to the ultimate development of asthma, COPD or both. Novel approaches that involve multidimensional assessment should facilitate identification and management of the components that generate this heterogeneity. Ultimately, patients with chronic inflammatory lung diseases may be treated based on these endotypes as determined by the respective biomarkers that correspond to individual endotypes instead of on disease labels such as asthma, COPD or even asthma-COPD overlap syndrome (ACOS).

Revisiting the Dutch hypothesis

Revisiting the Dutch hypothesis

Are Asthma and COPD a Continuum of the Same Disease?

Asthma and chronic obstructive pulmonary disease (COPD) are common heterogeneous diseases with significant impact on morbidity, mortality, and health care costs. In most of the cases, the main features and pathophysiology differ substantially between both asthma and COPD, which allows differentiating both entities and providing appropriate treatment. The recognition of a subgroup of patients who present clinically with features of both conditions, asthma chronic obstructive pulmonary disease overlap syndrome, has reignited the question of whether asthma and COPD are different manifestations of the same disease or unique processes, the so-called Dutch hypothesis versus British hypothesis controversy. There is enough heterogeneity in the clinical and mechanistic profiles of these 3 diseases, and subsets of these 3 diseases, to suggest that a new approach relying on the concept of endotypes of obstructive airways disease may be more useful. This characterization has provided the basis for opening new areas of research that may eventually lead to the development of new targeted drugs. This review focuses on the current knowledge of asthma, COPD, and asthma chronic obstructive pulmonary disease overlap syndrome phenotypes with emphasis on mechanisms of disease and how these may define endotypes, providing a more rational approach to research and clinical care.

Total serum IgE level in COPD patients

ObjectiveThe Dutch Hypothesis has been used to suggest that Asthma and COPD may be considered as different expressions of one disease entity. The purpose of this study is to evaluate the levels of IgE in COPD patients and its relation with respiratory symptoms and lung functions this may be a suggestive of atopy as a mechanism for initiation of their exacerbations. MethodsA cross-sectional case-control study was conducted on 50 subjects recruited from the outpatient clinic (11 healthy volunteers, 39 diagnosed as COPD) COPD patients (31 males (79%) and 8 females (21%)) diagnosed as mild, moderate and severe. The studied groups were also divided according to total serum IgE levels and compared in demographic data, clinical data, spirometric data, and HRCT findings. ResultsCOPD patients with elevated IgE had a longer history of illness, high smoking index, higher number of exacerbation in the last year, and more lower FEV1.HRCT finding in both groups was hyperinflation was high in COPD patients with normal IgE levels, 10 cases (45%), while bronchiectasis was higher in COPD patients with elevated IgE, 7 cases (41%). Sputum culture was positive for aspergillosis in 5 cases (29%) in COPD patients with elevated IgE. ConclusionsThere was a high prevalence of elevated serum T-IgE in patients with COPD but without obvious atopy. Serum T-IgE levels were found to be associated with symptoms such as dyspnea and impairment of lung function. Recurrent exacerbation of COPD is believed to accelerate disease progression and impairment of pulmonary function.

