Genetic risk factors for the development of pulmonary disease identified by genome‐wide association

Chronic respiratory diseases are a major cause of morbidity and mortality. Asthma and chronic obstructive pulmonary disease (COPD) combined affect over 500 million people worldwide. While environmental factors are important in disease progression, asthma and COPD have long been known to be heritable with genetic components playing an important role in the risk of developing disease. Identification of genetic variation contributing to disease progression is important for a number of reasons including identification of risk alleles, understanding underlying disease mechanisms and development of novel therapies. Genome‐wide association studies (GWAS) have been successful in identifying many loci associated with lung function, COPD and asthma. In recent years, meta‐analyses and improved imputation have facilitated the growth of GWAS in terms of numbers of subjects and the number of single nucleotide polymorphisms (SNP) that can be interrogated. As a consequence, there has been a significant increase in the number of signals associated with asthma, COPD and lung function. SNP that have shown association with lung function reassuringly show a significant overlap with SNP associated with COPD giving a glimpse at pathways that may be involved in COPD mechanisms including genes in, for example, developmental pathways. In asthma, association signals are often in or near genes involved in both adaptive and innate immune response pathways, epithelial cell homeostasis and airway structural changes. The challenges now are translating these genetic signals into a new understanding of lung biology, understanding how variants impact health and disease and how they may provide opportunities for therapeutic intervention.     

Asthma and chronic obstructive pulmonary disease: common genes, common environments?

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.     

Genome-Wide Association Studies of Asthma

Bronchial asthma is a common inflammatory disease caused by a combination of genetic and environmental factors. To discover the genes and cellular pathways underlying asthma, a large number of genetic studies have been conducted. Genome-wide association studies (GWAS), which comprehensively assess genes related to multifactorial diseases and drug reactivity, have enhanced understanding of human diseases. From 2007, GWAS of susceptibility to asthma in Caucasian, Mexican, and African-ancestry populations have been conducted and several susceptible loci were identified. Recently, much larger consortium-based GWAS analyses of collaborative samples with adequate statistical power were performed, and the implicated genes suggested a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Furthermore, GWAS identified candidate loci associated with natural variations in lung function, blood eosinophilia and eosinophilic esophagitis, which is inflammation of the esophagus with abnormal infiltration of eosinophils in an allergic reaction. Comparing GWAS in asthma and these clinical phenotypes might help to clarify the mechanisms underlying asthma. Pharmacogenomics analyses using GWAS regarding genetic factors related to the effectiveness of inhaled corticosteroid (ICS) therapy and inhaled beta₂-adrenergic agonists are ongoing now. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWAS provide valuable insights into the pathophysiology of asthma and contribute to the development of better treatment and preventive strategies.     

慢性阻塞性肺疾病气道基因表达与肺癌的易感性关系

COPD和肺癌均是全球高发病率、高病死率的疾病，临床上COPD合并肺癌的病例较为常见，长期以来人们将其作为两个独立的疾病分别进行了广泛研究，但目前两者相关的危险因素及潜在关联的发病机制已引起国内外临床医师及研究者的关注。研究也表明两者共同存在一些环境因素、遗传因素、异常的免疫炎症反应，影响COPD和肺癌的发生发展，本文就COPD气道基因表达与肺癌易感性的关系作一综述，以了解这两种疾病在分子水平的联系。     

