Nutritional Genomics of Pulmonary Function

描述（由申请人提供）：肺功能测量-即一秒钟用力呼气量（FEV1）及其与用力肺活量（FEV1/FVC）的比值-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。基因组流行病学心脏与衰老研究（CHARGE）联盟和其他研究团队进行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FEV1或FEV1/FVC。其中一些snp与慢性阻塞性肺疾病（COPD）和其他肺部疾病的风险相关。肺功能也容易受到环境因素的影响。吸烟有害健康，而具有抗炎特性的膳食营养素，如欧米伽-3脂肪酸和纤维，则具有保护作用。认识到基因-环境相互作用对肺功能的重要性，我们之前应用联合2自由度（2df）方法研究全基因组SNP-by-smoking相互作用，这导致了新的遗传发现。联合2df方法通过同时检测SNP主效应和相互作用效应，而不是通常的单独检测相互作用的1df方法，提高了统计能力。在这里，我们建议应用联合2df方法来测试与3fas和纤维的全基因组相互作用。在这首个肺功能全基因组营养基因组学研究中，我们将利用两个正在进行合作的大型联盟和现有的全基因组基因型、食物频率问卷（FFQs）、生物标志物和肺功能测量。我们的研究目标将使我们能够识别影响肺功能的新遗传变异，以及表征已知遗传变异的营养相互作用。在Aim 1中，我们将对CHARGE患者（N= 31979名白种人和7187名非裔美国人）的FEV1和FEV1/FVC进行全基因组联合2df荟萃分析，研究SNP与ffq衍生的- 3 FAs摄入量的相互作用，并测试SpiroMeta联合体（N=23,000名白种人）的独立复制。为了增加因果推断，将进一步评估复制的snp与3 FAs生物标志物的相互作用，在5项CHARGE研究（N=16,179）中测量血浆和红细胞。在平行的Aim 2中，我们将对CHARGE中的FEV1和FEV1/FVC进行全基因组联合2df荟萃分析，研究SNP与ffq来源的纤维摄入量的相互作用，并测试SpiroMeta中的独立复制。这项涉及肺功能两种重要膳食营养素的全基因组相互作用研究建立在我们在研究基因-环境相互作用方面的成熟经验、强大的统计方法和来自CHARGE和SpiroMeta联盟的丰富现有数据的基础上。通过增加我们对肺功能遗传学的理解以及与- 3 FAs和纤维的相互作用，我们的发现可能会导致新的药理学靶点和个性化的饮食指南，以预防和治疗肺部疾病。

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.