Nutritional Genomics of Pulmonary Function

Accelerated pulmonary function decline is a key risk factor for development of chronic obstructive pulmonary disease (COPD), the 3rd leading cause of death worldwide. Chronic inflammation is central to the pathogenesis of steep pulmonary function decline and COPD and a healthy diet rich in sources of antioxidant and anti-inflammatory nutrients is hypothesized to counter inflammation and contribute to better lung function and lower risk of COPD. This dissertation investigated whether higher levels of biomarkers of nutrients with anti-inflammatory function (i.e., vitamin D, omega-3 fatty acids) and nutrient with antioxidant function (i.e., vitamin E) were associated with higher pulmonary function and whether the nutrients’ positive effects were stronger in cigarette smokers, given the oxidative damage smoking causes in the lungs. In addition, given the role of genetic variation in nutrient metabolism and pulmonary function, this dissertation also investigated whether nutritional status and genetic variation jointly affect pulmonary function. First, we designed a cohort-specific analysis plan and conducted a meta-analysis in 8 cohort studies to investigate the cross-sectional association of serum vitamin D concentration with pulmonary function (measured by forced expiratory volume in the 1st second [FEV1] and forced vital capacity [FVC]). We found consistently positive associations across the cohorts and the ancestries (European ancestry [EA] and African ancestry [AA]), with a stronger effect in ever smokers. Next, we investigated another set of nutrients that contribute to anti-inflammatory pathways, specifically the omega-3 fatty acids. We conducted a meta-analysis in 7 cohorts to investigate whether the association of genetic variants with pulmonary function depends on blood levels of omega-3 fatty acids. We found that docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) were positively associated with pulmonary function, with a stronger effect in current smokers. In the genome-wide interaction analysis, we identified a novel genetic variant, the major allele (A) of rs11683320 on the DPP10 gene that was inversely associated with FVC. The negative association of rs11683320 was attenuated by a higher DHA concentration, with a stronger effect in former smokers. This novel locus, which was missed in previous standard genome-wide association studies (GWAS) that did not account for the interaction with DHA, was replicated in one independent cohort study and passed the Bonferroni-corrected genome-wide significance level (P < 1.25×10^-8). In the third study, we analyzed data from a completed randomized controlled trial to conduct an ‘as-treated’ analysis of vitamin E supplementation on FEV1 decline in healthy males over 50 years old. Greater increase in plasma vitamin E over 3 years was associated with slower FEV1 decline, with evidence of effect modification by smoking. We also found that the minor allele (T) of a missense mutation (frequency = 31% in EA and 13% in AA), rs2108622, on the CYP4F2 gene, which was identified in a previous GWAS of plasma response to vitamin E supplementation in heavy male smokers, was associated with greater increase in plasma vitamin E after supplementation in our study of healthy men. This dissertation research used novel methods, including a gene-by-nutrient interaction study of large multi-ethnic cohort studies to contribute to the knowledge base on nutrition and lung health. Ultimately, such information is needed to understand whether population subgroups, for example as defined by genetic variation and/or by smoking status, might benefit differentially from dietary interventions