慢性阻塞性肺疾病易感基因的研究进展

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是一种气流受限为特征的疾病,目前研究表明它是一种多基因遗传病,在基因多态性的研究中有两个平衡假说引起普遍的关注;这两个平衡就是蛋白酶/抗蛋白酶平衡和氧化物/抗氧化物平衡,由于这两个平衡被破坏,导致过分的炎症反应和组织破坏.涉及这方面的基因包括:α1-抗胰蛋白酶、金属基质蛋白酶、金属蛋白酶组织抑制剂-2、VitD相关蛋白、谷胱甘肽转移酶S、微粒体环氧化物水解酶,HOX-1、肿瘤坏死因子α和白介素1等.有报道表明不同基因或同一基因的不同位点间可能存在联合作用.动物模型基因研究会帮助区分一些病理过程,如果这种研究继以定量分析可能会帮助确定将来人的易感基因.但是全基因组的相关分析意味着需要分析大量的基因数据,计算机辅助软件或医工结合可能会解决部分问题.由于存在人种差异,所以应该寻求在不同独立的人种间确定阳性结果.对这些结果进行整合可能可以更准确的确定COPD,并且对那些更可能发生COPD的亚群进行靶向治疗.     

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.     

The genetics of asthma

Asthma is a complex respiratory disease that, based on familial aggregation studies, has long been recognized to have a significant genetic component. Understanding the genetics of asthma is complicated by the fact that there are multiple different pathophysiological mechanisms leading to a complicated heterogeneous phenotype that is difficult to define. It is generally recognized as a complex genetic disease that cannot be explained by single gene models, and in most cases it appears to result from the interaction of multiple genetic and environmental factors. Although linkage and association studies have demonstrated several important relationships between asthma and a variety of genetic loci, no single gene or group of genes has been definitively demonstrated to be responsible for asthma. However, population studies, candidate gene approaches, genome-wide screens, and pharmacogenetic studies have all resulted in an increased understanding of the complexities of asthma genetics and may lead to better preventive strategies, diagnostic tools, and therapies for this disease.     

The new genetics and chronic obstructive pulmonary disease

Epidemiological and family studies provide evidence for genetic factors contributing to chronic obstructive airways disease (COPD) susceptibility. Studies to date have focused on candidate genes implicated in the pathogenesis of the disease. In general, many of these studies have been underpowered or have not been extensive enough in investigating the full extent of genetic variation in these genes. This has resulted in conflicting data with potential false positives or findings that have not been replicated. More recently, larger studies and extensive coverage of candidate genes have implicated genetic variants that may contribute to the disease. The use of unbiased genome-wide association studies offer the prospect of identifying new genes involved in COPD susceptibility and genetic modifiers of disease phenotypes. There is cause for optimism as a number of major complex diseases have been successfully tackled in this way. The review will highlight what has been achieved by genetic studies to date, some of the related problems and the future impact of high throughput technologies such as genome-wide association studies on our understanding of the genetic basis of COPD.     

Genetic risk factors for chronic obstructive pulmonary disease

Numerous epidemiologic studies have indicated that there is a genetic basis to COPD. This result suggests that COPD develops in genetically susceptible individuals after sufficient exposure to cigarette smoke. At present, most of the genes that contribute to the genetic component to COPD are unknown. alpha 1-Antitrypsin deficiency is clearly a risk factor for COPD, but the other genetic associations with this disease must be considered as tentative. The key to establishing that a gene modifies the risk for a disease is replication of the association in different populations. This is a difficult task, however, because different genetic risk factors may be present in different populations. In addition, these genetic factors may interact with each other and with environmental risk factors, obscuring the effect of the gene on the phenotype. Apart from alpha 1-AT only the GST-M1, VDBP and CFTR genes have been implicated as risk factors in more than one population. Identification of other candidate genes awaits further understanding of the pathogenesis of COPD at the molecular level. There is good evidence that the propensity to smoke cigarettes and the likelihood of quitting smoking are influenced by genetic factors. This information may be useful in efforts directed toward cessation; however, most of the genetic studies so far have shown a rather small effect. The responses to hypoxia and hypercapnia also seem to be influenced by genetic factors. Identification of the genes involved could yield important insights into the pathogenesis of COPD and may highlight new targets for therapeutic intervention for this debilitating disease.     

The genetics of cardiovascular disease

Recent advances in genotyping technology and insights into disease mechanisms have increased interest in the genetics of cardiovascular disease. Several candidate genes involved in cardiovascular diseases were identified from studies using animal models, and the translation of these findings to human disease is an exciting challenge. There is a trend towards large-scale genome-wide association studies that are subject to strict quality criteria with regard to both genotyping and phenotyping. Here, we review some of the strategies that have been developed to translate findings from experimental models to human disease and outline the need for optimizing global approaches to analyze such results. Findings from ongoing studies are interpreted in the context of disease pathways instead of the more traditional focus on single genetic variants.     

