Nutritional Omics of Pulmonary Function Decline

肺功能下降的营养组学

• 批准号: 10453457
• 负责人: PATRICIA A CASSANO
• 金额: $ 78.98万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453457
• 关键词: Accounting; Adult; African American population; Age; Aging; American; Anti-Inflammatory Agents; Attenuated; Biological; Biological Markers; Biology; Blood; Blood Tests; Carbon; Cause of Death; Childhood; Chronic Obstructive Pulmonary Disease; Clinical; DNA Methylation; DNA Sequence; Data; Diagnosis; Disease Progression; Elderly; Environment; Environmental Risk Factor; Epigenetic Process; Etiology; European; Fatty Acids; Fishes; Freedom; Functional disorder; General Population; Genetic; Genetic Risk; Genome; Genomic DNA; Genotype; Goals; Heart; Heritability; Hispanic Americans; Inflammation; Intervention; Joints; Knowledge; Lung; Maps; Measures; Mediation; Meta-Analysis; Metabolism; Methylation; Modeling; Nutrient; Nutritional; Omega-3 Fatty Acids; Patients; Persons; Pharmacotherapy; Plant Sources; Principal Investigator; Pulmonary function tests; Quantitative Trait Loci; Research; Risk; Risk Factors; Role; Route; Running; Sample Size; Site; Smoking; Smoking History; Testing; Time; United States; Variant; base; biobank; case control; cigarette smoking; clinically relevant; cohort; dietary; disorder risk; emerging adult; epigenomics; functional decline; gene environment interaction; genetic variant; genome wide association study; genome-wide; genomic epidemiology; genomic locus; improved; lung development; middle age; new therapeutic target; novel; novel therapeutics; prevent; pulmonary function; pulmonary function decline; sex; trait

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).

项目总结/摘要 这项研究的目的是发现肺功能的遗传和表观遗传因素 中年至老年人的下降，包括与ω-3脂肪酸（ω3 FAs）相互作用的因素， 其减弱肺功能下降。我们将确定遗传变异和表观遗传（DNA甲基化， 与肺功能下降相关的生物标志物，绘制DNA m基础遗传变异图 差异，并将遗传和表观遗传相关性扩展到临床定义的慢性阻塞性肺疾病 肺疾病（COPD）。研究结果将增加COPD发病前的病理生理学知识。 肺功能的加速下降，如肺功能测试（PFT）所测量的，通常在 COPD是美国第四大死亡原因。PFT随时间的下降是 受环境影响（例如，吸烟是有害的，ω3脂肪酸是有益的）和遗传学 （平均遗传率为38%）。单次测量PFT的全基因组关联研究（GWAS） 点（反映肺发育，直到成年早期和下降之后）已确定270+ 基因位点的影响。然而，这些基因座影响成年人PFT下降的证据 是有限的，明确的协会已经回避了少数小规模的GWAS的PFT下降。 基因-环境相互作用可能是PFT下降病因学的关键。我们将模拟ω3的相互作用 血液中的FAs浓度（“[ω3 FAs]”），以发现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：对变异和变异× [ω3 FA]进行GWAS和全基因组联合荟萃分析 PFT下降的相互作用。 具体目标2：鉴定PFT下降的DNAm生物标志物并绘制顺式甲基化数量性状基因座 （cis-meQTL），解释了[ω3 FAs]互作。 具体目标3：扩展PFT下降与COPD的相关性，解释[ω3 FAs]相互作用。 目标1 - 2将在一般人群队列中进行： 基因组流行病学、SpiroMeta和UK生物样本库（总N= 60，586）。Aim 3将利用COPDGene 临床定义的COPD病例和对照队列。我们整合了GWAS、DNAm和[ω3 FAs]， 扩展到COPD将大大提高有意义的发现的可能性， 生物学和临床相关性。PFT下降相关的遗传变异和DNAm生物标志物，包括 与[ω3 FAs]相互作用以减弱下降的那些，可能为开发干预提供特定目标 策略，如量身定制的饮食指导或新的药物靶点，以预防或延迟COPD的发作， 由于遗传风险或环境损害而具有更陡PFT下降的人（例如，吸烟）。