Genetic Susceptibility for Occupational Asthma

Details

• Personal Author:
  Bernstein DI ; Lummus ZL ; Yucesoy, Berran
• Description:
  Diisocyanates cause occupational asthma (DA) in 5-15% of exposed workers. Specific bronchial sensitization to diisocyanates are associated with airway inflammation and remodeling. Unlike IgE dependent asthma, biomarkers of IgE dependent sensitization have not been consistently demonstrated. Due to inherent toxicity, the DA phenotype is likely attributable to innate immune responses, oxidative stress, and epithelial cell barrier injury. We have investigated DA associated genotypes, using candidate gene studies, GWAS and Next Generation Sequencing (NGS) to identify gene variants associated with DA. DNA was collected from consented workers with specific inhalation challenge (SIC) confirmed DA recruited in Canada and Spain. The initial NIOSH R01 grant award (2006-2012) identified candidate variants (snps) linked to Th2 cytokines, antioxidant enzymes, and HLA class I and II antigens. GWAS was performed revealing novel DA associated SNPs in 74 DA subjects compared with 824 healthy controls using Omni-2.5 and Omni-5 SNP microarrays; 11 SNPs exceeded genome-wide significance with the strongest association with rs12913832 SNP on chromosome 15, mapping to HERC2 gene (p=6.94x10-14). Disease associated SNPs were detected near ODZ3 and CDH17 genes (rs908084, p=8.59x10-9 and rs2514805, p=1.22x10-8, respectively). We prioritized 38 SNPs with suggestive genome-wide significance (p <1x10-6) with 17 SNPs mapping to PITPNC1, ACMSD, ZBTB16, ODZ3, and CDH17 gene loci. We replicated a Korean GWAS study showing two DA associated SNP variants (rs10762058, rs7088181) on the CTNNA3 gene. CTNNA codes for a-T-catenin, a protein that complexes with E-cadherin to form the epithelial junctional complex (EJC). In this renewal (2013-2019), high-throughput methods were used to identify DA associated tagging SNPs (tSNP) within E-cadherin, a, beta and gamma catenin genes in DA workers (n=150) and 150 asymptomatic workers (AWs) exposed to HDI or MDI. We focused on SNPs within or near TACR1/LOC105374811 (chromosome 2) and CTNNA3/DNAJC12 (chromosome 10). Based on a previous GWAS study, 14 DA associated loci and flanking regions were selected for NGS (6,996,180 base pairs). NGS was performed in 91 workers with DA (cases) and in 293 subjects from the 1,000 genomic (1KG) control data set. NGS yielded 143 SNP associations with DA (x2; p ≤ 10-3) (range 10-3.006- 10-5.504, nearly all located in intronic regions. Analysis of transcription factor (TF) and ChIP- seq datasets identified overlap of 70 SNPs with TF binding regions of relevant lung cell lines (e.g., A549 and IMR90). The top 22 DA associated SNPs were contained in 7 loci: CDH17 (10), ATF3 (6), FAM71A (2), PITPNC1, TACR1, ZBTB16, LOC101929565. 22 top-ranked SNPs associated with DA (x2 p< 1 x 10-3). Electrophoretic mobility shift assays (EMSA) identified oligonucleotide-protein binding for risk and non-risk SNPs to nuclear extracts of A549, BEAS 2B, and IMR-90 lung cell lines. EMSA detected A549 nuclear extract binding to 10 variants, with 8 displaying preferential binding to non-risk alleles (rs1001304, rs2287231,rs2513789, rs2513791, rs11571537, rs14798008) or risk alleles (rs2513788, rs2513790). Bound proteins were purified by DNA affinity precipitation assays (DAPA) and eluted proteins analyzed by mass spectrometry (MS), demonstrating that rs14798008 bound H1 histones. A luciferase reporter assay, in A549 cells, identified allele-dependent mRNA transcription. Four SNPs exhibited allele-dependent increases in gene expression (rs2287231, rs2513789, rs11571537 and rs2446824). [Description provided by NIOSH]
• Subjects:
  Asthma, Occupational Genetics Hypersensitivity Isocyanates Occupational Exposure Occupational Health Safety
• Keywords:
  4,4-Methylene Diphenyl Diisocyanate Allergic Reactions Allergies Diisocyanates Genes Genetic Factors Genetic Predisposition Hexamethylene Diisocyanate Occupational Asthma Occupational Exposure
• Series:
  Grant Final Reports
• Publisher:
  National Institute for Occupational Safety and Health
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Final Grant Report
• Place as Subject:
  Ohio ; OSHA Region 5
• 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:
  1-14
• NIOSHTIC Number:
  nn:20060996
• NTIS Accession Number:
  PB2022-100355
• 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, 2020 Jan; :1-14
• 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
• CAS Registry Number:
  Diphenylmethane diisocyanate (CAS RN 101-68-8) ; Hexamethylene diisocyanate (CAS RN 822-06-0)
• Federal Fiscal Year:
  2020
• NORA Priority Area:
  Construction ; Manufacturing
• 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):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:2b4dca1112397eb8d004a3ece2406f0285c5e6fe999a0e065f85d8050f0aee793ca63e887db4bb09a7e347f8b4082fdb6658b8f18cf25b9ab4cfbfdbe44dd35c
• Download URL:
  https://stacks.cdc.gov/view/cdc/219018/cdc_219018_DS1.pdf
• File Type:
  [PDF - 579.09 KB ]