Genetic Basis Of Asthma Research Articles

Genetic differences according to onset age and lung function in asthma: A cluster analysis.

The extent of differences between genetic risks associated with various asthma subtypes is still unknown. To better understand the heterogeneity of asthma, we employed an unsupervised method to identify genetic variants specifically associated with asthma subtypes. Our goal was to gain insight into the genetic basis of asthma. In this study, we utilized the UK Biobank dataset to select asthma patients (All asthma, n=50,517) and controls (n=283,410). We excluded 14,431 individuals who had no information on predicted values of forced expiratory volume in one second percent (FEV1%) and onset age, resulting in a final total of 36,086 asthma cases. We conducted k-means clustering based on asthma onset age and predicted FEV1% using these samples (n=36,086). Cluster-specific genome-wide association studies were then performed, and heritability was estimated via linkage disequilibrium score regression. To further investigate the pathophysiology, we conducted eQTL analysis with GTEx and gene-set enrichment analysis with FUMA. Clustering resulted in four distinct clusters: early onset asthmanormalLF (early onset with normal lung function, n=8172), early onset asthmareducedLF (early onset with reduced lung function, n=8925), late-onset asthmanormalLF (late-onset with normal lung function, n=12,481), and late-onset asthmareducedLF (late-onset with reduced lung function, n=6508). Our GWASs in four clusters and in All asthma sample identified 5 novel loci, 14 novel signals, and 51 cluster-specific signals. Among clusters, early onset asthmanormalLF and late-onset asthmareducedLF were the least correlated (rg =0.37). Early onset asthmareducedLF showed the highest heritability explained by common variants (h2 =0.212) and was associated with the largest number of variants (71 single nucleotide polymorphisms). Further, the pathway analysis conducted through eQTL and gene-set enrichment analysis showed that the worsening of symptoms in early onset asthma correlated with lymphocyte activation, pathogen recognition, cytokine receptor activation, and lymphocyte differentiation. Our findings suggest that early onset asthmareducedLF was the most genetically predisposed cluster, and that asthma clusters with reduced lung function were genetically distinct from clusters with normal lung function. Our study revealed the genetic variation between clusters that were segmented based on onset age and lung function, providing an important clue for the genetic mechanism of asthma heterogeneity.

Genomic Predictors of Asthma Phenotypes and Treatment Response.

Asthma is a complex respiratory disease considered as the most common chronic condition in children. A large genetic contribution to asthma susceptibility is predicted by the clustering of asthma and allergy symptoms among relatives and the large disease heritability estimated from twin studies, ranging from 55 to 90%. Genetic basis of asthma has been extensively investigated in the past 40 years using linkage analysis and candidate-gene association studies. However, the development of dense arrays for polymorphism genotyping has enabled the transition toward genome-wide association studies (GWAS), which have led the discovery of several unanticipated asthma genes in the last 11 years. Despite this, currently known risk variants identified using many thousand samples from distinct ethnicities only explain a small proportion of asthma heritability. This review examines the main findings of the last 2 years in genomic studies of asthma using GWAS and admixture mapping studies, as well as the direction of studies fostering integrative perspectives involving omics data. Additionally, we discuss the need for assessing the whole spectrum of genetic variation in association studies of asthma susceptibility, severity, and treatment response in order to further improve our knowledge of asthma genes and predictive biomarkers. Leveraging the individual's genetic information will allow a better understanding of asthma pathogenesis and will facilitate the transition toward a more precise diagnosis and treatment.

Asthma as a Respiratory Disorder

This article reviews causes, symptoms and genetic basis of asthma as well as the pharmaceutical therapies currently being practiced for its treatment. Asthma is a worldwide respiratory disorder characterized by recurring conditions of inflammation and the narrowing of respiratory passage ways termed as bronchoconstriction, bronchial hyper-responsiveness, bronchospasm, chest tightening, shortness of breath, etc. About 300 million people suffer from asthma globally with 250,000 annual deaths attributed to asthma. In many populations, the main cause of an increased occurrence of asthma is the lack of awareness amonggeneral public. Smoking, allergens, microbes, pollutants, dust, chemicals, vapors, fumes, exercise etc. act as stimulants and triggers of asthma. Various gene-gene and genetic-environmental factors act together resulting in asthmatic pathogenesis. Various loci have been identified that play a potential role in this regard. Genetic polymorphism among patients makes the treatment a bit difficult as patients with similar symptoms show varied responses to the same medications and therapeutic strategies. Asthma is not completely curable; therefore, most medications aim to lower the exacerbations rather than fixing the underlying causes and mechanisms of the disease. Short and Long Acting Beta-antagonists (SABAs and LABAs) and inhaled corticosteroids (ICS) have been found to be effective against asthma. Phytomedicines and biological agents such as omalizumab are being developed currently for the modulation of asthma-related immunologic and cell-signaling mechanisms. Asthma and psychological disorders are often found to be correlated. The need arises for greater public awareness regarding asthma, improved genetic analysis techniques, assessment of underlying molecular mechanisms, optimization of current therapeutic strategies and the development of new personalized target drugs for its efficient prevention and control.

