Introduction
Asthma is the most common chronic disease in children1 and it is defined as an obstructive and often underlying airway inflammatory disease 2. In allergic asthma, allergen exposure and allergic reaction leads to type 2 (T2) inflammation 3 and clinical available markers to measure possible inflammation are exhaled nitric oxide (FENO), immunoglobulin E (IgE) sensitization and blood eosinophils 3,4.
FENO is easy to measure, and its level corresponds directly with asthma and inflammation in the bronchial epithelium5. It is widely used in clinical care and is introduced to reflect asthma with T2 inflammation mediated by allergic reactions, eosinophilia and production of allergen-specific IgE antibodies 6. FENO can therefore aid asthma diagnosis, and, if correctly applied and interpreted, identify patients at risk of exacerbation 7. In clinical practice, generalized cut-off values of FENO have so far been difficult to translate to individual patients due to unknown contribution of factors that influence the FENO value, such as allergen-specific IgE level, blood eosinophil counts8, tobacco smoke 9, upper airway infection, age, and height 10.
The interest of measuring the number of blood eosinophils has increased in recent years since the introduction of anti-interleukin-5 therapy for severe eosinophil asthma 11. High blood eosinophils appear to be related to poor asthma control, hospitalisation12 and reduced lung function development in adults13. Hence, both FENO and blood eosinophil count reflects ongoing T2 inflammation. However, the different mechanisms involved in regulating these biomarkers seems different. FENO levels is activated by interleukin-4/-13 and blood eosinophil count by interleukin-5 14. The inflammatory contribution of blood eosinophil counts on the asthma-FENO association is not completely understood and debated 12. IgE is an important clinical biomarker, which is often involved in the inflammation associated with atopic asthma, the most common form of asthma in children 15. The airway inflammation involved in atopic asthma is recognized with both increased total IgE concentration and an elevated FENO fraction, as well as activation of eosinophilic granulocytes 15,16. In sensitized children, blood eosinophil count have been shown to be associated with increased level of FENO 17. Still, the relative contribution of allergen-specific IgE level and blood eosinophil count on FENO in children with asthma is not established.
Twin studies provide a unique method for determining the contribution of genetic and environmental sources of variation in a disease or phenotype18. The multivariate twin design can aid in the estimation of the same genetic and/or environmental factors influence different diseases and intermediate phenotypes 19. This can broaden our understanding of asthma biomarkers and inform gene-mapping efforts 20. We have previously shown that the association between asthma and FENO was mainly explained by genetics and sensitization 21. Therefore, our goal here was to further disentangle the association between asthma and FENO, by estimate the relative contribution of genetic and/or environmental effects from both allergen-specific IgE level and blood eosinophils. These potential shared genetic origins and environmental contributions will be studied in a multivariate twin study, thereby avoiding inflated type 1 error by multiple testing.