Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

Abstract

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P JMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest P JMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest P JMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

“…For example, a meta-analysis of genome-wide studies of respiratory phenotypes, which included gene-smoking interactions, identified multiple functional variants that had been missed in analyses neglecting interaction effects. 49 A secondary methodological study found some evidence for an interaction of smoking with a variant located in the proximity of FMO4 with respect to incident coronary heart disease. 50 These results should motivate secondary analyses of the evergrowing number of (epi)genome-wide data sets of cardiovascular disease, which usually will feature at least crude smoking exposure data, but have neither been compiled nor analyzed with tobacco-related disease in mind.…”

A Genome-Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos

“…One identified a novel variant near MAN2B1 that was associated with percent emphysema on computed tomography (CT) (16) and the other identified two loci that approached genome wide statistical 4 significance for COPD (13). This literature contrasts with that among persons of European ancestry, in whom GWAS have identified multiple loci in genes for lung function and COPD (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) To improve our current understanding of the genetic architecture of lung functionrelated traits in Hispanics/Latinos, we performed a meta-analysis for FEV1, FEV1/FVC, airflow limitation and COPD among six Hispanic/Latino groups in the HCHS/SOL cohort (10,32). Findings were replicated in European, Hispanic and African populations.…”

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…To date, seven meta-analyses of GWAS have now been completed and identified SNP associations with FEV1 and/or FEV1 decline (Hancock et al, 2012;Hancock et al, 2010;Repapi et al, 2010;Soler ArtigasLoth, et al, 2011;Tang et al, 2014;Wain L, 2015).…”

“…SNPs at the 4q24 locus (Castaldi et al, 2011;Repapi et al, 2010;Soler Artigas, Wain, et al, 2011), SNP rs12604628 in HHIP (Repapi et al, 2010;Soler Artigas, Wain, et al, 2011), rs3995090 in HTR4 (Repapi et al, 2010;Soler Artigas, Wain, et al, 2011) and SNPs in SRY (Sex Determining Region Y)-Box 9 (SOX9) (Hancock et al, 2012;Kim et al, 2014). For SNPs associated with FEV1/FVC and COPD, different SNPs in Transforming Growth Factor, Beta 2 (TGFB2) were identified Soler Artigas, Wain, et al, 2011), rs2869967 in FAM13A (Hancock et al, 2010; J. H. Lee et al, 2014), rs12504628 in HHIP (Repapi et al, 2010;Soler Artigas, Wain, et al, 2011) and different SNPs in HTR4 (Hancock et al, 2010;Soler Artigas, Wain, et al, 2011;Wilk et al, 2012).…”