Interferon-gamma promoter is hypermethylated in blood DNA from workers with confirmed diisocyanate asthma.
Ouyang-B; Bernstein-DI; Lummus-ZL; Ying-J; Boulet-LP; Cartier-A; Gautrin-D; Ho-SM
Toxicol Sci 2013 Jun; 133(2):218-224
Risk factors have not been identified that determine susceptibility for development of diisocyanate-induced occupational asthma (DA). We hypothesized that diisocyanate (DI) exposure could modify gene promoter regions regulating transcription of cytokine mediators and thereby influence expression of DA. A cross-sectional study was designed to investigate the promoter methylation status of candidate genes in DI-exposed workers. Subjects consisted of 131 workers in three groups: 40 cases with DA confirmed by a positive specific inhalation challenge (SIC) (DA+), 41 exposed workers with lower respiratory symptoms and negative SIC (DA-), and 50 asymptomatic exposed workers (AWs). We studied four candidate genes (GSTM1, DUSP22, IFN-y, and IL-4) for which altered promoter methylation has been previously investigated for relationships with a variety of other environmental exposures. Methylation status was determined using methylation-specific quantitative PCR performed on genomic DNA extracted from whole blood. Results showed that relative methylation of IFN-? promoter was significantly increased in DA+ in comparison with both comparator groups (DA- and AW), and it exhibited good sensitivity (77.5%) and specificity (80%) for identifying DA workers in a multivariate predictive model after adjusting for type of DI exposure, smoking status, methacholine PC20, and gender. IL-4 promoter was slightly less methylated only in DA+ compared with AW among nonsmoking workers. Both GSTM1 and DUSP22 promoter methylations were found not associated with DA. Our finding suggests that exposure to occupational chemicals could play a heretofore undefined mechanistic role via epigenetic modification of specific genes in the promoter region.
Risk-factors; Respiratory-system-disorders; Pulmonary-system; Pulmonary-system-disorders; Pulmonary-function; Exposure-levels; Blood-cells; Genetics; Humans; Men; Women;
Author Keywords: DNA methylation; IFN-gamma; environmental exposure; diisocyanate; asthma; occupational asthma
Shuk-Mei Ho, University of Cincinnati Medical Center, 3223 Eden Ave, Kettering Complex, Cincinnati, OH 45267-0056
University of Cincinnati