Overlap of asthma and chronic obstructive pulmonary disease

PURPOSE OF REVIEW: Asthma and chronic obstructive pulmonary disease (COPD) are both defined by the presence of airflow obstruction, but they present distinguishing differences in terms of both risk factors and clinical phenotypes. Yet it is quite common in the clinical setting to observe patients with asthma showing COPD-like phenotypes, and vice versa, making it a priority to search for optimal prevention, treatment, and management strategies for these cases of coexisting lung obstructive diseases. RECENT FINDINGS: Recent studies have provided further evidence of strong epidemiologic and clinical links between asthma and COPD. Adult subjects with active asthma are as much as 12 times more likely to acquire COPD over time than subjects with no active asthma. Signs identifying patients with asthma predisposed to developing COPD may already be present at the early stages of the disease, a finding with potential implications for prevention of COPD. In addition to spirometry and other pulmonary function tests (such as measurements of residual volume and diffusing capacity of the lung for carbon monoxide), recent evidence suggests that the assessment of type and degree of airway remodeling and the evaluation of inflammatory markers might prove useful in the future to characterize phenotypically patients with coexisting asthma and COPD. SUMMARY: The nature of the association between asthma and COPD remains unclear and open to discussion. Further research is required to develop effective management algorithms for patients with multiple obstructive lung diseases, determine to what extent early treatment and optimal management of asthma may protect against progression into COPD, and identify genetic markers of individual susceptibility to specific lung disease phenotypes and pharmacologic treatments.     

Lung development and adult lung diseases

Adult respiratory diseases are caused by many factors, including genetic-environmental interaction. Genetic abnormalities can impact early fetal lung development, postnatal lung maturation, as well as adult lung injury and repair. Studies suggest that abnormally developed lung structure and function may contribute as a susceptibility factor for several adult lung diseases. This review focuses on the relationship between lung development and pathogenesis of several lung diseases including COPD, cystic fibrosis (CF), and asthma. COPD with emphysema has been considered to be an accelerated involutional disease of aging smokers. However, since only a proportion (approximately 15%) of smokers get COPD with emphysema, clearly genetic susceptibility must play a significant part in determining both the age of onset and the rapidity of decline in lung function. In mice, interference with key genes either by null mutation, hypomorphism, or gain or loss of function results in phenotypes comprising either neonatal lethal respiratory distress if the structural effect is severe, or reduced alveolarization and/or early onset emphysema if the effect is milder. Reported susceptibility candidate genes are therefore discussed in some detail, including elastin, lysyl oxidase, fibrillin, the transforming growth factor-beta-Smad3 pathway, as well as extracellular matrix proteases. In the case of CF, the Cftr gene has been shown to regulate fetal lung epithelial cell differentiation and maturation. Subtle abnormalities of lung structure and function are found in clinically asymptomatic CF infants. Finally, airway remodeling due to chronic inflammation is important in infants who later acquire asthma.     

Génétique de l'asthme et des allergies

Asthma and allergic diseases are conditions with variable clinical presentations that run in families. The positional cloning of five new susceptibility genes (ADAM33, PHF11, DPP10, GPRA, and TIM1) and the (sometimes inconsistent) association of increased susceptibility to asthma with variants of more than 60 genes suggest that genetic heterogeneity underlies asthma. Many of these polymorphic genes are involved in innate immunity to microbial factors, the initiation of a polarized T-cell response to common allergens, the expression of the IgE Fc receptor, and the production of and response to pro-inflammatory mediators, or their expression is limited to the bronchial mucosa. Genetic inheritance of alleles of modest effect, epigenetic allele-specific gene expression, interactions among genes, and between genes and environmental triggers appear to drive the onset and severity of asthma.     

Innate immunity to influenza in chronic airways diseases

Influenza presents a unique human infectious disease that has a substantial impact on the public health, in general, and especially for those with chronic airways diseases. People with asthma and chronic obstructive pulmonary disease (COPD) are particularly vulnerable to influenza infection and experience more severe symptoms with the worsening of their pre‐existing conditions. Recent advances in reverse genetics and innate immunity has revealed several influenza virulence factors and host factors involved in influenza pathogenesis and the immune responses to infection. Early innate immunity plays a critical role of limiting viral infection and spread; however, the underlying mechanisms that lead to enhanced susceptibility to influenza infection and severe symptoms in those with asthma and COPD to infection remain un‐investigated. This review will explore the importance of early innate antiviral responses to influenza infection and how these responses are altered by influenza virus and in those with chronic airways diseases.     

