HSP70-hom gene polymorphisms modify the association of diethylhexyl phthalates with insulin resistance

Recent studies suggest that diethylhexyl phthalates (DEHP) could contribute to the development of insulin resistance (IR) through oxidative stress, and that heat shock protein (HSP) could be related with the association between DEHP and IR. Therefore, we evaluated the effect modification of genetic polymorphisms of HSP70-hom, an oxidative stress related gene, on the relation between exposure to DEHP and IR. We obtained repeated blood and urine samples from 414 elderly female participants and measured urinary levels of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) as metabolites of DEHP. We also measured serum levels of fasting glucose and insulin, derived the homeostatic model assessment (HOMA) index to assess IR, and genotyped two HSP70-hom polymorphisms (rs2227956 and rs2075800). A mixed effect model and penalized regression spline were used to estimate the associations between DEHP exposure and IR by genetic polymorphisms. The molar sum of MEHHP and MEOHP (∑DEHP) were significantly associated with HOMA (β = 0.30, P = 0.022). When stratified by genotype at rs2227956, the relationship between ∑DEHP and HOMA was statistically significant in participants with TT (β = 0.32, P = 0.048) or TC (β = 0.60, P = 0.008), while at rs2075800 there was a marginal association for the GA genotype (β = 0.33, P = 0.097). When haplotypes were constituted across the two HSP70-hom polymorphisms (rs2227956 and rs2075800), the association was apparent only in participants with the T-A haplotype (β = 0.39, P = 0.029). Our study suggests that HSP70-hom polymorphisms modify the association of DEHP with IR.