Genetic susceptibility in air pollution-induced aging traits

先前和后续的长期SALIA队列（研究空气污染对肺功能、炎症和衰老的影响）的项目杠杆。SALIA研究等纵向研究非常适合研究空气污染引起的合并症、衰老特征以及遗传变异在环境引起的衰老过程中的作用。在本研究的背景下，我们将再次利用真正的SALIA队列，这为研究基因-环境相互作用提供了一个很好的机会，因为研究参与者的暴露史特征良好，并且研究参与者的健康数据保存良好。这项队列研究追溯到近30年前，参与研究的女性现在已经85岁了。这将允许分析从中年（55岁）到老年的健康和疾病的亚临床表现的变化。先前研究的主要目的是研究慢性阻塞性肺疾病（COPD）、2型糖尿病（T2D）和轻度认知障碍（MCI）是否为合并症，并由常见的空气污染诱发。第二个目标是亚临床炎症是否代表了他们发展的重要潜在机制，第三个目标是探索一些单一的遗传标记，这些标记可能是对空气污染的共同反应的易感因素。我们最重要的发现是COPD、MCI和糖尿病的标志物相关，表明合并症都与空气污染有关，从而证实了我们的主要假设。然而，初步证据表明，在SALIA中存在一些亚群，其特征在于它们在某些遗传位点上的等位基因状态，这可能使携带者更容易受到空气污染对衰老性状的有害影响。由于之前的项目只考虑了位于某些候选基因中的少量遗传标记，我们现在建议将这些分析扩展到某些机制途径中的遗传变异，这些途径最有可能介导空气污染暴露对衰老疾病的影响。具体来说，我们的目标是了解基因对不同衰老特征的空气污染反应的影响，这将有助于更好地了解潜在的生物学途径以及高危个体的变异性和发病机制。在此更新提案中，我们的目标是通过(1)通过开发遗传风险评分（GRS）来评估空气污染诱导衰老性状的遗传易感性，并将其应用于SALIA研究中的特定基因-环境相互作用分析。(2)此外，我们将与国内和国际队列研究合作验证和复制我们的研究结果，在这些研究中，我们将最终验证GRS的应用以及观察到的衰老性状遗传易感性结果。

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.