Epigenome analysis links gene regulatory elements in group 2 innate lymphocytes to asthma susceptibility

Group 2 innate lymphoid cells (ILC2s) are major producers of the cytokines driving allergic asthma, and increased ILC2 numbers have been detected in blood and sputum of asthmatic patients. Asthma susceptibility has a strong genetic component, but the underlying mechanisms and whether asthma genetics affect ILC2 biology remain unclear. We sought to study the ILC2 transcriptome and epigenome during airway inflammation (AI) to couple these to genes and genetic variants associated with asthma pathogenesis. Mice harboring a reporter for the key ILC2 transcription factor GATA-3 were subjected to IL-33-driven AI, and ILC2s were isolated from bronchoalveolar lavage fluid and mediastinal lymph nodes. Human ILC2s were purified from peripheral blood and activated invitro. We used RNA sequencing, genome-wide identification of histone-3 lysine-4 dimethylation-marked chromatin, and computational approaches to study the ILC2 transcriptome and epigenome. Activated ILC2s in mice displayed a tissue-specific gene expression signature that emerged from remarkably similar epigenomes. We identified superenhancers implicated in controlling ILC2 identity and asthma-associated genes. More than 300 asthma-associated genetic polymorphisms identified in genome-wide association studies localized to H3K4Me2+ gene regulatory elements in ILC2s. Arefined set of candidate causal asthma-associated variants was uniquely enriched in ILC2, but not TH2 cell, regulatory regions. ILC2s in AI use a flexible epigenome that couples adaptation to new microenvironments with functional plasticity. Importantly, we reveal strong correlations between gene regulatory mechanisms in ILC2s and the genetic basis of asthma, supporting a pathogenic role for ILC2s in patients with allergic asthma.

Genetic basis of asthma.

Asthma is a chronic, inflammatory disease which affects individuals of all age groups. Most commonly, it is seen in children and young adults. The prevalence of asthma in India has been variably reported in the past1. The two recent studies report the prevalence of about two per cent in the general population2,3. The Indian Study on Epidemiology of Asthma, Respiratory symptoms and Chronic bronchitis (INSEARCH) employed a cross-sectional survey design using a standardized, validated questionnaire for interviewing a population sample of 169575 individuals selected in a randomized fashion at 12 different centres across India2. In the second study, the investigators used the data from India's third National Family Health Survey (NFHS-3; 2005-2006) and reported the prevalence of self-reported asthma3. The prevalence in children is generally reported to be higher. Multiple risk factors, both genetic and environmental are important in the aetiology of asthma. Exposure to different allergens (such as the pollens, house-dust mites), micro-organisms, chemicals, vapours, fumes and dusts can precipitate asthma, but cannot alone be blamed to cause asthma. On the other hand, asthma is not a pure genetic disorder. It arises de novo in a large number of patients without the presence of any family history. Presumably, the environmental exposures produce asthma in the genetically susceptible individuals.

Multivariate Asthma Phenotypes in Adults: The Quebec City Case-Control Asthma Cohort

