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 of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a complex disease with multifactorial background, based on the interaction of environmental and genetic factors. Environmental factors are clearly related to the development of the disease. However, family and twin studies suggested genetics factors to be one of the important determinants for the development of COPD. Different approaches have been used to identify genes of interest. Genomewide linkage analysis found areas of interest on different chromosomes, with some genes located in this regions being identified and replicated as susceptibility genes. Numerous of candidate genes that could be linked to disease pathogenesis have been implicated in COPD genetics. However, the candidate gene approach is often limited by inconsistent results in other study populations. Recently, a combination of different methods is used giving more evidence for some candidate genes, including TGFß-1, Surfactant, SERPINE2 and microsomal epoxide hydrolase. In the future ongoing exact phenotype definition, combination of several approaches, genome-wide association studies and animal model genetics will lead to new insights into the genetics of COPD, with epigenetic factors needs to be further investigated and considered in concert with genetic findings.     

Genome-wide association studies for discovery of genes involved in asthma

Asthma is the result of a complex interaction between environmental factors and genetic variants that confer susceptibility. Studies of the genetics of asthma have previously been conducted using linkage designs and candidate gene association studies. Recently, the association study design has been extended from specific candidate genes to an unbiased genome-wide approach: the genome-wide association study (GWAS). To date, there have been 12 GWAS to look for susceptibility loci for asthma and related traits. The first GWAS for asthma discovered a novel associated locus on chromosome 17q21 encompassing the genes ORMDL3, GSDMB and ZPBP2. None of these genes would have been selected in a candidate association study based on current knowledge of the functions of these genes. Nevertheless, this finding has been consistently replicated in independent populations of European ancestry and also in other ethnic groups. Thus, chromosome 17q21 seems to be a true asthma susceptibility locus. Other genes that were identified in more than one GWAS are IL33, RAD50, IL1RL1 and HLA-DQB1. Additional novel susceptibility genes identified in a single study include DENND1BI and IL2RB. Discovering the causal mechanism behind these associations is likely to yield great insights into the development of asthma. It is likely that further meta-analyses of asthma GWAS data from existing international consortia will uncover more novel susceptibility genes and further increase our understanding of this disease.     

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.     

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.     

Between Candidate Genes and Whole Genomes: Time for Alternative Approaches in Blood Pressure Genetics

Blood pressure has a significant genetic component, but less than 3% of the observed variance has been attributed to genetic variants identified to date. Candidate gene studies of rare, monogenic hypertensive syndromes have conclusively implicated several genes altering renal sodium balance, and studies of essential hypertension have inconsistently implicated over 50 genes in pathways affecting renal sodium balance and other functions. Genome-wide linkage scans have replicated numerous quantitative trait loci throughout the genome, and over 50 single nucleotide polymorphisms (SNPs) have been replicated in multiple genome-wide association studies. These studies provide considerable evidence that epistasis and other interactions play a role in the genetic architecture of blood pressure regulation, but candidate gene studies have limited scope to test for epistasis, and genome-wide studies have low power for both main effects and interactions. This review summarizes the genetic findings to date for blood pressure, and it proposes focused, pathway-based approaches involving epistasis, gene-environment interactions, and next-generation sequencing to further the genetic dissection of blood pressure and hypertension.     

What Have Genome-Wide Studies Told Us About Psoriatic Arthritis?

There is convincing evidence to suggest a strong genetic component to psoriatic arthritis (PsA), with studies reporting a 40-fold risk to first-degree relatives of patients with disease. However, compared with rheumatoid arthritis, our understanding of the genetic etiology of PsA is less well-developed. Only three modestly sized genome-wide association studies of PsA have been undertaken to date, but they have identified the HLA-C region, IL12B, TRAF3IP2, and FBXL19 genes as being associated with PsA susceptibility. Results of genome-wide association studies of psoriasis and rheumatoid arthritis have been used to identify candidate genes for subsequent testing in PsA and have led to the identification of additional susceptibility factors for PsA. Most show overlap with psoriasis, whereas the overlap with rheumatoid arthritis is less pronounced. However, two loci show strong evidence for association with PsA but not psoriasis: HLA-B27 and the IL-13 gene locus.     

