Periodic Reporting for period 3 - ALLERGENE (Allergic multimorbidity from birth to young adulthood: determinants, epigenetic regulation and inflammatory processes)
Reporting period: 2024-03-01 to 2025-08-31
The prevalence of allergic diseases, such as asthma, atopic dermatitis and rhinitis, has increased over the past decades and is currently estimated to be up to 40%. Allergic diseases bear considerable burden, mostly affecting children but often tracking into adulthood, thereby posing a major public health concern. Prevention strategies play a pivotal role, as there are no curative treatments available. Therefore, the aim of ALLERGENE is to understand the complex interplay of genetic, environmental and lifestyle factors in the development of allergic diseases and to identify involved mechanisms that distinguish between young adults free of allergic diseases and those suffering from allergic multimorbidity. The specific aims of the present project are to: 1. Define allergic disease trajectories from birth to young adulthood, describe their determinants and identify risk and protective early-life environmental and lifestyle factors contributing to the progression towards allergic multimorbidity or remission of allergic diseases. 2. Investigate molecular mechanisms of epigenetic regulation of allergic disease trajectories and test effect modification by inclusion of selected environmental and lifestyle actors. 3. Characterise the underlying inflammation profile of allergic disease trajectories and determine interactions with environmental and lifestyle factors.
The project makes use of two long-standing, prospective German birth cohort studies, GINIplus and LISA, with data available from birth to 20 years of age and the 25-year follow-up currently ongoing.
The project makes use of two long-standing, prospective German birth cohort studies, GINIplus and LISA, with data available from birth to 20 years of age and the 25-year follow-up currently ongoing.
Allergic disease trajectories have been modelled using already existing longitudinal data on allergy symptoms and doctor diagnoses from birth up to adolescence. A collaboration with the Swedish BAMSE birth cohort has been established for replication purposes. Seven robust allergic disease trajectories have been identified: “early-transient asthma“, “early-resolving dermatitis,” “mid-persisting dermatitis,” “persisting dermatitis plus rhinitis”, “rhinitis”, “multimorbid” and “intermittently allergic”. Those groups were defined by a distinct risk profile, including associations with early-life determinants such as older siblings, pet exposure or parental history of allergies. Additionally, specific trajectories with early onset and more severe disease courses were associated with polygenic risk scores for the respective allergic diseases and could be described by clinical characteristics, such as a higher food or aeroallergen sensitisation as well as reduced lung function in the multimorbid cluster. This work was published in the Allergy journal.
To identify novel genetic risk variants for atopic dermatitis, more than 40 studies including individuals of European, Japanese, Latino and African ancestry were invited to contribute to a meta-analysis of genome-wide association studies. A total of 81 loci were identified amongst individuals of European ancestry and an additional 10 loci in a multi-ancestry analysis. Comprehensive post-GWAS analyses implicated many genes related to the immune system as potential causal genes at the loci that could serve as potential novel drug targets in the future. These findings were published in Nature Communications.
DNA methylation has been measured in 250 paired samples at ages 6 and 10 years and has been analysed regarding allergic diseases and aeroallergen sensitisation. Six methylation risk scores have been calculated based on effect estimates from previous epigenome-wide association studies on various phenotypes related to allergic disease and their association with aeroallergen sensitisation has been evaluated. All allergy-related methylation risk scores were significantly associated with aeroallergen sensitisation in cross-scectional models, but limited evidence was found for MRS as prospective predictors of sensitisation development. Therefore, three high-dimensional mediation approaches (DACT, HIMA, gHMA) have been applied in a follow-up analysis to test whether altered DNA methylation is a cause or a consequence of aeroallergen sensitisation. Results indicated that depending on the genomic location DNA methylation might be both: a cross-sectional biomarker as well as a potential clinical predictor of disease development. These analyses were published in Clinical Epigenetics and Allergy.
A meta-analysis on the association between early-life respiratory tract infections and the risk of school-age lower lung function and asthma was conducted. In total, 38 cohorts comprising 150,090 mother-child pairs were included in the analyses, which were performed by the Generation R Study Group, the lead institute, in the Netherlands. Upper respiratory tract infections early in life were associated with an increased risk of asthma at school-age whereas lower respiratory tract infections were associated both with an increased asthma risk and lower lung function. The results were published in the European Respiratory Journal.
To identify novel genetic risk variants for atopic dermatitis, more than 40 studies including individuals of European, Japanese, Latino and African ancestry were invited to contribute to a meta-analysis of genome-wide association studies. A total of 81 loci were identified amongst individuals of European ancestry and an additional 10 loci in a multi-ancestry analysis. Comprehensive post-GWAS analyses implicated many genes related to the immune system as potential causal genes at the loci that could serve as potential novel drug targets in the future. These findings were published in Nature Communications.
DNA methylation has been measured in 250 paired samples at ages 6 and 10 years and has been analysed regarding allergic diseases and aeroallergen sensitisation. Six methylation risk scores have been calculated based on effect estimates from previous epigenome-wide association studies on various phenotypes related to allergic disease and their association with aeroallergen sensitisation has been evaluated. All allergy-related methylation risk scores were significantly associated with aeroallergen sensitisation in cross-scectional models, but limited evidence was found for MRS as prospective predictors of sensitisation development. Therefore, three high-dimensional mediation approaches (DACT, HIMA, gHMA) have been applied in a follow-up analysis to test whether altered DNA methylation is a cause or a consequence of aeroallergen sensitisation. Results indicated that depending on the genomic location DNA methylation might be both: a cross-sectional biomarker as well as a potential clinical predictor of disease development. These analyses were published in Clinical Epigenetics and Allergy.
A meta-analysis on the association between early-life respiratory tract infections and the risk of school-age lower lung function and asthma was conducted. In total, 38 cohorts comprising 150,090 mother-child pairs were included in the analyses, which were performed by the Generation R Study Group, the lead institute, in the Netherlands. Upper respiratory tract infections early in life were associated with an increased risk of asthma at school-age whereas lower respiratory tract infections were associated both with an increased asthma risk and lower lung function. The results were published in the European Respiratory Journal.
The aim of ALLERGENE is to enhance the understanding of how modifiable factors contribute to allergic disease aetiology. This will be an essential prerequisite to develop effective early intervention strategies for susceptible populations and to identify disease-specific biomarkers for the development and progression of allergic disease in the future.One of the expected results is the characterisation of participants in biomarkers relevant for allergic diseases at the age of 25 years such as allergic sensitisation, methylation and inflammatory biomarkers, allowing longitudinal modelling and risk profiling.