What can genetics tell us about the cause of fixed airflow obstruction?

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide with smoking being the most important risk factor of the disease. However, lung function and COPD are known to also have a genetic component and a deeper knowledge of the genetic architecture of the disease could lead to further understanding of predisposition to COPD and also to development of new therapeutic interventions. Genetic linkage studies and candidate gene association studies have not provided evidence to convincingly identify the genes underlying lung function or COPD. However, recent large genome-wide association studies (GWAS) including tens of thousands of individuals have identified 26 variants at different loci in the human genome that show robust association with quantitative lung function measures in the general population. A growing number of these variants are being shown to be associated with COPD. Following the identification of these new lung function loci, the challenge now lies in refining the signals to identify the causative variants underlying the association signals and relating these signals to the molecular pathways that underlie lung function.     

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.     

Progress in chronic obstructive pulmonary disease genetics

Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, suggesting that genetic factors likely influence the variable development of chronic airflow obstruction in response to smoking. A variety of approaches have been used to identify novel COPD susceptibility genes, including association studies, linkage analysis, and rare variant analysis. Future directions for COPD research include genomewide association studies and animal model genetic studies.     

1. COPD pathogenesis from the viewpoint of risk factors

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation in the lungs. Smoking is one of the amongst major risk factors for the development of COPD. Environmental pollution, age, and airway hyperreactivity are also the risk factors. The protease-antiprotease imbalance and the oxidant-antioxidant imbalance cause airway inflammation and destruction. The genes related to these balances may contribute to development of COPD pathology. Candidate gene-association studies and linkage analyses have been reported for COPD patients. The alpha-1 antitrypsin, glutathione S-transferase, microsomal epoxide hydrolase, and matrix metalloproteinase, are candidate genes. In acquired factors for COPD pathology, the adenoviral latent infection may enhance airway inflammation, leading to airflow obstruction. The current progress and future visions of genetic predisposition of COPD are discussed.     

Genetic risk factors of chronic obstructive pulmonary disease

Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). However, only a minority of cigarette smokers develop symptomatic disease. Family and twin studies suggest that genetic factors also contribute to the development of COPD. We present a detailed literature review of the genes which have been investigated as potential risk factors for this disease.     

Genetics of COPD

Previous family studies suggested that genetic variation contributes to COPD susceptibility. The only gene proven to influence COPD susceptibility is SERPINA1, encoding α1-antitrypsin. Most studies on COPD candidate genes except SERPINA1, have not been consistently replicated. However, longitudinal studies of decline in lung function, meta-analyses of candidate gene studies, and family-based linkage analyses suggested that variants in EPHX1, GST, MMP12, TGFB1, and SERPINE2 were associated with susceptibility to COPD. A genome-wide association (GWA) study has recently demonstrated that CHRNA3/5 in 15q25 was associated with COPD compared with control smokers. It was of interest that the CHRNA3/5 locus was associated with nicotine dependence and lung cancer as well. The associations of HHIP on 4q31 and FAM13A on 4q22 with COPD were also suggested in GWA studies. Another GWA study has shown that BICD1 in 12p11 was associated with the presence or absence of emphysema. Although every genetic study on COPD has some limitations including heterogeneity in smoking behaviors and comorbidities, it has contributed to the progress in elucidating the pathogenesis of COPD. Future studies will make us understand the mechanisms underlying the polygenic disease, leading to the development of a specific treatment for each phenotype.     

National Emphysema Treatment Trial state of the art: genetics of emphysema

Although a hereditary contribution to emphysema has been long suspected, severe alpha1-antitrypsin deficiency remains the only conclusively proven genetic risk factor for chronic obstructive pulmonary disease (COPD). Recently, genome-wide linkage analysis has led to the identification of two promising candidate genes for COPD: TGFB1 and SERPINE2. Like multiple other COPD candidate gene associations, even these positionally identified genes have not been universally replicated across all studies. Differences in phenotype definition may contribute to nonreplication in genetic studies of heterogeneous disorders such as COPD. The use of precisely measured phenotypes, including emphysema quantification on high-resolution chest computed tomography scans, has aided in the discovery of additional genes for clinically relevant COPD-related traits. The use of computed tomography scans to assess emphysema and airway disease as well as newer genetic technologies, including gene expression microarrays and genome-wide association studies, has great potential to detect novel genes affecting COPD susceptibility, severity, and response to treatment.     

Genetics and the Dutch Hypothesis

BACKGROUND: Increasingly, molecular genetic techniques are being used to improve our understanding of a number of common late onset complex disorders, such as hypertension, Alzheimer's disease and noninsulin dependent diabetes mellitus. Molecular genetic approaches have the potential to yield new information about disease pathogenesis that may be of great importance for the development of future treatments. AIMS: This review discusses the evidence for a genetic contribution to the development of chronic obstructive pulmonary disease (COPD) and specifically focuses on the hypothesis that asthma and COPD share some pathogenic mechanisms as originally proposed in 1960 in a theory that has since become known as the Dutch Hypothesis. In particular we will review the evidence from molecular genetics, both in support of and against the theory.     