Complement activation pathways: a bridge between innate and adaptive immune responses in asthma

Although it is widely accepted that allergic asthma is driven by T helper type 2 (Th2)-polarized immune responses to innocuous environmental allergens, the mechanisms driving these aberrant immune responses remain elusive. Recent recognition of the importance of innate immune pathways in regulating adaptive immune responses have fueled investigation into the role of innate immune pathways in the pathogenesis of asthma. The phylogenetically ancient innate immune system, the complement system, is no exception. The emerging paradigm is that C3a production at the airway surface serves as a common pathway for the induction of Th2-mediated inflammatory responses to a variety of environmental triggers of asthma (i.e., allergens, pollutants, viral infections, cigarette smoke). In contrast, C5a plays a dual immunoregulatory role by protecting against the initial development of a Th2-polarized adaptive immune response via its ability to induce tolerogenic dendritic cell subsets. On the other hand, C5a drives type 2-mediated inflammatory responses once inflammation ensues. Thus, alterations in the balance of generation of the various components of the complement pathway either due to environmental exposure changes or genetic alterations in genes of the complement cascade may underlie the recent rise in asthma prevalence in westernized countries.     

The epithelial cell and lung cancer: the link between chronic obstructive pulmonary disease and lung cancer

Chronic obstructive pulmonary disease (COPD) and lung cancer currently form the basis for an enormous disease burden in the developed world. As a result of changing smoking trends and tobacco use, regrettably, a similar picture is arising rapidly within the developing world. COPD is a recognised risk factor for lung cancer, and a significant proportion of patients diagnosed with lung cancer have COPD. An association between both conditions has long been suspected but has proven difficult to demonstrate thus far. However, the common factors between both conditions are now becoming apparent thanks to recent clinical and molecular advances. Abnormal regulation of the immune system and the establishment of chronic inflammation appear to be key events in this process. In addition, the complex interplay between genes and environment and the possibility of a genetic basis to lung cancer susceptibility in the context of COPD are becoming clearer concepts. As we begin to unravel the common pathways and molecules in the pathogenesis of both conditions, we may be able to not only identify novel strategies to prevent and treat COPD and lung cancer, but also recognise molecular markers to identify patients at high risk of developing lung cancer.     

Viral infections in asthma and COPD

Airway viral infections are associated with the pathogenesis of asthma and COPD. It has been argued that respiratory syncytial virus (RSV) infection in infancy is a probable causal factor in the development of pediatric asthma. RSV infections tend to induce Th2-biased immune responses in the host airways. RSV infection, atopy, and low pulmonary function in neonates may work synergistically toward the development of pediatric asthma. Human rhinovirus (HRV) is a representative virus associated with the exacerbation of asthma in both children and adults. Viral infections trigger innate immune responses including granulocytic inflammation and worsen the underlying inflammation due to asthma and COPD. The innate immune responses involve type-I and -III interferon (IFN) production, which plays an important role in anti-viral responses, and the airway epithelia of asthmatics reportedly exhibit defects in the virus-induced IFN responses, which renders these individuals more susceptible to viral infection. A similarly impaired IFN response is seen in COPD, and several investigators propose that latent adenoviral infection may be involved in COPD development. Persistent RSV infections were detected in a sub-population of patients with COPD and were associated with the accelerated decline of lung function. The virus-induced upregulation of co-inhibitory molecules in the airway epithelium partly accounts for the persistent infections. Experimental animal models for virus-asthma/COPD interactions have shed light on the underlying immune mechanisms and are expected to help develop novel approaches to treat respiratory diseases.     

State of the art. Chronic obstructive pulmonary disease, inflammation, and lung cancer

Both lung cancer and chronic obstructive pulmonary disease (COPD) are associated with cigarette smoking, which, by generating reactive oxidant species, induces a chronic inflammatory state in the lung. Activation, particularly of nuclear factor-kappaB, occurs in both cancer and COPD, and expression of a number of genes is altered in both diseases. In lung cancer, DNA damage, lack of DNA repair, and genomic instability predominate, whereas matrix degradation, lack of repair, and an intense immune response predominate in COPD. The reasons for the different responses to a common inflammatory response induced by smoking remain to be determined, but likely lie in genetic polymorphisms in genes that regulate genome integrity in cancer and that regulate the immune response to tissue destruction in COPD.     

