Genome-Wide Association Study of Pulmonary Function Decline in Taiwan Biobank Dataset

• Main Authors: Chia-Jung Lee, 李佳容
• Other Authors: Yungling Leo Lee
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/5fc4y5

碩士 === 國立臺灣大學 === 流行病學與預防醫學研究所 === 105 === Background Pulmonary function varies by ages. Both genetic and environmental factors influenced the decline of pulmonary function. Researchers interpreted the spirometric indices by percentage of predicted value (% predicted) and the reference value differs from age, sex, height, and ethnic origin. We aim to generate the reference equation of pulmonary function indices and elucidate the SNPs contributing to pulmonary function decline in Taiwanese population. Materials and methods Taiwan Biobank is a large-scale population-based representative cohort in Taiwan. Participants were aged 30 to 70-year-old without cancer diagnosis. Participants with first pulmonary function results and smoking status were enrolled as baseline population; those with follow-up pulmonary function results were left for longitudinal analysis. Generalized additive models for location, scale and shape (GAMLSS) and quantile regression were used to generate predictive equations for FVC and FEV1. Model validation processes included extremely phenotype prediction and ten-fold internal cross-validation. Longitudinal analysis was for investigating environmental risk factors associated with pulmonary function decline. Genome-wide association study with additive genetic model were performed for SNP investigation. The found SNPs were replicated in an independent cohort. Results After removing smokers and unreliable data, there were 8764 men and 19905 women enrolled at baseline. The equations generated from GAMLSS and quantile regression models showed better fitting, compared to Pan 1997 and GLI 2012 equations. After validation, we chose formulae for pulmonary function reference generated by quantile regression model. We found chronic obstructive pulmonary disease would significantly decrease pulmonary function annually than predicted. Smoking did not significantly accelerate pulmonary function decline. Besides, three novel SNPs, rs35517282, rs11122803 and rs12376178, were validated to be associated with accelerating FVC decline. SNP rs12376178 was located in CFAP77 gene region and CFAP77 expressed selectively in ciliated cell of human bronchial epithelium. SNP, rs971889 was found associated with FEV1 annual decline. SNP, rs971889 located in KCNAB1gene region and plays a role in pulmonary vascular tone regulation. Conclusions This is the first study using Taiwanese representative dataset and comprehensive methodology to generate pulmonary function predictive equation. Quantile regression model was the best suitable method. GWAS for pulmonary function decline revealed four novel SNPs, rs35517282, rs11122803, rs12376178, and rs971889, and two novel genes, CFAP77 and KCNAB1 contributing pulmonary function decline.