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.     

Genetic influences in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disease with widely variable phenotypes extending from simple steatosis, through nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma. Inevitably, this reflects the interplay of well-recognized environmental factors and disease associations such as obesity and insulin resistance with host genetic factors, which are polygenic or complex in nature. Most of the observed phenotypic variability will probably be explained by variations in single nucleotide polymorphism frequency, although knowledge of the effect of most polymorphisms on biologic function is currently limited. Several observational studies of kindred with NASH suggest a genetic contribution. Most data characterizing genetic variation in different NAFLD phenotypes is derived from case-control association studies involving putative candidate genes. These candidate genes have been selected largely based upon the "two-hit hypothesis" of the pathogenesis of NAFLD, although other hypothesis-independent approaches can also be informative in gene selection. Thus far, candidate gene association studies have had significant limitations such as small cohort sizes and poor reproducibility. Rapid technologic developments are increasing the capability of detecting genetic variation. Identification of the genetic contribution to NAFLD will inform theories of disease pathogenesis and progression and ultimately improve management.     

Can the genetic factors influence the treatment of systemic hypertension? The case of the renin-angiotensin-aldosterone system.

The hereditary nature of familial hypertension has been clearly established by a number of clinical studies. About 30% of the blood pressure variance can be attributed to genetic factors. As a consequence, the relative risk for developing coronary artery disease or cardiovascular death is increased in patients with a family history of hypertension and cardiovascular disease. Patients with such familial history should be considered at the same risk as those who have independent epidemiologic risk factors. The development of molecular genetics allows establishment of a link between high blood pressure, intermediate phenotypes, and the genes involved in blood pressure regulation. Gene markers should be available in the near future that will help to identify patients predisposed to hypertension. The genes of the renin-angiotensin-aldosterone system are good examples of candidate genes whose products are known to participate in blood pressure regulation. The possible involvement of these genes in essential hypertension is critically analyzed.     

Genetik von Vorhofflimmern: seltene Mutationen, häufige Genvarianten und klinische Relevanz?

Atrial fibrillation (AF) is considered the, by far, the most common arrhythmia of man, affecting millions of patients worldwide. The high socio-economic relevance is due to several severe complications and therefore requires profound scientific research in the field of etiology and treatment options. Atrial fibrillation typically occurs in the older patient who often suffers from a number of underlying diseases that act as predisposing factors. That genetics contribute strongly to this rhythm disorder is therefore not evident at a first glance. However, there are a number of investigations that prove familial accumulation for lone AF. Furthermore it is remarkable that many older patients suddenly develop atrial fibrillation without underlying disease, while others remain in sinus rhythm although suffering from a series of risk factors. Considering all this, genetic interference becomes most probable. Therefore in the recent past remarkable endeavours have been ventured to clarify the genetic basis of both lone AF and AF in the context of underlying diseases. For the former, until now four different genetic loci and three disease genes have been identified as causative. Concerning AF in the general population, mainly studies turning the spotlight on single-nucleotide polymorphisms (SNPs) have been applied. It is assumed that SNPs in disease-causing genes are distributed differentially among healthy and diseased individuals. These differences in frequency have been investigated with case-control studies. Up to now six different genes have been found to be associated with AF, including the genes for angiotensin-converting enzyme, angiotensinogen and several cardiac ion channels. Promising new technologies, especially high-throughput SNP genotyping and the genome wide scan for new candidate genes using chip arrays capable of genotyping up to 500 000 SNPs at a time, will multiply the speed to achieve new results. With that the possibility, approaches to optimize existing therapies and to open up new pathways to treat AF.     

Dissecting the genetics of Type 1 diabetes: relevance for familial clustering and differences in incidence

A combination of genetic and environmental factors is most likely the cause of Type 1 diabetes. Results from twin data, familial clustering of the disease and difference in incidence according to ethnicity infer the presence of specific disease genes. The genetic component of Type 1 diabetes cannot be classified according to a classical model of inheritance but is due to an interaction between different genes and environmental factors. The major genes are within the HLA region that are responsible for 40% of the genetic susceptibility, although other genes are important (non-HLA genes). To date, more than 10 specific loci have been localized on different chromosomes. The gene involved has been characterized only for two of such loci, IDDM1 and IDDM2, while in the other cases the presence of some susceptibility genes can be envisaged and their identification represents the goal of genetic research in coming years. Fine mapping of the loci will certainly increase our understanding of the genetics of Type 1 diabetes; the limitation in detecting some of the remaining genes by linkage studies can be overcome by association studies. That is possible via the collection of a large number of affected families (over 1000) in homogeneous populations. © 1998 John Wiley & Sons, Ltd.