036. Asthma and chronic obstructive pulmonary disease (COPD): the importance of their coexistence

Asthma is a heterogenous illness, characterized by airway inflammation and expressing mainly with wheezing, dyspnea, chest tightness and cough. These symptoms vary, regarding intensity and time. Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease, where you can notice persistent airflow obstruction, usually progressive. Enhanced chronic inflammatory response in noxious particles or gases is associated with COPD. There is a strong relation of asthma with allergies and atopy, displayed mainly in childhood, while COPD is related with smoking and concerns people over 40 years old, having worse prognosis compared to asthma. Multiple recent reviews of literature try to define the asthma-COPD coexistence, using mainly the word overlap. American Thoracic Society-ATS guidelines of 1995 already, define asthma, chronic bronchitis, emphysema, COPD, airway obstruction, recognizing 11 different syndromes, with overlap in six of them. There are three common clinical characteristics in airway diseases: airway inflammation, airway obstruction and bronchial hyper responsiveness. The inflammation in asthma is mostly eosinophilic, driven by CD4 cells, in contrast with COPD where inflammation is neutrophilic, driven by CD8 cells. Eosinophilic inflammation is adequately controlled with steroids, while smoking promotes neutrophilic inflammation which is corticosteroids resistant. Remodeling, especially of distal, small airways happening in long standing asthma, as well as in COPD, is responsible for pulmonary function decline (airway obstruction). It is impressive the fact that up to 16% of asthmatics develop insufficient airway reversibility, after a period of 21-33 years. Bronchial hyper responsiveness is present in almost all asthmatics and in up to 2/3 of COPD patients. A cohort study proved that 17% of general population had positive challenge test in metacholine, while 50% of them were asymptomatic. Why overlap happens? “Dutch hypothesis” supports the theory that asthma and bronchial hyper responsiveness evolve in COPD later, and that asthma, COPD, chronic bronchitis and emphysema constitute different expressions of a single disease that are affected of host and environmental factors. In the biomarkers field, recent clinical trials have shown that increased levels of sputum NGAL (Neutrophil Gelatinase-Associated Lipocalin), puts the diagnosis of asthma-COPD overlap syndrome, and that overlap patients have elevated values of IL-6. Summarizing, given the fact that overlap patients are presenting more frequent exacerbations, have poorer quality of life, a more rapid decline in lung function, and higher hospital impact and mortality, in comparison to asthmatics or COPD patients, it is crucial to study further the pathogenesis of overlap syndrome, in order to understand and even to modificate the progressive functionality decline that leads to COPD.

Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis.

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background ("Dutch hypothesis"). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) κβ pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10(-9)). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-κβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution.

Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

1. The Dutch Hypothesis and British Hypothesis

1. The Dutch Hypothesis and British Hypothesis

Association of SERPINE2 With Asthma

The "Dutch hypothesis" suggests that asthma and COPD have common genetic determinants. The serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2 (SERPINE2) gene previously has been associated with COPD. We sought to determine whether SERPINE2 is associated with asthma and asthma-related phenotypes. We measured the association of 39 SERPINE2 single-nucleotide polymorphisms (SNPs) with asthma-related phenotypes in 655 parent-child trios from the Childhood Asthma Management Program (CAMP), and we measured the association of 19 SERPINE2 SNPs with asthma in a case-control design of 359 CAMP probands and 846 population control subjects. We attempted to replicate primary asthma-related phenotype findings in one independent population and primary asthma affection status findings in two independent populations. We compared association results with CAMP proband expression quantitative trait loci. Nine of 39 SNPs had P < .05 for at least one phenotype in CAMP, and two of these replicated in an independent population of 426 people with childhood asthma. Six of 19 SNPs had P < .05 for association with asthma in CAMP/Illumina. None of these replicated in two independent populations. The expression quantitative trait loci revealed that five SNPs associated with asthma in CAMP/Illumina and one SNP associated with FEV(1) in CAMP are strongly correlated with SERPINE2 expression levels. Comparison of results to previous COPD studies identified five SNPs associated with both asthma- and COPD-related phenotypes. Our results weakly support SERPINE2 as a Dutch hypothesis candidate gene through nominally significant associations with asthma and related traits. Further study of SERPINE2 is necessary to verify its involvement in asthma and COPD.

Asthma and Chronic Obstructive Pulmonary Disease

Asthma and chronic obstructive pulmonary disease (COPD) show similarities and substantial differences. The Dutch hypothesis stipulated that asthma and COPD have common genetic and environmental risk factors (allergens, infections, smoking), which ultimately lead to clinical disease depending on the timing and type of environmental exposures (Postma and Boezen, Chest 2004;126:96S-104S). Thus, a particular group of shared genetic factors may lead to asthma when combined with specific environmental factors that are met at a certain stage in life, whereas combination with other environmental factors, or similar environmental factors at a different stage in life, will lead toward COPD. Multiple genes have been found for asthma and COPD. In addition to genes unique to these diseases, some shared genetic risk factors exist. Moreover, there are both common host risk factors and environmental risk factors for asthma and COPD. Here we put forward, based on the data available, that genes that affect lung development in utero and lung growth in early childhood in interaction with environmental detrimental stimuli, such as smoking and air pollution, are contributing to asthma in childhood and the ultimate development of COPD. Additional genes and environmental factors then drive specific immunological mechanisms underlying asthma, and others may contribute to the ultimate development of specific subtypes of COPD (i.e., airway disease with mucous hypersecretion, small airway disease, and emphysema). The genetic predisposition to the derailment of certain pathways may further help to define subgroups of asthma and COPD. In the end this may lead to stratification of patients by their genetic make-up and open new therapeutic prospects.

