Am. J. Respir. Crit. Care Med., Volume 162, Number 6, December 2000, 2043-2047

Exhaled Nitric Oxide in Patients with Asthma
Association with NOS1 Genotype

MICHAEL E. WECHSLER, HARTMUT GRASEMANN, AARON DEYKIN, EDWIN K. SILVERMAN, CHANDRI N. YANDAVA, ELLIOT ISRAEL, MATT WAND, and JEFFREY M. DRAZEN

Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, and Harvard School of Public Health, Boston, Massachusetts

An increased concentration of nitric oxide (NO) in exhaled air (FENO) is now recognized as a critical component of the asthmatic phenotype. When we identified patients with asthma on the basis of a standard case definition alone, we found that they were remarkably heterogeneous with respect to their FENO. However, when we included genotype at a prominent asthma candidate gene (i.e., NOS1) in the case definition, and determined the number of AAT repeats in intron 20, we identified a remarkably homogenous cohort of patients with respect to FENO. Both mean FENO (p = 0.00008) and variability around the mean (p = 0.000002) were significantly lower in asthmatic individuals with a high number ( 12) of AAT repeats at this locus than in those with fewer repeats. These data provide a biologically tenable link between genotype at a candidate gene in a region of linkage, NOS1, and an important component of the asthmatic phenotype, FENO. We show that addition of NOS1 genotype to the case definition of asthma allows the identification of a uniform cohort of patients, with respect to FENO, that would have been indistinguishable by other physiologic criteria. Our isolation of this homogenous cohort of patients ties together the well-established associations among asthma, increased concentrations of NO in the exhaled air of asthmatic individuals, and variations of trinucleotide repeat sequences as identified in several neurologic conditions.

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