Genetics of chronic obstructive pulmonary disease

Variability in the susceptibility to develop chronic obstructive pulmonary disease (COPD) is related to both genetic and environmental factors. COPD is likely a genetically complex disease, but severe alpha 1-antitrypsin (AAT) deficiency [e.g., protease inhibitor (PI) Z] remains the only proven genetic risk factor for COPD. Even among PI Z individuals, substantial variability in lung function is observed, suggesting that genetic modifiers may influence the expression of lung disease in severe AAT deficiency. The variable development of COPD in smokers without alpha 1-antitrypsin deficiency and the familial aggregation of lung function measurements also suggest the presence of genetic influences on lung function growth and decline leading to COPD. Many candidate gene loci have been investigated as potential COPD genetic determinants by case-control genetic association studies. However, inconsistent results of these association studies have been frequent. Genetic heterogeneity and population stratification are two potential reasons for the conflicting findings between association studies. Linkage analysis studies have recently been published that may identify regions of the genome that contain COPD susceptibility genes. Future investigations of genetic influences in COPD should consider the use of family-based designs for association studies and the study of positional candidate genes within regions of linkage.     

Mycobacteria in Crohn's disease: a persistent hypothesis

Efforts to explore a mycobacterial origin for Crohn's disease typically have involved an epidemiological approach, searching for Mycobacterium avium subsp. paratuberculosis in patient tissue. An alternative approach involves consideration of genetic and experimental data regarding host resistance to mycobacteria. From human and mycobacterial genetics, it is known that mycobacterial diseases depend on both pathogen and host factors and that tuberculosis and leprosy are effectively genetic diseases. The discovery of a number of Crohn's susceptibility genes, including NOD2/CARD15, demonstrates that Crohn's also is a complex genetic disease. Mutations in NOD2/CARD15 do not necessarily lead to Crohn's disease, so other mitigating factors, genetic and/or environmental, probably are required to produce illness. Recent work has shown that NOD2/CARD15 serves a role in bacterial sensing and activation of innate immune responses, providing a link between Crohn's genetics and an environmental factor, potentially a bacterial trigger. In this review, we discuss the current understanding of mycobacterial and Crohn's genetic susceptibility and review the evidence that NOD2/CARD15 may mediate host resistance to mycobacterial infection.     

Intronic single-nucleotide polymorphisms in Bcl-2 are associated with chronic obstructive pulmonary disease severity

BACKGROUND AND OBJECTIVE: COPD is a multifactorial disease influenced by genetic and environmental factors, and gene-by-environmental interactions. There is considerable variability in the degree of airflow obstruction, moreover only 10-15% of chronic smokers develop COPD. These observations indicate that additional risk factors, possibly genetic, contribute to not only the susceptibility to COPD but also the development and severity of COPD. Recent paradigms highlight the presence and causal role of apoptosis in emphysema. There is a large amount of information on the genes involved in the regulation of apoptosis and one of the most studied is Bcl-2. The aim of this study was to investigate the genetic association of Bcl-2 gene with the level of lung function, that is, the severity, of COPD. METHODS: The genetic association of Bcl-2 polymorphisms with lung function was investigated in 261 Japanese patients with COPD using 12 single-nucleotide polymorphisms (SNPs) in Bcl-2. RESULTS: Four SNPs showed a significant association between the high and low lung function groups in a dominant trait comparison. Subsequent linkage-disequilibrium mapping and analyses of haplotype structure also showed a significant association between the level of lung function and two haplotypes comprised of the associated SNPs in Bcl-2. CONCLUSIONS: Although the linkage between Bcl-2 gene and the susceptibility to COPD remains to be clarified, the findings of the current study indicate that Bcl-2 might be influencing the level of lung function, that is, the development and severity of COPD.     

