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The STOPPA Twin Study Explains the Exhaled Nitric Oxide and Asthma Link by Genetics and Sensitization

  • Björn Nordlund (a1) (a2) (a3), Cecilia Lundholm (a1), Vilhelmina Ullemar (a1), Marianne van Hage (a4), Anne K. Örtqvist (a1) and Catarina Almqvist (a1) (a2)...
Abstract

Background: The link between asthma and exhaled nitric oxide (FENO) is not completely understood. The aim of this study was to estimate the association between FENO and asthma, taking genetics, sensitization, and inhaled corticosteroids (ICS) into account. Methods: A total of 681 twins (53% monozygotic [MZ] and 47% dizygotic [DZ]) from the population-based STOPPA study (mean age 12.6 years) were recruited and information on FENO (parts per billion), parental report of current asthma, sensitization to airborne allergens (Phadiatop; IgE ≥0.35 kUA/l), and ICS-treatment was collected. We estimated the association between FENO and asthma, sensitization, and ICS in all twins and within pairs (DZ and MZ) to address shared genetic and environmental factors. Linear regression of log-transformed FENO was used and results presented as exponentiated regression coefficients (exp[β]), with 95% confidence interval (CI). Results: We found an association between asthma and FENO in all twins, exp(β) 1.31 [1.11, 1.54]. In within-pairs analysis, the association was stronger within DZ pairs discordant for FENO, exp(β) 1.50 [1.19, 1.89], compared to MZ pairs, exp(β) 1.07 [0.84, 1.37], p = .049. There was no difference in FENO in non-sensitized children with asthma, compared to children with neither asthma nor sensitization, exp(β) 0.89 [0.77, 1.03]. However, increased FENO was associated with sensitization, exp(β) 1.48 [1.30, 1.69], and with sensitization together with asthma, exp(β) 1.98 [1.57, 2.51], in all twins and within DZ pairs discordant for FENO, but not in MZ pairs. The FENO asthma association remained in DZ pairs without regular ICS-treatment. Conclusions: The association between FENO and asthma is explained by genetics and sensitization.

