Genetic and Genomic Approaches to Asthma: New Insights for the Origins Youming Zhang Miriam F. Moffat William O.C. Cookson Molecular Genetics Group Division of Respiratory Sciences Imperial College London Address for correspondence: Dr Youming Zhang Molecular Genetics Group National Heart and Lung Institute Dovehouse Street London SW3 6LY Email: [email protected] Short running head: Genetics and genomics of asthma 1
Purpose of review The review is to update current understanding of the genes identified by recent genome-wide association studies of asthma and its associated traits. The review also discusses how to dissect the functional roles of novel genes in future research. Recent findings More than ten genome wide association studies (GWAS) aimed at identifying the genes underlying asthma and relevant traits have been published in past three years. The largest of these was from the GABRIEL consortium, which discovered that the IL18R1, IL33, SMAD3, ORMDL3 , , HLA-DQ and IL2RB loci were all significantly associated with asthma. Many novel asthma genes, including those previously identified by positional cloning, are expressed within the respiratory epithelium, emphasising the importance of epithelial barriers in asthma aetiology. The genes controlling IgE levels have surprisingly litle overlap with the genes mediating asthma susceptibility, suggesting that atopy is secondary to asthma rather than a primary driver of the disease. The next challenge will be the systematic analysis of the precise functions of these genes in the pathogenesis of asthma. Summary GWAS have uncovered many novel genes underlying asthma and detailed functional dissection of their roles in asthma will point the way to new therapies for the disease. Keywords : GWAS, Genomics, Genetics, Asthma, IgE 2
Introduction Asthma is a disease characterized by intermitent inflammation of the small airways of the lung with symptoms of wheeze and shortness of breath. The presence of inflammation can lead to irreversible airway scarring and intractable airflow limitation. Asthma has a high prevalence and a chronic relapsing course. Clinically, severe asthma remains difficult to treat. Environmental and genetic factors contribute to the aetiology of the disease. Understanding the genetic predisposition to asthma offers a means of developing new therapies and strategies for the prevention of disease. In last three years there has been a huge influx of data from genetic and genomics approaches to asthma. This review will look into the possible functional roles of the genes identified by GWAS. We will also update on recent progress with asthma genes previously identified by positional cloning and we will discuss future systemic approaches to understand the function of novel genes.
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