Nutritional Genomics of Pulmonary Function

肺功能的营养基因组学

• 批准号: 8976239
• 负责人: PATRICIA A CASSANO
• 金额: $ 23.76万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976239
• 关键词: Accounting; Affect; African American; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bioinformatics; Biological; Biological Markers; Caucasians; Cause of Death; Chronic Obstructive Airway Disease; Clinical; Collaborations; Complex; Data; Development; Diagnosis; Diet; Dietary Factors; Dietary Fiber; Environmental Risk Factor; Epidemiology; Erythrocytes; Ethnic Origin; Fiber; Food; Food Interactions; Forced expiratory volume function; Freedom; Frequencies; Gene Expression; General Population; Genes; Genetic; Genetic Enhancer Element; Genome; Genomics; Genotype; Health; Heart; Human; Inflammation; Inflammatory Response; Intake; Joints; Knowledge; Lead; Linear Regressions; Lung; Lung diseases; Measures; Meta-Analysis; Methods; Modeling; Nutrient; Obstruction; Omega-3 Fatty Acids; Pathway interactions; Patients; Plasma; Prevention Guidelines; Principal Investigator; Property; Protein C Inhibitor; Public Health; Pulmonary Function Test/Forced Expiratory Volume 1; Questionnaires; Recommendation; Recording of previous events; Research; Respiratory physiology; Risk; Role; Sample Size; Series; Single Nucleotide Polymorphism; Smoking; Spirometry; Statistical Methods; Testing; United States; Variant; Vital capacity; Work; cigarette smoking; cigarette smoking; cohort; epidemiology study; experience; gene discovery; gene environment interaction; genetic association; genetic profiling; genetic variant; genome wide association study; genome-wide; genome-wide analysis; insight; lifestyle factors; novel; nutrition; nutritional genomics; prevent; promoter; protective effect; pulmonary function; pulmonary function decline; smoking cessation; success; tool

DESCRIPTION (provided by applicant): Pulmonary function measures-namely, forced expiratory volume in one second (FEV1) and its ratio to forced vital capacity (FEV1/FVC)-are used clinically to diagnose and follow the progression of lung disease. Pulmonary function is heritable. Genome-wide association studies (GWAS) by our Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and others found single nucleotide polymorphisms (SNPs) from at least 30 gene regions that significantly influence FEV1 or FEV1/FVC. Several of these SNPs have since been associated with risk of chronic obstructive pulmonary disease (COPD) and other lung diseases. Pulmonary function is also susceptible to environmental factors. Cigarette smoking poses harmful effects, whereas dietary nutrients with anti-inflammatory properties-such as, omega-3 fatty acids (�3 FAs) and fiber-exert protective effects. Recognizing the importance of gene-environment interaction for pulmonary function, we previously applied the joint 2 degrees-of-freedom (2df) method to study genome-wide SNP-by-smoking interactions, which resulted in new genetic discoveries. The joint 2df method enhances statistical power by simultaneously testing SNP main and interactive effects, instead of the usual 1df test of the interaction alone. Here, we propose to apply the joint 2df method to test genome-wide interactions with both �3 FAs and fiber. In this first genome-wide nutritional genomics study of pulmonary function, we will capitalize on two large consortia with ongoing collaborations and existing genome-wide genotypes, food frequency questionnaires (FFQs), biomarkers, and pulmonary function measures. Our study's aims will enable us to identify new genetic variants that influence pulmonary function as well as characterize nutrient interactions for the known genetic variants. In Aim 1, we will conduct genome-wide joint 2df meta-analyses of FEV1 and FEV1/FVC in CHARGE (N=31,979 Caucasians and 7,187 African Americans), studying SNP interactions with FFQ-derived �3 FAs intake, and test for independent replication in the SpiroMeta consortium (N=23,000 Caucasians). To increase causal inferences, the replicated SNPs will be further evaluated for interaction with biomarkers of �3 FAs, as measured in plasma and red blood cells in 5 CHARGE studies (N=16,179). In the parallel Aim 2, we will conduct genome-wide joint 2df meta-analyses of FEV1 and FEV1/FVC in CHARGE, studying SNP interactions with FFQ-derived fiber intake, and test for independent replication in SpiroMeta. This genome-wide interaction study with two important dietary nutrients for pulmonary function builds on our proven experience in studying gene-environment interaction, a powerful statistical method, and a wealth of existing data from the CHARGE and SpiroMeta consortia. By adding to our understanding of the genetics of pulmonary function and the interplay with �3 FAs and fiber, our findings may lead to new pharmacological targets and personalized dietary guidelines for the prevention and treatment of lung disease.

描述（由申请人提供）：肺功能测量-即一秒用力呼气量（FEV 1）及其与用力肺活量的比值（FEV 1/FVC）-在临床上用于诊断和跟踪肺部疾病的进展。肺功能是遗传的。我们的基因组流行病学心脏和衰老研究队列（CHARGE）联盟和其他人的全基因组关联研究（GWAS）发现，至少30个基因区域的单核苷酸多态性（SNP）显著影响FEV 1或FEV 1/FVC。其中一些SNP与慢性阻塞性肺病（COPD）和其他肺部疾病的风险有关。肺功能也容易受到环境因素的影响。吸烟会造成有害影响，而具有抗炎特性的膳食营养素-如ω-3脂肪酸（ω-3 FA）和纤维-则会发挥保护作用。认识到基因-环境相互作用对肺功能的重要性，我们以前应用联合2自由度（2df）方法研究全基因组SNP与吸烟的相互作用，这导致了新的遗传发现。联合2DF方法通过同时测试SNP主效应和交互效应来增强统计功效，而不是通常的单独交互的1DF测试。在这里，我们建议应用联合2df方法来测试全基因组与β 3 FA和纤维的相互作用。 在这第一个全基因组营养基因组学肺功能研究中，我们将利用两个正在进行合作的大型财团和现有的全基因组基因型，食物频率问卷（FFQ），生物标志物和肺功能测量。我们研究的目的将使我们能够识别影响肺功能的新的遗传变异，以及表征已知遗传变异的营养相互作用。在目标1中，我们将在CHARGE中对FEV 1和FEV 1/FVC进行全基因组联合2df荟萃分析（N= 31，979名白人和7，187名非洲裔美国人），研究SNP与FFQ衍生的β 3 FA摄入量的相互作用，并在SpiroMeta联盟中测试独立复制（N= 23，000名白人）。为了增加因果关系的推断，将进一步评估重复的SNP与5个CHARGE研究（N= 16，179）中血浆和红细胞中测量的3种FA生物标志物的相互作用。在平行目标2中，我们将在CHARGE中对FEV 1和FEV 1/FVC进行全基因组联合2df荟萃分析，研究SNP与FFQ衍生纤维摄入量的相互作用，并在SpiroMeta中测试独立复制。 这项全基因组相互作用研究与两种重要的膳食营养素对肺功能的影响建立在我们在研究基因-环境相互作用方面的成熟经验、强大的统计方法以及来自CHARGE和SpiroMeta财团的大量现有数据的基础上。通过增加我们对肺功能遗传学的理解以及与β 3脂肪酸和纤维的相互作用，我们的研究结果可能会导致新的药理学靶点和个性化的饮食指南，用于预防和治疗肺部疾病。