Gene-environment interaction effects on lung function- a genome-wide association study within the Framingham heart study

Xihong Lin,Shu-Yi Liao,David C Christiani

doi:10.1186/1476-069x-12-101

Abstract

BackgroundPrevious studies in occupational exposure and lung function have focused only on the main effect of occupational exposure or genetics on lung function. Some disease-susceptible genes may be missed due to their low marginal effects, despite potential involvement in the disease process through interactions with the environment. Through comprehensive genome-wide gene-environment interaction studies, we can uncover these susceptibility genes. Our objective in this study was to explore gene by occupational exposure interaction effects on lung function using both the individual SNPs approach and the genetic network approach.MethodsThe study population comprised the Offspring Cohort and the Third Generation from the Framingham Heart Study. We used forced expiratory volume in one second (FEV1) and ratio of FEV1 to forced vital capacity (FVC) as outcomes. Occupational exposures were classified using a population-specific job exposure matrix. We performed genome-wide gene-environment interaction analysis, using the Affymetrix 550 K mapping array for genotyping. A linear regression-based generalized estimating equation was applied to account for within-family relatedness. Network analysis was conducted using results from single-nucleotide polymorphism (SNP)-level analyses and from gene expression study results.ResultsThere were 4,785 participants in total. SNP-level analysis and network analysis identified SNP rs9931086 (Pinteraction =1.16 × 10-7) in gene SLC38A8, which may significantly modify the effects of occupational exposure on FEV1. Genes identified from the network analysis included CTLA-4, HDAC, and PPAR-alpha.ConclusionsOur study implies that SNP rs9931086 in SLC38A8 and genes CTLA-4, HDAC, and PPAR-alpha, which are related to inflammatory processes, may modify the effect of occupational exposure on lung function.

Highlights

Previous studies in occupational exposure and lung function have focused only on the main effect of occupational exposure or genetics on lung function
The disease aggregates in families [12], and genome-wide association studies (GWAS) [13,14,15,16,17] have identified single nucleotide polymorphisms (SNPs) that are associated with Chronic obstructive pulmonary disease (COPD) or lung function
Mean Forced expiratory volume in one second (FEV1) was higher in the group with highly likely dust exposure, but the mean FEV1/forced vital capacity (FVC) was similar in the two groups overall

Summary

Introduction

Previous studies in occupational exposure and lung function have focused only on the main effect of occupational exposure or genetics on lung function. Our objective in this study was to explore gene by occupational exposure interaction effects on lung function using both the individual SNPs approach and the genetic network approach. An association between COPD or poor lung function and occupational exposure to dust, gas, and fumes has been reported in both industry-based studies [3,4,5,6] and community-based [7,8,9,10,11] cross-sectional studies. The disease aggregates in families [12], and genome-wide association studies (GWAS) [13,14,15,16,17] have identified single nucleotide polymorphisms (SNPs) that are associated with COPD or lung function

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