Proteostasis: a new therapeutic paradigm for pulmonary disease

Among lung pathologies, α1AT, chronic obstructive pulmonary disease (COPD), emphysema, and asthma are diseases triggered by local environmental stress in the airway that we refer to herein collectively as airway stress diseases (ASDs). A deficiency of α-1-antitrypsin (α1AT) is an inherited genetic disorder that is a consequence of the misfolding of α1AT during protein synthesis in liver hepatocytes, reducing secretion to the plasma and delivery to the lung. Deficiency of α1AT in the lung triggers a similar pathological phenotype to other ASDs. Moreover, the loss of α1AT in the lung is a well-known environmental risk factor for COPD/emphysema. To date there are no effective therapeutic approaches to address ASDs, which reflects a general lack of understanding of their cellular basis. Herein, we propose that ASDs are disorders of proteostasis. That is, they are initiated and propagated by a common theme-a challenge to protein folding capacity maintained by the proteostasis network (PN) (see Balch et al., Science 2008;319:916-919). The PN is a network of chaperones and degradative components that generates and manages protein folding pathways responsible for normal human physiology. In ASD, we suggest that the PN system fails to respond to the increased burden of unfolded proteins due to genetic and environmental stresses, thus triggering pulmonary pathophysiology. We introduce the enabling concept of proteostasis regulators (PRs), small molecules that regulate signaling pathways that control the composition and activity of PN components, as a new and general approach for therapeutic management of ASDs.     

Dangerous Allergens: Why Some Allergens are Bad Actors

Immune responses can be compartmentalized into innate versus adaptive components. This relatively recent dichotomy positioned the innate immune system at the interface between the host and the external environment and provided a new conceptual framework with which to view allergic diseases, including asthma. Airway epithelial cells and dendritic cells are key components of the innate immune system in the nose and lung and are now known to be intimately involved in allergen recognition and in modulating allergic immune responses. Here we review current thinking about how these two key cell types sense and respond to inhaled allergens, and emphasize how an understanding of “allergic innate immunity” can translate into new thinking about mechanisms of allergen sensitization and potentially lead to new therapeutic targets.     

The genetics of bronchial asthma in children

Bronchial asthma is a chronic inflammatory disease based on an inappropriate stimulation of the immune system, for instance by environmental aeroallergens. It is characterised by bronchial hyperreactivity, reversible airway obstruction and mucus overproduction. During the last decades bronchial asthma has become the most common disease of childhood. Accordingly, many epidemiological and genetic studies have dealt with its origin. In fact, hundreds of genome-wide linkage analyses and association studies have identified several chromosomal regions harbouring asthma susceptibility genes like chromosome 2q, 5q, 6q, 11q, 12q and 13q. Also about 100 candidate genes for asthma have been described. However, not all of them have been confirmed in independent studies. Besides the genetic predisposition environmental factors play an important role in the development of allergic diseases. Studies predominantly performed in farmer children have shown that exposure to bacterial endotoxin early in life reduces the risk to develop asthma or atopy later on. Thus, recent studies focussed also on the interaction of genes variants with environmental factors which is summarised under the term genetic epidemiology. Further dissection of asthma genetics and its complex interaction with surrounding factors will hopefully help us in the development of new very specific drugs. In addition, the generation of a genetic risk profile for bronchial asthma should enable us for the first time to take well-directed preventive measurements early in live.     

Pathophysiology of asthma: lessons from genetic research with particular focus on severe asthma

There is good evidence that both inherited and environmental factors influence the risk of developing asthma. Only recently, large well-designed studies have been undertaken with the power to identify the genetic causes for asthma, and methods developed in parallel with the Human Genome Project, such as gene expression and epigenetic studies, have made large-scale analyses of functional genetics possible. In this review, we discuss the recent findings from genetic and genomic research studies of asthma, particularly severe asthma, and highlight specific genes for which there are multiple lines of evidence for involvement in asthma pathogenesis. Bio-ontologic enrichment analyses of the most recently identified asthma-related genes point to attributes such as 'molecular and signal transducer activity' and 'immune system processes', which indicates the importance of immunoregulation and inflammatory response in the pathogenesis of asthma. Finally, we discuss how genetic and environmental factors jointly influence asthma susceptibility and summarize how the results may increase understanding of the pathophysiology of asthma-related diseases.