Oxidative Stress-Related Genetic Variants May Modify Associations of Phthalate Exposures with Asthma.

ABSTRACT

Background: Phthalate exposure may increase the risk of asthma. Little is known about whether oxidative-stress related genes may alter this association. First, this motivated us to investigate whether genetic polymorphisms of the oxidative-stress related genes glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase pi 1 (GSTP1), superoxide dismutase 2 (SOD2), catalase (CAT), myeloperoxidase (MPO), and EPHX1 in children are associated with phthalate urine concentrations. Second, we addressed the question whether these genes may affect the influence of phthalates on asthma.Methods: In a case-control study composed of 126 asthmatic children and 327 controls, urine phthalate metabolites (monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono(2-ethyl-5-hydroxyhexyl)phthalate (MEHHP) were measured by UPLC-MS/MS at age 3. Genetic variants were analyzed by TaqMan assay. Information on asthma and environmental exposures was also collected. Analyses of variance and logistic regressions were performed. Results: Urine MEHHP levels were associated with asthma (adjusted OR 1.33, 95% CI (1.11-1.60). Children with the GSTP1 (rs1695) AA and SOD2 (rs5746136) TT genotypes had higher MEHHP levels as compared to GG and CC types, respectively. Since only SOD2 TT genotype was significantly associated with asthma (adjusted OR (95% CI) 2.78 (1.54-5.02)), we estimated whether SOD2 variants modify the association of MEHHP levels and asthma. As MEHHP concentrations were dependent on GSTP1 and SOD2, but the assessment of interaction requires independent variables, we estimated MEHHP residuals and assessed their interaction, showing that the OR for SOD2 TT was further elevated to 3.32 (1.75-6.32) when the residuals of MEHHP were high. Conclusions: Urine phthalate metabolite concentrations are associated with oxidative-stress related genetic variants. Genetic variants of SOD2, considered to be reflect oxidative stress metabolisms, might modify the association of phthalate exposure with asthma.