Genome-wide assessment of gene-by-smoking interactions in COPD

Abstract

Cigarette smoke exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) and its interactions with genetic variants could affect lung function. However, few gene-smoking interactions have been reported. In this report, we evaluated the effects of gene-smoking interactions on lung function using Korea Associated Resource (KARE) data with the spirometric variables-forced expiratory volume in 1 s (FEV₁). We found that variations in FEV₁ were different among smoking status. Thus, we considered a linear mixed model for association analysis under heteroscedasticity according to smoking status. We found a previously identified locus near SOX9 on chromosome 17 to be the most significant based on a joint test of the main and interaction effects of smoking. Smoking interactions were replicated with Gene-Environment of Interaction and phenotype (GENIE), Multi-Ethnic Study of Atherosclerosis-Lung (MESA-Lung), and COPDGene studies. We found that individuals with minor alleles, rs17765644, rs17178251, rs11870732, and rs4793541, tended to have lower FEV₁ values, and lung function decreased much faster with age for smokers. There have been very few reports to replicate a common variant gene-smoking interaction, and our results revealed that statistical models for gene-smoking interaction analyses should be carefully selected.

Figure 1

Changes of FEV₁ along age Smoothing lines of FEV₁ (L) according to age and their 95% confidence interval were estimated with generalized additive model.

Figure 2

QQ plots for FEV₁ Figure 2A is obtained from the proposed 3 DF test on FEV₁ and Figure 2B is obtained from the homoscedasticity model.

Figure 3

Linkage disequilibrium among the four most significant SNPs and regional plots Figure 3A shows the LD plot generated with Haploview software and D’ values were used. Figure 3B is a regional plot r² around rs17765644 SNPs created with LocusZoom. SOX9 TAD is located between 68.67 to 70.45 Mb.

Figure 4

SNP-smoking interaction Figure 4 visualize the effects of rs17765644 by smoking status. X axis presents the number of minor alleles, and left and right of Y axis represent mean FEV₁ values of never smokers, and ever smoker, respectively.