Nutritional Omics of Pulmonary Function Decline

项目摘要/摘要 这项拟议的研究的目标是发现肺功能背后的遗传和表观遗传因素。 中年到老年人的下降，包括与omega-3脂肪酸(ω3 FA)相互作用的因素， 减轻肺功能衰退的影响。我们将识别遗传变异和表观遗传学(DNA甲基化， DNaM)与肺功能下降相关的生物标记物，绘制dNaM背后的遗传变异 差异，并将遗传学和表观遗传学的关联扩展到临床定义的慢性阻塞性 肺部疾病(COPD)。结果将增加COPD之前的病理生理学知识。 通过肺功能测试(PFTs)测量的肺功能加速下降通常先于 慢性阻塞性肺疾病─的诊断是美国第四大死因。随着时间的推移，PFT的下降是 受环境(如吸烟有害，ω3脂肪酸有益)和遗传因素的影响 (平均遗传力为38%)。一次测量的PFTs的全基因组关联研究(GWAS) Points(反映到成年早期的肺部发育和此后的下降)确定了270+ 来自大量样本积累的遗传基因座。然而，这些基因座影响成人PFT下降的证据 是有限的，而且明确的联系躲过了PFT下降的少数几个较小规模的GWAS。 基因-环境的相互作用可能是PFT下降的原因关键。我们将对ω3的交互进行建模 血中Fas浓度(“[ω3 FAs]”)以寻找遗传变异和基于血液的dNaM生物标志物 与PFT下降相关，并测试这些相关性是否反映了COPD的风险因素，如下所示： 具体目标1：对变异体和变异体进行全球和全基因组联合荟萃分析×[ω3 FA] PFT的交互作用下降。 具体目标2：确定PFT下降的dNaM生物标志物并定位顺式甲基化数量性状基因座 (cis-meQTL)，说明[ω3 FA]相互作用。 具体目标3：扩大与慢性阻塞性肺疾病的相关性，解释[ω3 FA]的相互作用。 AIMS 1─2将在普通人群队列中进行：#年心脏和老龄化研究队列 基因组流行病学，SpiroMeta，英国生物库(TOTAL N=60,586)。AIM 3将利用COPDgene 临床确定的COPD病例和对照的队列。我们将GWA、dNaM和[ω3 FA]和 扩展到COPD将极大地提高有意义的发现的可能性，通过识别具有高风险的因素 生物学和临床相关性。PFT下降相关的遗传变异和dNaM生物标记物，包括 那些与[ω3 FA]相互作用以减缓衰退的药物，可能为发展干预提供特定的靶点 预防或推迟慢性阻塞性肺疾病发病的策略，如量身定制的饮食指导或新的可用药靶点 由于遗传风险或环境侮辱(如吸烟)，PFT下降幅度较大的人。

PROJECT SUMMARY/ABSTRACT The goal of the proposed research is to discover genetic and epigenetic factors that underlie lung function decline in middle-aged to older adults, including factors that interact with omega-3 fatty acids (ω3 FAs), which attenuate lung function decline. We will identify genetic variants and epigenetic (DNA methylation, DNAm) biomarkers associated with lung function decline, map genetic variants underlying DNAm differences, and extend the genetic and epigenetic associations to clinically defined chronic obstructive pulmonary disease (COPD). Results will add knowledge of the pathophysiology that precedes COPD. Accelerated decline in lung function, as measured by pulmonary function tests (PFTs), often precedes a diagnosis of COPD─the 4th leading cause of death in the United States. The decline in PFTs over time is influenced by environment (e.g., cigarette smoking is harmful, and ω3 FAs are beneficial) and by genetics (average heritability of 38%). Genome-wide association studies (GWAS) of PFTs measured at a single time point (reflecting both lung development until early adulthood and decline thereafter) have identified 270+ genetic loci from amassing large sample sizes. Yet, evidence that these loci influence PFT decline in adults is limited, and definitive associations have eluded the few smaller-scale GWAS of PFT decline. Gene-environment interactions are likely key to the etiology of PFT decline. We will model interactions of ω3 FAs concentrations in blood (“[ω3 FAs]”) to find genetic variants and blood-based DNAm biomarkers associated with PFT decline and test whether the associations reflect risk factors for COPD, as follows: Specific Aim 1: Conduct GWAS and genome-wide joint meta-analyses of variant and variant × [ω3 FAs] interaction for PFT decline. Specific Aim 2: Identify DNAm biomarkers for PFT decline and map cis-methylation quantitative trait loci (cis-meQTLs), accounting for [ω3 FAs] interaction. Specific Aim 3: Extend associations for PFT decline to COPD, accounting for [ω3 FAs] interaction. Aims 1─2 will be carried out across general population cohorts: Cohorts for Heart and Aging Research in Genomic Epidemiology, SpiroMeta, and UK Biobank (total N=60,586). Aim 3 will leverage the COPDGene cohort of clinically defined COPD cases and controls. Our integration of GWAS, DNAm, and [ω3 FAs] and extension to COPD will greatly improve the likelihood of meaningful discovery by identifying factors with high biological and clinical relevance. PFT decline-associated genetic variants and DNAm biomarkers, including ones that interact with [ω3 FAs] to attenuate decline, may provide specific targets for developing intervention strategies, such as tailored dietary guidance or new druggable targets, to prevent or delay onset of COPD in people with steeper PFT decline due to genetic risk or environmental insults (e.g., smoking).