Novel Genetic Susceptibility Loci for FEV<sub>1</sub> in the Context of Occupational Exposure in Never-Smokers
Authors: Kim de Jong, Judith M. Vonk, Alen Faiz, Diana A. van der Plaat, Wim Timens, Yohan Bossé, Hans Kromhout, Ivana Nedeljkovic, Dirkje S. Postma, H. Marike Boezen
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Recently, we identified several novel and plausible genetic susceptibility loci for impaired lung function levels in the context of occupational exposure in a sample, including both never-and ever-smokers (1).Previous studies suggest that effects of genetic variants (2), occupational exposures (3), and their interactions (1) may be different in never-smokers and ever-smokers.Yet never-smokers generally make up a smaller proportion of subjects in general population studies (including current, former, and never-smokers), and effects solely present in never-smokers may therefore not be detected.Hence, to unravel why and how never-smokers develop impaired lung function levels and chronic respiratory diseases such as chronic obstructive pulmonary disease, it is important to study the effects of nonsmoking-related exposures without potential interference of tobacco smoke exposure.With the current genomewide interaction study, we aimed to identify novel genetic susceptibility loci for impaired levels of FEV 1 in the context of occupational exposure to biological dust, mineral dust, and gases/fumes in a sample including never-smokers only.We included never-smokers from two Dutch general population-based cohorts: LifeLines (N = 5,070) and Vlagtwedde-Vlaardingen (N = 431).First, in each cohort separately, genome-wide single-nucleotide polymorphism (SNP)-by-exposure interactions were assessed, using linear regression models specified as follows: FEV 1 = SNP (additive effect) 1 low exposure 1 high exposure 1 SNP 3 low exposure 1 SNP 3 high exposure 1 sex 1 age 1 height.To have a clear exposure contrast, we focused on the SNP-byhigh exposure interaction only.Subsequently, the SNP-by-high exposure interactions from both cohorts were metaanalyzed using effects estimates weighted by the SEs.SNPs with interaction P values ,5 3 10 28 and with the same direction of interaction in both cohorts were taken further for cis-acting expression quantitative trait loci (cis-eQTL) analysis in lung tissue of 1,087 subjects (4).Finally, we performed pathway analyses using all SNPs (5).More detailed information about the cohorts, phenotyping, genotyping, occupational exposure assessment, cis-eQTL, and pathway analysis can be found elsewhere (1).Subjects included from the LifeLines study had a median age of 46 years (range, 18-90 yr), with a mean FEV 1 of 104% predicted and mean FEV 1 /FVC of 78%.Subjects from the Vlagtwedde-Vlaardingen study had a median age of 54 years (range, 36-79 yr), with a mean FEV 1 of 98% predicted and mean FEV 1 /FVC of 76%.We identified four significant SNP-by-high exposure interactions, one with mineral dust and three with gases/fumes exposure (Table 1).No significant interactions were found with high exposure to biological dust.For all four SNPs, highly exposed subjects had substantially lower FEV 1 levels compared with subjects without exposure, yet only when carrying at least one copy of the risk allele and not when carrying the wild-type genotype (Figures 1A-1D).None of the four identified SNPs was a cis-eQTL in lung tissue.Finally, the Biocarta pathways patched 1 and the natural killer cells were suggestively associated (false discovery rate P value , 0.25) with FEV 1 in the context of mineral dust and gases/fumes exposure, respectively.The most significant interaction identified was between gases/fumes exposure and SNP rs10223081 located nearby the gene NMUR2, a G coupled-protein receptor for neuromedin U (NMU) (6).NMU can induce mast cell degranulation leading to, for example, early-phase inflammation, such as neutrophil infiltration in inflamed sites (7), and can induce eosinophil infiltration in allergic inflammatory sites in an antigen-induced asthma model.We found modest expression of NMUR2 in lung tissue (data not shown), yet this expression was not associated with the identified SNP.Importantly, effects of high exposure on gases/fumes were large and of