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Genetic Susceptibility for Occupational Asthma



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  • Personal Author:
  • Description:
    Diisocyanates are highly reactive chemicals that cause occupational asthma (OA) in 5-15% of exposed workers. Since new cases are not entirely preventable, there is a need to find markers of susceptibility to identify those worker groups at risk for OA, caused by diisocyanates (DA) to further guide risk assessment strategies. The clinical manifestations of DA are similar to those found in non-occupational asthma, including airway hyperresponsiveness, airway remodeling, as well as a unique ability to illicit isolated late phase responses, with infiltration of eosinophils, basophils, and/or neutrophils. Evidence suggesting immune mechanisms underlying DA susceptibility include a latency period of exposure preceding sensitization, and elicitation of asthmatic responses by sub]irritant levels of chemical. However, unlike OA induced by high molecular weight sensitizers, no sensitive and specific antibody markers of DA have yet been identified. Due to the inherent toxic nature of these chemicals, pathogenesis of DA is likely to be multifactorial in nature, involving innate and acquired immune mechanisms, oxidative stress, and impaired epithelial cell barrier function. Our approach has been to investigate candidate genes in exposed workers for polymorphisms associated with susceptibility to DA. Using DNA from workers at risk for OA, recruited from occupational respiratory clinics in Canada and Spain, we have identified Th2 cytokine gene polymorphisms, antioxidant enzyme gene polymorphisms, HLA class I and II alleles, and a-catenin (CTNNA3) SNP variants significantly associated with the DA phenotype. In the current study, we confirmed results of a previous study in which we identified single nucleotide polymorphisms (SNPs) in the IL-4Ra, IL-13, and CD-14 genes that were statistically associated with diisocyanate asthma in workers exposed to hexamethylene diisocyanate (HDI), using an expanded number of symptomatic workers (DA+ and DA], confirmed by SIC),as well as a new group of asymptomatic controls (AWs) for comparison. Further studies emanating from this grant yielded finding of significant associations between novel MHC Class I (HLA-E, HLA-B) and Class II (HLA-DOA, HLA-DQA2 and HLA-DBP1) SNPs and DA. Candidate gene association studies were then extended to investigate SNPs of genes were selected based on their functional role in oxidative stress and inflammation. Antioxidant enzyme genes including: glutathione S-transferase [GSTM1 (null), GSTM3 (3 SNPs), GSTT1 (null) and GSTP1 (Ile-Val) SNPs]; mitochondrial superoxide dismutase (SOD2; Ala-Val SNP); and eight epoxide hydrolase (EPHX1) SNPs. Using logistic regression modeling, SOD2 rs4880, EPHX1 2740171 and GSTP1 rs1695 variants are significantly associated with DA. After adjustment for confounding variables, variants of GSTM1, GSTT1, GSTP1, EPHX1 and GSTM3 genes also showed significant positive or negative associations with DA. Finally, we were able to replicate the findings from a GWAS study of Korean DA workers that demonstrated an association between two closely linked CTNNA3 gene SNPs and DA, in our European population of DA workers. As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs were significantly associated with DA+ when compared to AWs. The CTNNA3 gene codes for a-T-catenin, a cytoplasmic anchorage protein in the epithelial adherens junctional complex (AJC), which is critical for maintaining epithelial cell]cell adhesion and epithelial barrier function. These finding served as the basis for our renewal proposal in which we plan to perform next generation DNA sequences of informative loci in the AJC and to identify functional variants. The genetic risk factors identified can contribute to future intervention studies to reduce the occurrence of DA in workers. [Description provided by NIOSH]
  • Subjects:
  • Keywords:
  • Series:
    Grant Final Reports
  • Publisher:
    National Institute for Occupational Safety and Health
  • Document Type:
    Text
  • Funding:
    Grant
  • Genre:
    Final Grant Report
  • Place as Subject:
  • CIO:
    National Institute for Occupational Safety and Health (NIOSH)
  • Division:
    OEP - Office of Extramural Programs
  • Topic:
    Workplace Safety & Health
  • Location:
    North America
  • Pages in Document:
    1-16
  • NIOSHTIC Number:
    nn:20046677
  • NTIS Accession Number:
    PB2016-100067
  • Citation:
    Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, R01-OH-008795, 2014 Oct; :1-16
  • Contact Point Address:
    Dr. David Bernstein, Professor, University of Cincinnati College of Medicine, Internal Medicine, Department of Allergy and Immunology, 3255 Eden Ave, Cincinnati OH 45267-0563
  • Email:
    David.bernstein@uc.edu
  • Federal Fiscal Year:
    2015
  • NORA Priority Area:
  • Performing Organization:
    University of Cincinnati
  • Peer Reviewed:
    False
  • Start Date:
    20060901
  • Source Full Name:
    National Institute for Occupational Safety and Health
  • End Date:
    20180831
  • Collection(s):
  • Main Document Checksum:
    urn:sha-512:c1d84c787658714873c4b477db90ef086acca6f164585c37fba28e72363dfd85073ade5a2a0dbf83be89ae15ba641f40e9dd07634f2fecaa9f63d94582c8166e
  • Download URL:
  • File Type:
    Filetype[PDF - 253.07 KB ]
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