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Corresponding author
address for correspondence: Björn Nordlund, Department of Medical Epidemiology and Biostatistics, Box 281, Karolinska Institutet, SE-171 77 Stockholm, Sweden. E-mail: bjorn.nordlund@ki.se
References
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Almqvist, C., Adami, H. O., Franks, P. W., Groop, L., Ingelsson, E., Kere, J., . . . Pedersen, N. L. (2011). LifeGene - a large prospective population-based study of global relevance. European Journal of Epidemiology, 26, 6777.
Almqvist, C., Ortqvist, A. K., Ullemar, V., Lundholm, C., Lichtenstein, P., & Magnusson, P. K. (2015). Cohort profile: Swedish twin study on prediction and prevention of Asthma (STOPPA). Twin Research and Human Genetics, 18, 273280.
Alving, K., Weitzberg, E., & Lundberg, J. M. (1993). Increased amount of nitric oxide in exhaled air of asthmatics. European Respiratory Journal, 6, 13681370.
American Thoracic, S., & European Respiratory, S. (2005). ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. American Journal of Respiratory and Critical Care Medicine, 171, 912930.
Asher, M. I., Keil, U., Anderson, H. R., Beasley, R., Crane, J., Martinez, F., . . . Williams, H. C. (1995). International Study of Asthma and Allergies in Childhood (ISAAC): Rationale and methods. European Respiratory Journal, 8, 483491.
Balzar, S., Strand, M., Rhodes, D., & Wenzel, S. E. (2007). IgE expression pattern in lung: Relation to systemic IgE and asthma phenotypes. Journal of Allergy and Clinical Immunology, 119, 855862.
Bland, J. M., & Altman, D. G. (1996). The use of transformation when comparing two means. BMJ, 312 (7039), 1153.
Blomme, K., Tomassen, P., Lapeere, H., Huvenne, W., Bonny, M., Acke, F., . . . Gevaert, P. (2013). Prevalence of allergic sensitization versus allergic rhinitis symptoms in an unselected population. International Archives of Allergy and Immunology, 160, 200207.
Dweik, R. A., Sorkness, R. L., Wenzel, S., Hammel, J., Curran-Everett, D., Comhair, S. A., . . . Blood Institute Severe Asthma Research Program. (2010). Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. American Journal of Respiratory and Critical Care Medicine, 181, 10331041.
Gratziou, C., Lignos, M., Dassiou, M., & Roussos, C. (1999). Influence of atopy on exhaled nitric oxide in patients with stable asthma and rhinitis. European Respiratory Journal, 14, 897901.
Gustafsson, L. E., Leone, A. M., Persson, M. G., Wiklund, N. P., & Moncada, S. (1991). Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochemical and Biophysical Research Communications, 181, 852857.
Lane, C., Knight, D., Burgess, S., Franklin, P., Horak, F., Legg, J., . . . Stick, S. (2004). Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath. Thorax, 59, 757760.
Lichtenstein, P., De Faire, U., Floderus, B., Svartengren, M., Svedberg, P., & Pedersen, N. L. (2002). The Swedish Twin Registry: A unique resource for clinical, epidemiological and genetic studies. Journal of Internal Medicine, 252, 184205.
Ludviksdottir, D., Diamant, Z., Alving, K., Bjermer, L., & Malinovschi, A. (2012). Clinical aspects of using exhaled NO in asthma diagnosis and management. Clinical Respiratory Journal, 6, 193207.
Lund, M. B., Kongerud, J., Nystad, W., Boe, J., & Harris, J. R. (2007). Genetic and environmental effects on exhaled nitric oxide and airway responsiveness in a population-based sample of twins. European Respiratory Journal, 29, 292298.
Magnusson, P. K., Almqvist, C., Rahman, I., Ganna, A., Viktorin, A., Walum, H., . . . Lichtenstein, P. (2013). The Swedish Twin Registry: Establishment of a biobank and other recent developments. Twin Research and Human Genetics, 16, 317329.
Malmberg, L. P., Petays, T., Haahtela, T., Laatikainen, T., Jousilahti, P., Vartiainen, E., & Makela, M. J. (2006). Exhaled nitric oxide in healthy nonatopic school-age children: Determinants and height-adjusted reference values. Pediatric Pulmonology, 41, 635642.
Morley, R., & Dwyer, T. (2005). Studies of twins: What can they tell us about the fetal origins of adult disease? Paediatric and Perinatal Epidemiology, 19 (Suppl. 1), 27.
Ortqvist, A. K., Lundholm, C., Carlstrom, E., Lichtenstein, P., Cnattingius, S., & Almqvist, C. (2009). Familial factors do not confound the association between birth weight and childhood asthma. Pediatrics, 124, e737–743.
Palmer, L. J., Burton, P. R., Faux, J. A., James, A. L., Musk, A. W., & Cookson, W. O. (2000). Independent inheritance of serum immunoglobulin E concentrations and airway responsiveness. American Journal of Respiratory and Critical Care Medicine, 161, 18361843.
Perez-de-Llano, L. A., Carballada, F., Castro Anon, O., Pizarro, M., Golpe, R., Baloira, A., . . . Boquete, M. (2010). Exhaled nitric oxide predicts control in patients with difficult-to-treat asthma. European Respiratory Journal, 35, 12211227.
Ricciardolo, F. L., Sterk, P. J., Gaston, B., & Folkerts, G. (2004). Nitric oxide in health and disease of the respiratory system. Physiological Reviews, 84, 731765.
Salam, M. T., Bastain, T. M., Rappaport, E. B., Islam, T., Berhane, K., Gauderman, W. J., & Gilliland, F. D. (2011). Genetic variations in nitric oxide synthase and arginase influence exhaled nitric oxide levels in children. Allergy, 66, 412419.
Simonsson, B. G. (1980). Clinical implications of bronchial hyperreactivity. European Journal of Respiratory Diseases, 106, 718.
Stern, G., de Jongste, J., van der Valk, R., Baraldi, E., Carraro, S., Thamrin, C., & Frey, U. (2011). Fluctuation phenotyping based on daily fraction of exhaled nitric oxide values in asthmatic children. Journal of Allergy and Clinical Immunology, 128, 293300.
Strunk, R. C., Szefler, S. J., Phillips, B. R., Zeiger, R. S., Chinchilli, V. M., Larsen, G., . . . Blood, I. (2003). Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children. Journal of Allergy and Clinical Immunology, 112, 883892.
Thomsen, S. F., Ferreira, M. A., Kyvik, K. O., Fenger, M., & Backer, V. (2009). A quantitative genetic analysis of intermediate asthma phenotypes. Allergy, 64, 427430.
Ullemar, V., Lundholm, C., & Almqvist, C. (2015). Twins' risk of childhood asthma mediated by gestational age and birthweight. Clinical & Experimental Allergy, 45, 13281336.
van der Valk, R. J., Baraldi, E., Stern, G., Frey, U., & de Jongste, J. C. (2012). Daily exhaled nitric oxide measurements and asthma exacerbations in children. Allergy, 67, 265271.
van Dongen, J., Slagboom, P. E., Draisma, H. H., Martin, N. G., & Boomsma, D. I. (2012). The continuing value of twin studies in the omics era. Nature Reviews Genetics, 13, 640653.
van Rensen, E. L., Straathof, K. C., Veselic-Charvat, M. A., Zwinderman, A. H., Bel, E. H., & Sterk, P. J. (1999). Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma. Thorax, 54, 403408.
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Twin Research and Human Genetics
  • ISSN: 1832-4274
  • EISSN: 1839-2628
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