title: Genetic variants in antioxidant genes are associated with diisocyanate-induced asthma.
abstract: Diisocyanates are a common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants of antioxidant defense genes, glutathione S-transferases (GSTM1, GSTT1, GSTM3, GSTP1), manganese superoxide dismutase (SOD2), and microsomal epoxide hydrolase (EPHX1) are associated with increased susceptibility to diisocyanate-induced asthma (DA). The main study population consisted of 353 Caucasian French-Canadians from among a larger sample of 410 diisocyanate-exposed workers in three groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95); symptomatic diisocyanate workers with a negative SIC (DA(-), n = 116); and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5'-nuclease PCR assay. The SOD2 rs4880, GSTP1 rs1695, and EPHX1 rs2740171 variants were significantly associated with DA in both univariate and multivariate analyses. In the first logistic regression model comparing DA(+) and DA(-) groups, SOD2 rs4880, GSTM1 (null), GSTP1 rs762803, and EPHX1 rs2854450 variants were associated with DA (p = 0.004, p = 0.047, p = 0.021, p <0.001, respectively). Genotype combinations GSTT1*GSTP1 rs762803, GSTM1*EPHX1 rs2854450, EPHX1 rs2740168*EPHX1 rs1051741, and GSTP1 rs762803*EPHX1 rs2740168 were also associated with DA in this model (p = 0.027, p = 0.002, p = 0.045, p = 0.044,  respectively). The GSTP1 rs1695 and EPHX1 rs1051741 and rs2740171 variants showed an association with DA in the  second model comparing DA(+) and AW groups (p = 0.040, p = 0.019, p = 0.002, respectively). The GSTM3 rs110913*EPHX1 rs1051741 genotype combination was also associated with DA under this model (p = 0.042). The results suggest that variations in SOD2, GST, and EPHX1 genes and their interactions contribute to DA susceptibility.
authors.affiliation: CDC/National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Morgantown, West Virginia 26505, USA. byucesoy@cdc.gov
authors.forename: Berran
authors.initials: B
authors.lastname: Yucesoy
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Johnson
authors.forename: Zana L
authors.initials: ZL
authors.lastname: Lummus
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kissling
authors.forename: Kara
authors.initials: K
authors.lastname: Fluharty
authors.forename: Denyse
authors.initials: D
authors.lastname: Gautrin
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Malo
authors.forename: André
authors.initials: A
authors.lastname: Cartier
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Boulet
authors.forename: Joaquin
authors.initials: J
authors.lastname: Sastre
authors.forename: Santiago
authors.initials: S
authors.lastname: Quirce
authors.forename: Dori R
authors.initials: DR
authors.lastname: Germolec
authors.forename: Susan M
authors.initials: SM
authors.lastname: Tarlo
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Cruz
authors.forename: Xavier
authors.initials: X
authors.lastname: Munoz
authors.forename: Michael I
authors.initials: MI
authors.lastname: Luster
authors.forename: David I
authors.initials: DI
authors.lastname: Bernstein
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000378:metabolism*; D001249:Asthma / Q000139:chemically induced* / Q000235:genetics; D002170:Canada; D003485:Cyanates / Q000633:toxicity*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D017953:Isocyanates / Q000633:toxicity*; D008297:Male; D014051:Toluene 2,4-Diisocyanate / Q000633:toxicity*; D001559:Benzhydryl Compounds
chemical_list: D000975:Antioxidants; D003485:Cyanates; D017953:Isocyanates; D014051:Toluene 2,4-Diisocyanate; C015262:1,6-hexamethylene diisocyanate; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds