Johanna Metsälä, Jaakko Nevalainen and Suvi M Virtanen
Traditionally, asthma and type 1 diabetes have been considered distinct immune-mediated diseases in which the underlying immune responses counteract each other, resulting in an inverse association between the diseases. In our study, recently published in the IJE, we explored the association between asthma and type 1 diabetes in childhood in a novel way, and observed that the direction of the association is dependent on the order of appearance of the diseases.
Increasing numbers of children and adolescents have diseases that are linked to inappropriate function of the immune system, such as asthma, allergic diseases and type 1 diabetes. However, the reasons for the parallel increases in incidence, or how the diseases are related, constitute an unsolved puzzle. Inconsistencies in the findings of previous observational studies and increasing evidence of the complexity of the immune responses related to both asthma and type 1 diabetes have brought into question the traditional view of an inverse association.
We used large, nationwide Finnish health registers to obtain information on asthma and type 1 diabetes diagnoses up to the year 2009 for all children born between 1981 and 2008. Our case-cohort study included 9541 children with type 1 diabetes, 81,473 with asthma and a reference cohort of 171,138 children. From the health registers, we also obtained information on various maternal and child background characteristics. To allow the sequential order of the diseases and the age of diagnosis to vary, we used a multistate modelling approach in our statistical analysis.
Our main finding was that the association between these diseases depended on the order of their appearance: if asthma had been diagnosed first, children had an increased risk of developing subsequent type 1 diabetes, compared with children who developed only type 1 diabetes. On the other hand, children who already had type 1 diabetes had a decreased risk of developing subsequent asthma, compared with children who developed only asthma. This curious phenomenon was seen in all age groups studied, and the results held true even after taking into consideration the sex and birth decade of the child, maternal asthma or diabetes and various other sociodemographic and perinatal factors.
What could explain why having asthma increases the risk of type 1 diabetes, but not the other way around? Our suggestion that use of inhaled corticosteroids may play a role in the development of type 1 diabetes is biologically plausible, although a novel hypothesis. However, the lack of potentially important information in our register data needs to be considered. For example, we did not have information on early dietary factors and infections, both of which have been linked to the development of asthma and type 1 diabetes. The original immunological explanation for an inverse association may be applicable to our observation that less asthma occurred after the development of type 1 diabetes.
It would be interesting to see if similar associations occur in other paediatric populations or with other allergic and autoimmune diseases. It is worth noting that Finland has the highest incidence of childhood type 1 diabetes in the world, while the prevalence of asthma is lower than in countries such as the UK and Australia, which have a high prevalence of asthma. It would also be interesting to see whether pre-existing asthma is an important confounder or effect modifier for the association between different environmental factors and the development of type 1 diabetes.
Our results support the view that an inverse association between asthma and type 1 diabetes is likely an oversimplification and that the association is more complex than previously thought. Sensitivity analyses using conventional analysis methods further strengthen our conclusion that the sequential order and timing of the diseases are important considerations for obtaining valid estimates of the association.
Although our study provided interesting new findings on the association between asthma and type 1 diabetes, no firm explanations or clinical implications can yet be drawn. However, our results further highlight the need for a wider perspective when exploring the causes of childhood immune-mediated diseases. The evidence is growing that asthma and type 1 diabetes may have common features (i.e. shared risk or protective environmental and genetic factors) in their development, but the causes of these diseases have traditionally been investigated by distinct research groups. There is thus a global need for interdisciplinary activities to better understand the complex relationships between, and determinants of, the broad range of childhood immune-mediated diseases.
Metsälä J, Lundqvist A, Virta LJ, et al. The association between asthma and type 1 diabetes: a paediatric case-cohort study in Finland, years 1981–2009. International Journal of Epidemiology, dyx245, https://doi.org/10.1093/ije/dyx245.
Johanna Metsälä (PhD) is a Visiting Researcher at the National Institute for Health and Welfare, Finland. Her research is focused on early-life environmental factors and the development of asthma, allergic diseases and type 1 diabetes, with a special emphasis on using register-based data.
Jaakko Nevalainen is a Professor of Biostatistics in the University of Tampere, Finland. His collaborative research is focused on modelling in longitudinal studies on type 1 diabetes, prostate cancer and nutrition, and his theoretical research is mainly on the framework of clustered, multivariate data and with potentially informative cluster size.
Suvi M Virtanen is a Research Professor and Head of Nutrition Unit at the National Institute for Health and Welfare, Finland, and a Professor of Epidemiology in the University of Tampere. Her research is focused on maternal and child nutrition and growth in the development of type 1 diabetes, asthma, allergic diseases, overweight and obesity in childhood. Twitter: @suvi_m_virtanen