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

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• 作者：Kim de Jong ; PhD^a ; ^b ; Judith M. Vonk ; PhD^a ; ^b ; Wim Timens ; PhD^b ; ^c ; Yohan Bossé ; PhD^d ; Don D. Sin ; PhD^e ; Ke Hao ; PhD^f ; Hans Kromhout ; PhD^g ; Roel Vermeulen ; PhD^g ; Dirkje S. Postma ; PhD^b ; ^h ; H. Marike Boezen ; PhD^a ; ^b ; ^{h.m.boezen@umcg.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Genetics ; occupational exposures ; interactions ; gene expression ; lung function
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：136
• 期：6
• 页码：1664-1672.e14
• 全文大小：2417 K

文摘

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.