Transmitted and acquired determinants for childhood asthma : from genes to teens

The interplay between genetic and environmental factors is central to childhood asthma and allergic disease. Transmitted and acquired risk factors collaborate to produce the phenotypic variation of a trait within the population. In this work, we have employed studies of twins to illustrate the relationship between twinship itself, early growth, and genetic and epigenetic factors with childhood asthma.

Twins have been suggested to be a high risk group for asthma. Study I was a large population-based register study of twinship in itself as a risk factor for childhood asthma. Asthma diagnoses and medication use among Swedish twins and singletons born 1993-2001 and 2005-2009 were compared before and after controlling for birth weight and gestational age. In the younger group, twins were at higher risk of developing asthma before controlling for perinatal factors – afterwards, twins were at lower risk of asthma in both age groups. This suggests that important mechanisms for asthma are shared between twins and singletons.

Low birth weight and rapid early growth have been shown to increase the risk of asthma. The aim of Study II was to describe the association between early growth and asthma in twins. Height and weight from 0 to 3 years of age were modelled in 2,874 twins. There was an association between later timing of maximum growth velocity and asthma both in terms of weight and height, although this relationship did not remain after controlling for birth weight or gestational age, which indicates that early postnatal growth may primarily be of interest as an extension of preceding foetal growth.

There is significant comorbidity between asthma and other allergic diseases. In Study III, we studied the influence of genetic factors on childhood asthma, hay fever, atopic eczema and food allergy. Using twin models and data from 25,306 twins, we concluded that asthma and all of the other allergic phenotypes were highly influenced by additive genetic effects. A preselected set of high-risk genetic variants were primarily associated with asthma or both asthma and hay fever (rs3771180 in IL1RL1).

Epigenetic factors have been suggested as a potential explanation for disease discordance within identical twin pairs. In Study IV, we analysed DNA methylation in whole blood of 708 twins with and without asthma using the Illumina 450k Beadchip. On the group level, 340 CpG sites were significantly associated with current asthma at 9-14 years of age, but these associations were not replicated within asthma-discordant pairs. Confounding by genetic factors or cell type composition in the samples seemed to be of importance, and should be considered as influences of potential importance in future epigenetic studies.

In conclusion, the work described in this thesis has combined the unique qualities of twin studies with data from population-based registers, interviews, and clinical examinations. The influences of transmitted (genetic) and acquired (twinship, early growth, and epigenetics) on childhood asthma were evaluated. From this selection, the transmitted factors proved to be of most importance to childhood asthma.

List of scientific papers

I. Ullemar, V, Lundholm, C, Almqvist, C. Twins' Risk of Childhood Asthma Mediated by Gestational Age and Birth Weight. Clin Exp Allergy 2015 Aug. 45(8);1328-36.
https://doi.org/10.1111/cea.12547

II. Ullemar V, Lundholm C, Magnusson PKE, Pershagen G, Lichtenstein P, Almqvist C. Delayed growth in twins with childhood asthma. [Submitted]

III. Ullemar V, Magnusson PKE, Lundholm C, Zettergren A, Melén E, Lichtenstein P, Almqvist C. Heritability and confirmation of genetic association studies for childhood asthma in twins. Allergy 2016 Feb. 71(2):230-8.
https://doi.org/10.1111/all.12783

IV. Ullemar V, Karlsson R, Örtqvist AK, Lichtenstein P, Magnusson PKE, Almqvist C. Differential DNA methylation in childhood asthma: A casecontrol and discordant twin study. [Manuscript]