Genome-wide interaction study of gene-by-occupational exposure and effects on FEV1 levels

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by impaired lung function and airway obstruction resulting from interactions between multiple genes and multiple environmental exposures. Thus far, genome-wide association studies have largely disregarded environmental factors that might trigger the development of lung function impairment and COPD, such as occupational exposures, which are thought to contribute to 15% to 20% of the COPD prevalence.

Objectives: We performed a genome-wide interaction study to identify novel susceptibility loci for occupational exposure to biological dust, mineral dust, and gases and fumes in relation to FEV1 levels.

Methods: We performed an identification analysis in 12,400 subjects from the LifeLines cohort study and verified our findings in 1436 subjects from a second independent cohort, the Vlagtwedde-Vlaardingen cohort. Additionally, we assessed whether replicated single nucleotide polymorphisms (SNPs) were cis-acting expression (mRNA) quantitative trait loci in lung tissue.

Results: Of the 7 replicated SNPs that interacted with one of the occupational exposures, several identified loci were plausible candidates that might be involved in biological pathways leading to lung function impairment, such as PCDH9 and GALNT13. Two of the 7 replicated SNPs were cis-acting expression quantitative trait loci associated with gene expression of PDE4D and TMEM176A in lung tissue.

Conclusion: This genome-wide interaction study on occupational exposures in relation to the level of lung function identified several novel genes. Further research should determine whether the identified genes are true susceptibility loci for occupational exposures and whether these SNP-by-exposure interactions consequently contribute to the development of COPD.

Keywords: Genetics; gene expression; interactions; lung function; occupational exposures.