Genome wide interaction study of genetic variants associated with lung function decline.

Abstract

Some genetic variants are associated with lung function decline and chronic obstructive pulmonary disease (COPD), but functional studies are necessary to confirm causality. We investigated the genetic susceptibility-associated lung function decline with or without COPD, using data from a community-based cohort (N = 8554). A genome-wide interaction study was conducted to identify the association between genetic variants and pulmonary function, and the way variants relate to lung impairment in accordance with smoking status and amount was examined. We further used a linear mixed model to examine the association and interaction to time effect. We found annual mean FEV₁ declines of 41.7 mL for men and 33.4 mL for women, and the annual rate of decline in FEV₁ was the fastest for current smokers. We also found a previously identified locus near FAM13A, the most significant SNPs from the results of two likelihood ratio tests for FEV₁/FVC (P = 1.56 × 10^-10). These selected SNPs were located in the upstream region of FAM13A on chromosome 4 and had similar minor allele frequencies (MAFs). Furthermore, we found that certain SNPs tended to have lower FEV₁/FVC values, and lung function decreased much faster with time interactions. The SNP most associated with lung function decline was the rs75679995 SNP on chromosome 7, and those SNPs located within the TAD of the DNAH11 region and the eQTL of rs9991425 revealed a higher expression of MFAP3L and AADAT genes (P = 2.28 × 10^-7 and 2.01 × 10^-6, respectively). This is the first study to investigate gene-time interactions in lung function decline as a risk factor for COPD in the Korean population. In addition to replicating previously known signals for FAM13A, we identified two genomic regions (DNAH11, AADAT) that are potentially involved in gene-environment interactions, warranting further investigation to confirm their roles.