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Genetic susceptibility in air pollution-induced aging traits

空气污染引起的衰老特征的遗传易感性

基本信息

批准号：
345757311
负责人：
Privatdozentin Dr. Tamara Schikowski
金额：
--
依托单位：
Leibniz-Institut für umweltmedizinische Forschung (IUF)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/345757311?language=en
关键词：
Genetic susceptibility air pollution induced

项目摘要

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.

长期SALIA队列（研究空气污染对肺功能，炎症和衰老的影响）的先前和后续项目杠杆作用。纵向研究，如SALIA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。在拟议研究的背景下，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非常好的机会，因为研究参与者的暴露史以及研究参与者的健康数据得到了很好的描述。队列研究可以追溯到近30年前，参与的女性现在已经85岁了。这将允许从中年（55岁）到老年的健康和疾病的亚临床表现的变化进行分析。先前研究的首要目标是检查慢性阻塞性肺疾病（COPD），2型糖尿病（T2 D）和轻度认知障碍（MCI）是否是合并症，并由常见的空气污染暴露引起。第二个目标是亚临床炎症是否代表其发展中的重要潜在机制，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性。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，它们都与空气污染有关，从而证实了我们的主要假设。然而，初步证据表明，在SALIA中有一些亚组的特征是它们在某些遗传基因座上的等位基因状态，这可能使携带者更容易受到空气污染对衰老特征的不利影响。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，这些机制途径最有可能介导空气污染暴露对衰老疾病的影响。具体而言，我们的目标是了解遗传学对不同衰老特征对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风险个体的变异性和发病机制。在这项更新提案中，我们的目标是通过以下方式推进我们的研究：（1）通过开发遗传风险评分（GRS）并将其应用于SALIA研究中的特定基因-环境相互作用分析，评估空气污染诱导的衰老性状的遗传易感性。(2)此外，我们将与国家和国际队列研究合作验证和复制我们的研究结果，最终验证GRS的应用以及观察到的衰老性状遗传易感性的结果。