Elucidation of pathways driving asthma pathogenesis: development of a systems-level analytic strategy

Front. Immunol., 23 September 2014 | doi: 10.3389/fimmu.2014.00447

Michael L. Walker¹, Kathryn E. Holt^2,3, Gary P. Anderson⁴, Shu Mei Teo^1,2, Peter D. Sly⁵, Patrick G. Holt^3,5* and Michael Inouye^1,3,6

• 1Medical Systems Biology, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
• 2Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia
• 3Telethon Kids Institute, The University of Western Australia, West Perth, WA, Australia
• 4Department of Pharmacology and Therapeutics, Lung Health Research Centre, The University of Melbourne, Melbourne, VIC, Australia
• 5Queensland Children’s Medical Research Institute, The University of Queensland, Brisbane, QLD, Australia
• 6Medical Systems Biology, Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, Australia

Asthma is a genetically complex, chronic lung disease defined clinically as episodic airflow limitation and breathlessness that is at least partially reversible, either spontaneously or in response to therapy.

Whereas asthma was rare in the late 1800s and early 1900s, the marked increase in its incidence and prevalence since the 1960s points to substantial gene × environment interactions occurring over a period of years, but these interactions are very poorly understood (1–6). It is widely believed that the majority of asthma begins during childhood and manifests first as intermittent wheeze. However, wheeze is also very common in infancy and only a subset of wheezy children progress to persistent asthma for reasons that are largely obscure. Here, we review the current literature regarding causal pathways leading to early asthma development and chronicity. Given the complex interactions of many risk factors over time eventually leading to apparently multiple asthma phenotypes, we suggest that deeply phenotyped cohort studies combined with sophisticated network models will be required to derive the next generation of biological and clinical insights in asthma pathogenesis.

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