Background and Objectives: Asthma is a heterogeneous disease where patient severity can be classified according to various models based on numerous variables. Large collections of well-phenotyped subjects are needed to find distinct clusters of patients for personalized medicine and future genetic studies. The objective of this study is to describe the collection of the Quebec City Case-Control Asthma Cohort and to identify homogeneous subgroups of asthma patients based on clinical characteristics. Methods: This cohort is part of an ongoing project initiated in 2007 to elucidate the genetic basis of asthma. All subjects are randomly recruited at the same site following advertisements. Subjects are unrelated French Canadian white adults 18 years of age or older. Each participant underwent a spirometry, methacholine challenge, and allergy skin-prick tests. Blood was collected for DNA, cell counts and total serum IgE measurements. So far, 982 subjects have been recruited and classified as cases (n = 566) or controls (n = 416). We performed factor and cluster analyses on collected phenotypes from this set to identify subgroups of phenotypically similar asthmatic patients. Results: Factor analysis with 13 variables led to the selection of five factors: lung function, numbers of allergens, blood eosinophil percentage, smoking status and age. K-means cluster analysis on the reduced dataset produced four significantly different groups with the following characteristics: smoking history, low atopy and low lung function, high atopy, and young non-smoking with average atopy. Conclusions: The Quebec City Case-Control Asthma Cohort is a new resource for local and collaborative clinical and genetic research on asthma. This new collection reveals distinct multivariate phenotypes of adult asthma that are likely to be important for future genetic studies and targeted therapies.

Genetic studies of the etiology of asthma.

Asthma is a heterogeneous disease for which a strong genetic basis is firmly established. Although the generally accepted definition includes three domains of symptoms (variable airway obstruction, airway hyper-responsiveness, and airway inflammation), there is general agreement that, rather than being a single disease entity, asthma consists of related, overlapping syndromes. A considerable proportion of asthma is IgE-mediated, but the observation that not all individuals with asthma are atopic adds to the heterogeneity. Although a genetic basis for asthma is undeniable, elucidation of polymorphisms that are "causal" is greatly hampered by variability in the clinical phenotype, which is likely due to the multiple molecular mechanisms underlying the complex pathological processes involved in disease development and progression. One objective of this review is to consider progress that has been made to date in gene discovery in the field of asthma, with a focus on the evolution of molecular genetic methods that have led to the discoveries thus far, and with a particular focus on the major advances owed to the published genome-wide association studies (GWAS) on asthma to date. A second objective is to consider a Darwinian approach toward understanding the genetic underpinnings of asthma, including evidence supporting a modified Hygiene Hypothesis, which suggests that there are co-associations between asthma risk polymorphisms and polymorphisms associated with another IgE-mediated disease, schistosomiasis. The overall conclusion is that the huge research efforts and expense committed to asthma genetics have changed the perception about disease etiology in general and the functional relevance of the asthma genes identified thus far in particular.

An association between IL-9 and IL-9 receptor gene polymorphisms and atopic dermatitis in a Korean population

The genes encoding IL-9 and IL-9R have recently been implicated in the genetic basis of asthma and allergy. Although studies performed on transgenic and knockout mice have shown conflicting results, no evidence of skin changes has ever been reported in these animals. To find association of the SNPs in IL-9 and IL-9R genes and interaction of these genes in atopic dermatitis. We genotyped 5 SNPs from the IL-9 and IL-9R genes of 1090 subject samples (631 AD patients and 459 normal controls). A luciferase assay was then performed for the rs31563 (-4091G/A) SNP located in the IL-9 gene promoter region. The rs31563 (-4091G/A) SNP in the IL-9 gene was significantly associated with the AD phenotype, especially allergic-type AD. In the luciferase assay, the rs31563 G construct was observed to have 1.54 times higher activity than the rs31563 A construct. Although no association was found between SNPs in IL-9R gene and AD, the rs3093467 SNP showed association with non-allergic AD. In the gene-gene interaction analysis, we found that IL-9/IL-9R genotype rs31563 GG/rs3093467 TT conveyed a greater risk for AD phenotype development. Significant evidence exists to suggest that the rs31563 SNP (-4091G/A) located in the IL-9 gene is associated with an increased susceptibility to AD. Similarly, the rs3093467 SNP in IL-9R gene seems to be associated with an increased risk for developing non-allergic AD. In a subsequent gene-gene interaction analysis, the rs31563 GG/rs3093467 TT genotype combination (IL-9/IL-9R) was found to exert a synergistic effect in the development of the AD phenotype. As the classes of helper T cells are diverse and the function of IL-9 cytokine has not been fully described, the cutaneous function of IL-9 needs to be further explored in future studies.

