The Role Of Genetics, Nutrition, And Cigarette Smoking In The Longitudinal Change In Lung Function

Abstract

Lung function is an important predictor of population morbidity and mortality. Decline in lung function is a natural part of aging, but accelerated loss in lung function over time is a harbinger of chronic obstructive pulmonary disease (COPD), a leading cause of death globally. Smoking is widely recognized as the key risk factor for reduced lung function and COPD, although additional risk factors, such as genetics and nutrition, have been suggested to also play important roles in contributing to changes in lung function. The overall aim of this research was to investigate the role of, and interaction between, genetics, nutrition, and cigarette smoking in relation to the longitudinal change in lung function, as an indicator of COPD susceptibility. First, we explored the association between genetic variation within a network of antioxidant enzyme genes and the rate of change in lung function in a prospective cohort study of African and European American elderly adults; this study also investigated gene-bysmoking interaction. Evidence of association was identified for genetic variants in several candidate genes, among which were two novel genes (mGST3 and IDH3B) that interacted with smoking in both races/ethnicities. Second, to expand the scope of investigation to all common genetic variants iii throughout the entire human genome, we conducted a large-scale meta-analysis of genomewide association studies of longitudinal change in lung function in a consortium of 14 individual cohort studies of adults of European ancestry. We found evidence of association at two novel genetic loci (IL16/STARD5/TMC3 and ME3) in the meta-analysis and performed additional gene expression analyses to demonstrate that both loci harbor candidate genes with biologically plausible functional links to lung function. Finally, we explored the role of nutrition directly by investigating the relation between overall dietary patterns and longitudinal change in lung function in a prospective cohort of male adults, considering diet-by-smoking interaction. We identified two distinct dietary patterns by applying principal component analysis to food frequency questionnaire data, and found that a prudent diet rich in fruits, vegetables, fish, and poultry attenuated the accelerated decline in lung function in cigarette smokers, but had no association in non-smokers. iv