title: Interferon-γ promoter is hypermethylated in blood DNA from workers with confirmed diisocyanate asthma.
abstract: 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-γ, 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-γ 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.
authors.affiliation: Department of Environmental Health Sciences, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Ouyang
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
authors.forename: Zana L
authors.initials: ZL
authors.lastname: Lummus
authors.forename: Jun
authors.initials: J
authors.lastname: Ying
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Boulet
authors.forename: André
authors.initials: A
authors.lastname: Cartier
authors.forename: Denyse
authors.initials: D
authors.lastname: Gautrin
authors.forename: Shuk-Mei
authors.initials: SM
authors.lastname: Ho
mesh_terms: D000328:Adult; D001249:Asthma / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D004247:DNA / Q000097:blood*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000737:chemistry / Q000235:genetics*; D008297:Male; D016210:Methacholine Chloride; D008875:Middle Aged; D009784:Occupational Diseases / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D016273:Occupational Exposure / Q000009:adverse effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D012680:Sensitivity and Specificity; D014051:Toluene 2,4-Diisocyanate / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D016210:Methacholine Chloride; D014051:Toluene 2,4-Diisocyanate; D007371:Interferon-gamma; D004247:DNA
keywords: DNA methylation; IFN-γ; asthma; diisocyanate; environmental exposure; occupational asthma.
references.citation: Am J Ind Med. 1997 Nov;32(5):522-7
references.pmid: 9327077
references.citation: Toxicol Sci. 2013 Jan;131(1):242-6
references.pmid: 22977168
references.citation: J Allergy Clin Immunol. 2002 May;109(5):867-72
references.pmid: 11994713
references.citation: Curr Opin Allergy Clin Immunol. 2011 Apr;11(2):86-9
references.pmid: 21325943
references.citation: J Allergy Clin Immunol. 1993 Sep;92(3):387-96
references.pmid: 8360389
references.citation: Eur Respir J. 1996 Feb;9(2):207-10
references.pmid: 8777952
references.citation: Environ Health Perspect. 2012 Aug;120(8):1195-200
references.pmid: 22562770
references.citation: Int Arch Allergy Immunol. 2009;150(2):156-63
references.pmid: 19439981
references.citation: J Allergy Clin Immunol. 1989 Oct;84(4 Pt 1):507-14
references.pmid: 2794294
references.citation: Occup Med (Lond). 2008 May;58(3):169-74
references.pmid: 18308695
references.citation: Clin Exp Allergy. 2005 Mar;35(3):352-7
references.pmid: 15784115
references.citation: PLoS One. 2009;4(2):e4488
references.pmid: 19221603
references.citation: Immunol Allergy Clin North Am. 2011 Nov;31(4):699-716, vi
references.pmid: 21978852
references.citation: Chest. 2010 Apr;137(4):797-804
references.pmid: 20139223
references.citation: PLoS One. 2011;6(7):e22233
references.pmid: 21789241
references.citation: PLoS One. 2012;7(11):e48796
references.pmid: 23226205
references.citation: Am J Respir Crit Care Med. 2002 Aug 15;166(4):445-50
references.pmid: 12186818
references.citation: Clin Exp Allergy. 2009 Feb;39(2):203-12
references.pmid: 19187332
references.citation: J Allergy Clin Immunol. 2006 Mar;117(3):663-9
references.pmid: 16522468
references.citation: Clin Epigenetics. 2012 Sep 25;4(1):17
references.pmid: 23009259
references.citation: Chest. 2008 Sep;134(3 Suppl):1S-41S
references.pmid: 18779187
references.citation: J Allergy Clin Immunol. 2013 Feb;131(2):592-4.e1-3
references.pmid: 23260754
references.citation: Am J Respir Crit Care Med. 1999 Jun;159(6):1879-83
references.pmid: 10351934
references.citation: Crit Rev Toxicol. 2001 Nov;31(6):737-72
references.pmid: 11763481
references.citation: Clin Exp Allergy. 2008 Jun;38(6):957-67
references.pmid: 18498542
references.citation: Clin Exp Allergy. 2007 Jul;37(7):1095-102
references.pmid: 17581205
references.citation: J Occup Environ Med. 2012 Jul;54(7):774-80
references.pmid: 22796920
references.citation: Chest. 2003 Apr;123(4):1276-9
references.pmid: 12684321