Influence of Genetic Variance on Biomarker Levels After Occupational Exposure to 1,6-Hexamethylene Diisocyanate Monomer and 1,6-Hexamethylene Diisocyanate Isocyanurate

Abstract

We evaluated the impact of genetic variance on biomarker levels in a population of workers in the automotive repair and refinishing industry who were exposed to respiratory sensitizers 1,6-hexamethylene diisocyanate (HDI) monomer and one of its trimers, HDI isocyanurate. The exposures and respective urine and plasma biomarkers 1,6-diaminohexane (HDA) and trisaminohexyl isocyanurate (TAHI) were measured in 33 workers; and genome-wide microarrays (Affymetrix 6.0) were used to genotype the workers' single-nucleotide polymorphisms (SNPs). Linear mixed model analyses have indicated that interindividual variations in both inhalation and skin exposures influenced these biomarker levels. Using exposure values as covariates and a false discovery rate < 0.10 to assess statistical significance, we observed that seven SNPs were associated with HDA in plasma, five were associated with HDA in urine, none reached significance for TAHI in plasma, and eight were associated with TAHI levels in urine. The different genotypes for the 20 significant SNPs accounted for 4- to 16-fold changes observed in biomarker levels. Associated gene functions include transcription regulation, calcium ion transport, vascular morphogenesis, and transforming growth factor beta signaling pathway, which may impact toxicokinetics indirectly by altering inflammation levels. Additionally, in an expanded analysis using a minor allele cutoff of 0.05 instead of 0.10, there were biomarker-associated SNPs within three genes that have been associated with isocyanate-induced asthma: ALK, DOCK2, and LHPP. We demonstrate that genetic variance impacts the biomarker levels in workers exposed to HDI monomer and HDI isocyanurate and that genetics can be used to refine exposure predictions in small cohorts when quantitative personal exposure and biomarker measurements are included in the models.

Keywords: biomarkers; biomonitoring; exposure assessment; gene–environment interactions; genome-wide association study; isocyanates.

FIGURE 1

Manhattan plots showing the single-nucleotide polymorphisms (SNPs) significantly associated with 1,6-diaminohexane (HDA) in plasma (A) and urine (B) and trisaminohexyl isocyanurate (TAHI) biomarker levels in plasma (C) and urine (D) when inhalation and skin exposures to 1,6-hexamethylene diisocyanate (HDI) monomer and HDI isocyanurate were used as covariates, respectively. Urine biomarker levels were adjusted with creatinine level. The solid line is the suggestive significance default line at -log₁₀(p = 1 × 10^–5), the dashed line is equivalent to false discovery rate (FDR) = 0.10 at −log₁₀(p = 1 × 10^–6), and the top dotted line is the genome-wide significance default line at −log₁₀(p = 5 × 10^–8).

FIGURE 2

Correlations between the unadjusted biomarker levels in urine or plasma and the genotypes for each of the 20 significant single-nucleotide polymorphisms (SNPs). Urine biomarker levels were adjusted with creatinine level (μg biomarker/g creatinine; μg/g Cr). The homozygous major allele is preceded by “(a),” the heterozygous genotype is preceded by “(b),” and the homozygous minor allele is preceded by “(c).”

FIGURE 3

GeneMANIA output for the products of genes proximal to the significant single-nucleotide polymorphisms (SNPs) associated with exposure-adjusted 1,6-diaminohexane (HDA) levels in plasma and urine. Query genes have black circles with white-striped lines, the networks are shown with the colored lines between genes, and the shading on the circles shows the functions.

FIGURE 4

GeneMANIA output for the products of genes proximal to the significant single-nucleotide polymorphisms (SNPs) associated with exposure-adjusted trisaminohexyl isocyanurate (TAHI) levels in urine. Query genes have black circles with white-striped lines, the networks are shown with the colored lines between genes, and the shading on the circles shows the functions.