Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma

Diisocyanates are the leading causes of occupational asthma (OA), estimated to cause asthma in 5%–15% of chronically exposed workers (Bakerly et al., 2008; Bernstein, 2011; Redlich and Karol, 2002). The most common isomers used in industry are: the aliphatic agent 1,6 hexamethylene diisocyanate (HDI), 4, 4-diphenylmethane diisocyanate (MDI), and toluene diisocyanate (TDI). Despite improved industrial hygiene efforts, new cases of diisocyanate asthma (DA) continue to occur (Booth et al., 2009; Campo et al., 2010; Kenyon et al., 2012). The National Institute for Occupational Safety and Health (NIOSH) National Occupational Exposure Survey database showed that at least 280 000 workers were potentially exposed to some form of diisocyanates in the United States alone (NIOSH, 1983). TDI was reported to account for between 2.9% and 13% of all cases of occupational asthma in Korea (Park et al., 2002). Considering the extent of workplace exposure to diisocyanates, identification of genetic variants increasing susceptibility to DA could be important in developing new risk assessment and preventive strategies for chronically exposed workers. In addition, incorporation of genetic data into human health risk assessment will be important for refining occupational exposure limits for diisocyanates to improve protection of worker health. We have previously identified a number of DA associated variants of: HLA genes (HLA-B, HLA-E, HLA-DOA, HLA-DPB1, and HLA-DQA2) (Yucesoy et al., 2014), Th2 immune response-associated genes (IL-4Rα, IL-13, and CD14) (Bernstein et al., 2006, 2011) and antioxidant defense genes (SOD2, GST, and EPHX1) (Yucesoy et al., 2012). Although genome-wide association studies (GWAS) have been performed in various asthma phenotypes, only one GWAS has investigated workers with OA. This study was conducted in 84 diisocyanate-exposed Korean workers with TDI-asthma confirmed by specific inhalation challenge (SIC) and 263 unexposed healthy controls and identified 4 CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) associated with DA (Kim et al., 2009). In this study, we aimed to increase our understanding of genetic susceptibility to DA by conducting a GWAS in a different background population of Caucasian subjects. Although population admixture, specific diisocyanate exposure, and genotyping platforms differed between the 2 GWAS studies, we searched for common overlapping genetic loci between the Korean population and ours. Our findings revealed several genes/SNPs that may offer promising avenues for future genetic and functional studies of DA susceptibility genes.