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Published ahead of print on May 8, 2003, doi:10.1164/rccm.200212-1491BC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 228-231, (2003)
© 2003 American Thoracic Society

Brief Communication

Association of a Missense Mutation in the NOS3 Gene with Exhaled Nitric Oxide Levels

Karin Storm van's Gravesande, Michael E. Wechsler, Hartmut Grasemann, Eric S. Silverman, Louis Le, Lyle J. Palmer and Jeffrey M. Drazen

Department of Medicine, Pulmonary Division, Brigham and Women's Hospital, Boston; Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; University Children's Hospital, Essen University Children's Hospital, Freiburg, Germany; and Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Jeffrey M. Drazen, M.D., Division of Pulmonary and Critical Care Medicine, Tower 4B, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. E-mail: jdrazen{at}nejm.org

There is evidence that genetic factors affect nitric oxide formation and that sequence variants in the nitric oxide synthase genes contribute to the observed variance of nitric oxide levels in exhaled air (fraction of expired nitric oxide, FENO) in subjects with asthma. We identified a strong association between a known functional NOS3 missense sequence variant in the endothelial nitric oxide gene (G894T) and FENO level in a cohort of subjects with asthma. Age- and sex-adjusted FENO levels were lowest in asthmatic subjects with the TT genotype (geometric mean FENO [95% CI] = 7.17 [4.48 to 11.48] ppb) and were significantly higher in those with either the GT genotype (geometric mean FENO [95% CI] = 17.11 [13.80 to 21.23] ppb) or the GG genotype (geometric mean FENO [95% CI] = 12.06 [9.91 to 14.67] ppb) (F2,59 = 5.97, p = 0.004). The G894T DNA variant explained 16.3% of the residual variance in FENO levels. Our results demonstrate that the endothelial nitric oxide synthase, a nitric oxide synthase constitutively expressed in epithelial cells, plays an important role in determining measured levels of exhaled nitric oxide, a marker of the asthmatic condition.

Key Words: asthma • endothelial nitric oxide synthase • exhaled nitric oxide • polymorphism




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