Susceptibility genes and B-chronic lymphocytic leukaemia

Common genetic variants are thought to increase the risk of chronic lymphocytic leukaemia (CLL), and case-control studies provide an approach to detect these variants. There have been multiple candidate gene studies published to date, but relatively few disease pathway studies or large genomic association studies. We summarize the results of these previous studies, as well as present results from our recent large pathway study of 9412 single nucleotide polymorphisms from 1253 immunity and inflammation genes in a study of 126 CLL cases and 484 frequency-matched controls. Several promising genes have been identified as susceptibility genes for risk of CLL across all of these association studies. However, a number of candidate gene studies have not been replicated in follow-up studies, whereas the results from disease pathway and large genomic studies have yet to be replicated in an independent sample. The challenge of future studies of this type will be overcoming study design issues, including definition of CLL, sample size limitations and multiple testing issues.     

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.     

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.     

Genetic predisposition to accelerated decline of lung function in COPD

Environmental exposures and genetic susceptibility can contribute to lung function decline in chronic obstructive pulmonary disease (COPD). The environmental factors are better known than the genetic factors. One of the commonest reasons of accelerated forced expiratory volume in one second (FEV₁) decline in COPD is the continuation of the smoking habit. In addition, COPD patients have frequent acute respiratory infections which can also accelerate the decline of FEV₁. All of the gene variants that have been reported in association with accelerated decline of lung function in COPD represent advancement because the findings generate plausible hypotheses about the possible mechanisms by which gene products could accelerate or avert FEV₁ decline. Unfortunately, the results have not been consistently replicated and, animal models required to functionally assess the genetic findings, have not yet yielded sufficient data. Genome-wide association studies should provide more definitive results in COPD and other multigenic conditions. Until these studies are reported, the data to date suggest that products encoded by the alpha-1 antitrypsin, some matrix metalloproteinases, and a number of antioxidant genes are associated with accelerated FEV₁ decline in COPD. Data on gene variants associated with acute exacerbations of COPD are now emerging.     

Genetics of inflammatory bowel disease. A personal view on progress and prospects

Clinical, epidemiological and molecular data reported in the last 5 years have provided strong evidence that genetic factors are important in susceptibility to both Crohn's disease and ulcerative colitis. The model of disease inheritance which best fits the epidemiological data is that Crohn's disease and ulcerative colitis are related polygenic diseases. However, genetic heterogeneity is likely to be extensive, and may well underlie the variability in clinical presentation associated with inflammatory bowel disease. Considerable progress has already been made in identifying potential disease susceptibility loci using the technique of genome-wide scanning. There is optimism that international collaborative studies will allow fine mapping of the loci implicated on chromosomes 16 and 12. The identification of novel susceptibility genes has become a realistic goal for investigators. Once this has been achieved, there are likely to be immediate clinical benefits, both in understanding disease pathophysiology, and in disease management.     

The Genetics of Scleroderma

The importance of the genetic component in the pathogenesis of scleroderma, or systemic sclerosis, has been strengthened in the past 2 years with studies on genetic markers–either candidate gene or genome-wide association studies—in large case–control series. Multiple genes have been consistently associated with susceptibility to scleroderma, and interestingly, several of them are involved in immune regulation. Because many of these genes are shared with other autoimmune diseases, a common underlying autoimmune mechanism has been proposed. The challenge that lies ahead is to confirm these associations and to find markers or pathways that are unique to scleroderma and that may define its distinctive phenotype.     

Corcoran Lecture. Cardiovascular genomics and oxidative stress

The majority of modifiable cardiovascular risk factors are complex, polygenic, or at least oligogenic traits, with genetic and environmental determinants playing important roles in disease risk and its phenotypic expression. The Human Genome Project and subsequent mouse and rat genome data have provided powerful tools to commence the dissection of genetic determinants of hypertension and other cardiovascular risk factors. Despite several new methodologies such as genome-wide scans, genome-wide gene expression profiling, and proteomic screens, it is fair to say that the progress of genetic studies designed as nonhypothesis driven has been relatively slow. On the other hand, several interesting candidate pathways have been identified, where investigators allowed for hypothesis-driven functional studies. One example of such pathway is vascular oxidative stress with its extensive network of genes and proteins, many with proven contributions to cardiovascular disease. Therefore, in parallel to genome-wide or proteome-wide studies, it will be constructive to pursue "pathwayomics" defined here as functional studies of a candidate pathway for disease pathogenesis.     

