Genetic susceptibility in air pollution-induced aging traits

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The previous as well as the continuation project leverage of the longterm SALIA cohort (Study on the influence of Air pollution on Lung function, Inflammation and Ageing). Longitudinal studies such as the SALIA study are well suited to study air pollution-induced comorbidities, and aging traits as well as the role of genetic variation in the environmentally-induced aging process. In the context of the proposed study we will again capitalize on the genuine SALIA cohort, which offers a very good opportunity to study gene-environment interactions, because of the well-characterized exposure history of the study participants as well as the well maintained health data of the study participants.The cohort study reaches back almost 30 years and the participating women are now up to 85 years old. This will allow for an analysis of changes in subclinical manifestations of health and disease from middle adulthood (55 years) to old age.The overarching objective of the previous study was to examine whether chronic obstructive pulmonary disease (COPD), type 2 diabetes (T2D) and mild cognitive impairment (MCI) are comorbidities and are induced by common air pollution exposure. The second objective was whether subclinical inflammation represents an important underlying mechanism in their development and third to explore some single genetic markers which could be a predisposition to a common reaction against air pollution. Our most important finding is that markers for COPD, MCI and diabetes were correlated indicating comorbidities and they were all associated with air pollution, thus confirming our main hypothesis. However, preliminary evidence suggests that there are subgroups within SALIA characterized by their allele status at certain genetic loci, which could render carriers more susceptible to the detrimental effect of air pollution on aging traits. Since the previous project only considered a small number of genetic markers located in certain candidate genes, we now propose to extend these analyses to genetic variation within certain mechanistic pathways which most probable mediate the effect of air pollution exposure to aging diseases. Specifically, we aim at understanding the influence of genetics on the response to air pollution in different aging traits which will help to better understand the underlying biological pathways as well as the variability and pathogenesis in at-risk individuals. In this renewal proposal, we aim to advance our research by (1) assessing genetic susceptibilities for air pollution-induced aging traits by developing genetic risk scores (GRS) and applying them for specific gene-environment interaction analysis in the SALIA study. (2) Furthermore, we will validate and replicate our findings in cooperation with national and international cohort studies, where we will finally validate the application of the GRS as well as the results regarding observed genetic susceptibilities for aging traits.