Single-Nucleotide Polymorphisms Associated with Skin Naphthyl-Keratin Adduct Levels in Workers Exposed to Naphthalene

BACKGROUND: Individual genetic variation that results in differences in systemic response to xenobiotic exposure is not accounted for as a predictor of outcome in current exposure assessment models. OBJECTIVE: We developed a strategy to investigate individual differences in single-nucleotide polymorphisms (SNPs) as genetic markers associated with naphthyl-keratin adduct (NKA) levels measured in the skin of workers exposed to naphthalene. METHODS: The SNP-association analysis was conducted in PLINK using candidate-gene analysis and genome-wide analysis. We identified significant SNP-NKA associations and investigated the potential impact of these SNPs along with personal and workplace factors on NKA levels using a multiple linear regression model and the Pratt index. RESULTS: In candidate-gene analysis, a SNP (rs4852279) located near the CYP26B1 gene contributed to the 2-naphthyl-keratin adduct (2NKA) level. In the multiple linear regression model, the SNP rs4852279, dermal exposure, exposure time, task replacing foam, age, and ethnicity all were significant predictors of 2NKA level. In genome-wide analysis, no single SNP reached genome-wide significance for NKA levels (all p >= 1.05 x 10(-5)). Pathway and network analyses of SNPs associated with NKA levels were predicted to be involved in the regulation of cellular processes and homeo-stasis. CONCLUSIONS: These results provide evidence that a quantitative biomarker can be used as an intermediate pheno-type when investigating the association between genetic markers and exposure-dose relationship in a small, well-characterized exposed worker population.