Novel gene-environment associations with diisocyanate induced asthma.
Lummus-ZL; Yucesoy-B; Cartier-A; Hershey-GK; Gautrin-D; Boulet-L; Sastre-J; Langmeyer-S; Kissling-G; Luster-M; Rao-M; Malo-J; Tarlo-S; Bernstein-DI
J Allergy Clin Immunol 125(2)(S1):AB357-AB358
Rationale: Risk and susceptibility factors for Diisocyanate Asthma (DA) are poorly defined. We used candidate gene approaches to define genetic susceptibility for DA in workers exposed to hexamethylene-(HDI), methylene diphenyl-(MDI) or toluene-(TDI) diisocyanate. Methods: DNA was collected from HDI, MDI or TDI exposed symptomatic workers with: DA (n=103) confirmed by specific inhalation challenge (SIC); non-DA defined by negative SIC (n=115). Asymptomatic HDI exposed workers (CTRL) (n=150) were also studied. Genotyping was performed with the following SNPs: IL-4 receptor alpha (IL4RA) (I75V, E400A, Q576R); IL-13 (R130Q); CD14 (C159T); glutathione transferases (GSTP1/Ile-Val, GSTT1/deletion, GSTM1); superoxide dismutase2 (MnSOD/A-V); epoxide hydrolase (EPHX Exon3, EPHX Exon4). DNA microarray was used to assess associations with 52 candidate asthma genes (772 SNPs) using a gene centric analytic approach. Results: Among HDI workers, workers with DA were more likely to have IL4RA II/CD14 CT (OR=3.1; 95%CI: 1.3, 7.3) and IL4RA II/IL13RR/CD14CT (OR=4; 95% CI: 1.4, 11.6) combined genotypes versus non-DA workers. The same combined genotypes were significantly associated with DA when compared with HDI CTRL workers. The MnSOD/VV genotype was individually associated with DA (p<0.05). Microarray data using gene centric analysis revealed three genes associated with DA: hydroxyacid oxidase/HAO1 (p= .01), plasminogen activator inhibitor 1/SERPIN1 (p= .05), and serine peptidase inhibitor B3/SERPINB3 (p=.05). Conclusions: Genotype combinations of SNPs associated with Th2 cytokines, anti-oxidant enzymes (MnSOD, HAO1), the innate immune response (CD14), airway remodeling (SERPIN1, SERPINB3), and HDI exposure may define susceptibility to DA.
Bronchial-asthma; Respiratory-system-disorders; Pulmonary-system-disorders; Gene-mutation; Genes; Genetics
110-82-7; 101-68-8; 584-84-9
Healthcare and Social Assistance; Services
Journal of Allergy and Clinical Immunology. 2010 American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting New Orleans, Louisiana, February 26-March 2, 2010