Genetics of asthma: a molecular biologist perspective

Asthma belongs to the category of classical allergic diseases which generally arise due to IgE mediated hypersensitivity to environmental triggers. Since its prevalence is very high in developed or urbanized societies it is also referred to as "disease of civilizations". Due to its increased prevalence among related individuals, it was understood quite long back that it is a genetic disorder. Well designed epidemiological studies reinforced these views. The advent of modern biological technology saw further refinements in our understanding of genetics of asthma and led to the realization that asthma is not a disorder with simple Mendelian mode of inheritance but a multifactorial disorder of the airways brought about by complex interaction between genetic and environmental factors. Current asthma research has witnessed evidences that are compelling researchers to redefine asthma altogether. Although no consensus exists among workers regarding its definition, it seems obvious that several pathologies, all affecting the airways, have been clubbed into one common category called asthma. Needless to say, genetic studies have led from the front in bringing about these transformations. Genomics, molecular biology, immunology and other interrelated disciplines have unearthed data that has changed the way we think about asthma now. In this review, we center our discussions on genetic basis of asthma; the molecular mechanisms involved in its pathogenesis. Taking cue from the existing data we would briefly ponder over the future directions that should improve our understanding of asthma pathogenesis.

Genes for asthma: much ado about nothing?

The identification of genes that make individuals susceptible to developing asthma is an area of increasing focus by both academic and industrial groups. The complexity of asthma genetics has made the identification of susceptibility genes difficult; however, genome-wide screens followed by positional cloning have started to identify such genes for both asthma and asthma-related traits. In addition, evidence from candidate gene studies indicates that gene-gene interactions also play an important role in conferring genetic risk for asthma development. Although progress in terms of identifying new therapeutic targets has not been dramatic, our understanding of the complexity of the genetic basis of asthma has greatly increased. There can be little doubt that, in the future, this knowledge will lead to fundamental insights into the molecular pathophysiology of asthma and the development of new therapies.

Genetics and asthma

Publisher Summary Genes causing disease may be found either by the process known as 'positional cloning', or by examining candidate genes. Positional cloning relies on the demonstration of genetic linkage (co-inheritance) of disease and genetic markers of known chromosomal localization. Once linkage is established, the linked region can be dissected by further genetic mapping with a dense array of closely linked markers. Genetic mapping is followed by 'physical mapping', the assembly of overlapping DNA clones covering the linked regions, and the eventual identification and sequencing of genes from the DNA. The positional cloning approach has the advantage of not requiring any pre-existing knowledge of the pathophysiology of the disease. Genetic linkage in complex disorders, however assessed, often replicates poorly, at least in the early stages. This is because linkage to a heterogeneous trait will normally only be found fortuitously, in samples that contain an exceptional proportion of individuals or families influenced by that particular gene. The genetic basis for asthma is gradually becoming more certain; the methodological tools for finding genetic linkage and association are now established, and it is likely that all the important genes and their variants will be found in future.

Defining the Asthma Phenotype for the Purpose of Genetic Analysis

In 1991, we began a project to search for the genetic basis of asthma using linkage analysis. We encountered discord between a history of asthma and physiological measures of variable airflow obstruction and sought to examine the frequency of such occurrences and the issues surrounding phenotyping of patients with asthma. We reviewed our experience in ascertaining the asthma phenotype in 50 nuclear families comprised of 219 subjects (110 male, 109 female). Three respiratory physicians reviewed data including a questionnaire, skin testing, objective measures of variable airflow obstruction [increase in FEV, ≥ 15% following salbutamol 400 μg or PC20 (methacholine) ≤ 4 mg/ml], and serum for IgE. Thirty-eight percent of subjects had both objective and questionnaire data consistent with asthma (++) whereas 39% had negative objective and negative questionnaire findings (–) (i.e., no asthma). A positive history but negative objective findings occurred in 7% of subjects, 2% had a negative history and positive objective findings. Retesting was requested in 13% of subjects; review of historical data was requested in 1% (i.e., childhood asthma but no present asthma). Retesting was requested for either (a) positive history, negative objective if symptoms were seasonal or the subject was using medications known to affect the challenge study, (b) viral infection within 6 weeks of a positive methacholine study, or (c) technically inadequate study. Overall, after the initial assessment, all members of only 22 families could be catagorized as either ++ or –. The diagnostic group requested at least 1 retest in 19 families and a review of historical records in 2 families. We conclude that discordance between self-reported questionnaire data and laboratory measures of variable airflow limitation is common and will increase the numbers of asthmatic subjects in studies that seek to determine the genetic basis of asthma.