Diversity of asthma: evolving concepts of pathophysiology and lessons from genetics

Asthma is a complex respiratory disorder characterized by reversible airflow obstruction and bronchial hyperreactivity. In recent years, our understanding of the mechanisms underlying allergic asthma has grown, and this has resulted in complex paradigms to define the immunobiology of the disorder. These paradigms conceive of asthma as a disorder with complex genetic and environmental interactions that affect the developing immune system and ultimately result in the episodic release of procontractile mediators, including leukotrienes and prostaglandins, causing susceptible individuals to wheeze. Genetic studies seek to advance our knowledge by identifying the differences in our genetic make-up that cause us to be susceptible. Surprisingly few of the verified asthma genes involve known asthma mediators. This article reviews several of the best-established asthma genes, including a disintegrin and metalloprotease 33, dipeptidyl peptidase 10, PHD finger protein 11 (PHF11), and the prostanoid DP1 receptor. Identification of these unsuspected genes is leading to models of asthma pathogenesis that go beyond our conception of asthma as a disease of smooth muscle abnormalities, inflammatory cell presence, and airway structural changes.