Abstract: Background: Oxidative stress is a central factor in the pathogenesis of Parkinson?s disease (PD). Heme oxygenase-1 (HO-1) is an antioxidant protein expressed in response to oxidative challenge, and its expression levels are inversely correlated with glycogen synthase kinase-3? (GSK3?) activity. Underexpression of HO-1 in concert with an upregulation of GSK3? would result in a less effective antioxidant response and might increase the risk of PD. Methods: We examined two functional polymorphism in the promoter regions of HO-1 (?413, rs2071746) and GSK3? (?157, rs6438552) in a group of 251 Spanish patients with PD and 234 controls. Results: Subjects carrying both the HO-1 (?413, rs2071746) TT genotype and the GSK3? (?157, rs6438552) TT genotype had a four times higher risk of developing PD than subjects without these genotypes (adjusted by age and sex OR?=?4.12; 95% CI?=?1.45?11.71; Bonferroni corrected P?=?0.024). Conclusions: Considering synergistic effects between polymorphisms in oxidative stress-related genes may help in determining the risk profile for PD.

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