Asthma and COPD in Alpha-1 Antitrypsin Deficiency. Evidence for the Dutch Hypothesis

ABSTRACTThis review summarizes the current information on the relationship between severe alpha-1 antitrypsin deficiency (AATD), asthma and COPD. AATD is a genetic predisposition to the development of early COPD in susceptible individuals and reduction in known factors that enhance lung function loss is the paramount aim of management. Asthma is one controllable condition that leads to the accelerated decline in lung function. Current literature indicates that asthma signs and symptoms are common in those AATD with or without COPD and that bronchodilator response is a risk factor for FEV1 decline. Furthermore AATD itself predisposes to airway hyper responsiveness, an essential ingredient for reversible airflow obstruction. In the absence of well-characterized markers to distinguish COPD from asthma, clinical diagnosis leads to a delay in the recognition that asthma symptoms such as wheezing can be an early manifestation of COPD in AATD. In addition failure to appreciate asthma overlap in AATD may lead to inadequate suppression of airway inflammation leading to the development of airflow obstruction. The implications of this are discussed as are potential approaches and recommendations for treatment.

Steroids in COPD: still up in the air?: Fig. 1—

Inhaled corticosteroids (ICS) have had a wild and controversial rollercoaster ride in chronic obstructive pulmonary disease (COPD). With the success of ICS in asthma and with the advent of the Dutch Hypothesis, suggesting that asthma and COPD had a similar pathogenic origin, there was great hope that ICS would be the saviour for millions of patients suffering from COPD, by palliating symptoms and changing its natural history. Based on this promise, by the mid 1980s, clinicians were routinely recommending ICS therapy to their patients, even though there was an absence of compelling grade A evidence from large randomised controlled trials (RCTs) demonstrating efficacy 1. By the late 1990s, the promise was shattered by the publication of several seminal RCTs that clearly showed that ICS did not modify the rate of decline in forced expiratory volume in 1 s (FEV1) and had only a modest effect on symptoms 2–4. These data re-inforced the notion that COPD was a steroid-resistant state and many leading experts in the field concluded that ICS had no role in COPD, except during exacerbations 5. Ostensibly, ICS were dead and buried. However, the new millennium brought new hope for ICS. Proponents argued that while ICS may not alter the rate of decline in FEV1, it improved patient based outcomes including survival. This optimism was fuelled by several large observational studies and meta-analyses 6–9 that demonstrated a distinct survival benefit for patients who were prescribed ICS. This enthusiasm, however, was dashed in 2007 by the publication of the long-awaited TORCH (TOwards a Revolution in COPD Health) Study, which failed to show an unequivocal survival advantage for patients assigned to a steroid-containing treatment …

ROLE OF ANTI-IGE ANTIBODY IN COPD

PURPOSE: The Dutch Hypothesis has been used to suggest that Asthma and COPD may be considered as different expressions of one disease entity. The purpose of this study is to evaluate the role of Anti-IgE treatment in patients who have COPD with elevated IgE levels suggestive of atopy as a mechanism for initiation of their exacerbations.

Beyond the Dutch Hypothesis

Beyond the Dutch Hypothesis

Beyond the Dutch Hypothesis

Beyond the Dutch Hypothesis

Genetics of Chronic Obstructive Pulmonary Disease, Beyond a1-Antitrypsin Deficiency

It is known that only 10-20% of smokers develop COPD, implying that apart from environmental features, additional factors such as genetic variability contribute to smoke susceptibility. This proposal is in compatibility with the "Dutch Hypothesis", formulated in the early 60's. Alpha-1-antitrypsin gene was implicated in the pathogenesis of COPD, especially the homozygous state of z allele. Since then many other genes have stepped forward as possible contributors to COPD development. In the present review we attempt to summarize the majority of these, including the genes of matrix metalloproteinases and their inhibitors, elastin, serpine2, tumor necrosis factor - a, transforming growth factor beta, a variety of interleukins and their receptors and antagonists, high affinity IgE receptor , human calcium-activated chloride channel 1, heme oxygenase, vascular endothelial growth factor, microsomal epoxide hydrolase, glutathione S-transferase, cytochrome P45O, superoxide dismutase, vitamin D binding protein, beta2-adrenergic receptor, Toll like receptor, human B defensins, mucins, cystic fibrosis transmembrane regulator, surfactant protein and Nuclear Factor E2 Related Factor 2.