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.