Grant Abstract: Nutritional Genomics of PUlmonary Function

Grant Number: 5R21HL125574-02
PI Name: Hancock
Project Title: Nutritional Genomics of PUlmonary Function

Abstract: 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

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