Polymorphisms in tumor necrosis factor and other cytokines as risks for infectious diseases and the septic syndrome

An increasing number of genetic association studies have implicated polymorphisms of cytokine genes as host genetic factors influencing susceptibility to infectious disease, primarily using a candidate gene approach based on knowledge of disease pathogenesis. The application and limitations of association studies are reviewed together with the impact of recent advances in single nucleotide polymorphism mapping on strategic approaches to defining genetic susceptibility loci. It often remains unclear whether associated genetic polymorphisms are themselves functionally relevant or acting only as markers within an extended haplotype, and experimental approaches to investigating the functional impact of polymorphisms in noncoding regulatory DNA sequences are discussed. An overview of genetic associations of cytokine genes with infectious disease is presented, together with discussion of recent studies in a number of infectious diseases including hepatitis, HIV, malaria, and sepsis.     

Polymorphisms in Tumor Necrosis Factor and Other Cytokines As Risks for Infectious Diseases and the Septic Syndrome

An increasing number of genetic association studies have implicated polymorphisms of cytokine genes as host genetic factors influencing susceptibility to infectious disease, primarily using a candidate gene approach based on knowledge of disease pathogenesis. The application and limitations of association studies are reviewed together with the impact of recent advances in single nucleotide polymorphism mapping on strategic approaches to defining genetic susceptibility loci. It often remains unclear whether associated genetic polymorphisms are themselves functionally relevant or acting only as markers within an extended haplotype, and experimental approaches to investigating the functional impact of polymorphisms in noncoding regulatory DNA sequences are discussed. An overview of genetic associations of cytokine genes with infectious disease is presented, together with discussion of recent studies in a number of infectious diseases including hepatitis, HIV, malaria, and sepsis.     

Genetics of ulcerative colitis

Ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic inflammatory bowel diseases (IBDs), with distinct and overlapping susceptibility loci. Recently, hypothesis-free genome-wide association (GWA) studies have revolutionized the field of complex disease genetics. Substantial advances have been achieved in defining the genetic architecture of IBD. To date, over 60 published IBD susceptibility loci have been discovered and replicated, of which approximately a third are associated with both UC and CD, although 21 are specific to UC and 23 to CD. In CD, the breakthrough identification of NOD2 as a susceptibility gene was followed by a rapid phase of gene discovery from GWA studies between 2006 and 2008. Progress in UC was slower; however, by initially testing hits for CD in UC, and later scanning larger UC cohorts, significant new loci for UC have been discovered, with exciting novel insights into disease pathogenesis. Notably, genes implicated in mucosal barrier function (ECM1, CDH1, HNF4α, and laminin B1) confer risk of UC; furthermore, E-cadherin is the first genetic correlation between colorectal cancer and UC. Impaired IL10 signaling has reemerged as a key pathway in intestinal inflammation, and is perhaps the most amenable to therapeutic intervention in UC. Collaborative international efforts with large meta-analyses of GWA studies and replication will yield many new UC genes. Furthermore, a large effort is required to characterize the loci found. Fine-mapping, deep resequencing, and functional studies will be critical to translating these gene discoveries into pathogenic insights, and ultimately into clinical insights and novel therapeutics.     

Genetic backgrounds of myocardial infarction

Myocardial infarction (MI) is among the leading causes of death in the world. Although coronary risk factors (eg, diabetes mellitus, hypercholesterolemia, and hypertension) have genetic components, a positive family history is an independent predictor that suggests an individual’s genetic background. To date, candidate MI susceptibility genes were identified on several chromosome loci by genome-wide, large-scale, case-control association studies using single-nucleotide polymorphisms (SNPs). Although roles of these gene products in development and/or progression of MI are poorly understood, several genes conferring risk of MI were related to inflammation. These findings provide a clue for new approaches to prevention, diagnosis, and therapy of MI.     

Autoimmune Addison disease: pathophysiology and genetic complexity

Autoimmune Addison disease is a rare autoimmune disorder with symptoms that typically develop over months or years. Following the development of serum autoantibodies to the key steroidogenic enzyme, 21-hydroxylase, patients have a period of compensated or preclinical disease, characterized by elevations in adrenocortocotropic hormone and renin, before overt, symptomatic adrenal failure develops. We propose that local failure of steroidogenesis, causing breakdown of tolerance to adrenal antigens, might be a key factor in disease progression. The etiology of autoimmune Addison disease has a strong genetic component in man, and several dog breeds are also susceptible. Allelic variants of genes encoding molecules of both the adaptive and innate immune systems have now been implicated, with a focus on the immunological synapse and downstream participants in T lymphocyte antigen-receptor signaling. With the exception of MHC alleles, which contribute to susceptibility in both human and canine Addison disease, no major or highly penetrant disease alleles have been found to date. Future research into autoimmune Addison disease, making use of genome-wide association studies and next-generation sequencing technology, will address the gaps in our understanding of the etiology of this disease.     

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.