Polymorphisms of Neural NOS and the Asthma Phenotype

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DESCRIPTION (provided by applicant) Nitric oxide (NO) is a potent bioactive mediator that has been implicated in the pathogenesis of asthma as it has been noted to have both proinflammatory and bronchodilatory effects. Clinically, it is well established that levels of mixed expired NO are, on average, considerably higher in patients with asthma than in nonasthmatics. However, a wide spectrum of heterogeneity exists among asthmatics in terms of levels of expired NO. NO is formed in the lung by a family of enzymes known as the nitric oxide synthases, and allelic variations of NOS1, the gene for neural nitric oxide synthase (type I NOS) on chromosome l2q, have been identified and associated with asthma. Animal studies have documented that targeted disruption of NOS1 resulted in lower levels of exhaled NO and decreased airway hyperresponsiveness following allergen challenge, thus demonstrating the potential importance of NOS1 in asthma pathogenesis. A potential role of NOS1 in asthma pathogenesis and heritability derives from the fact that one of the recently described NOS1 polymorphisms consists of intronic trinucleotide tandem repeats that are similar to the repeat sequences that have been implicated in the pathogenesis of several neurologic disorders including Huntington?s Disease. Preliminary human studies reviewed herein suggest that mild asthmatics who harbor NOS1 alleles with a greater number of intronic trinucleotide repeats have lower and less variable levels of expired NO. This association has been replicated in patients with cystic fibrosis. These observations prompt the following hypothesis: Polymorphisms of NOS1 are associated with variable levels of exhaled NO and airway hyperresponsiveness in subjects with asthma; these allelic variations in NOS1 with resultant variable NO production manifest as significant distinct asthma phenotypes with variable clinical features representing important clues to the genetic diversity of asthma. To test this hypothesis, we propose three specific aims. In the first specific aim, we will determine the relationship between genotype at the NOS1 locus, baseline lung function and mixed expired NO in a cohort of patients with mild-to-moderate asthma. If our hypothesis is correct, we expect to demonstrate that asthmatics harboring allelic variants with greater number of repeats excrete less NO in their exhaled breath and are relatively hyporesponsive to non-specific bronchoprovocative maneuvers as compared to asthmatics with similar clinical characteristics whose alleles harbor fewer repeats. In the next two specific aims, we will study the response of a cohort of subjects with asthma with different NOS1 polymorphisms to specific clinical interventions, including bronchoprovocation with allergen inhalation, bradykinin challenge, hypertonic saline challenge and withdrawal of inhaled corticosteroids. We expect to demonstrate that subjects harboring different NOS1 alleles will have differential responses to these various challenges. We hope that completion of these specific aims will help us understand the role of nitric oxide as a mediator and indicator of asthmatic airway inflammation, how genetic differences influence these roles, and how neural mechanisms may contribute to the pathophysiology and symptomatology of asthma.