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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-3β (GSK3β) activity. Underexpression of HO-1 in concert with an upregulation of GSK3β 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 GSK3β (−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 GSK3β (−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.

For the first time, the multilocus approach by the set-association method has been applied for the analysis of a cluster of five genes [tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-8, IL-1alpha and IL-10] involved in the brain neuroinflammatory pathway in Parkinson's disease (PD), in a well-defined group of 197 PD patients and 173 control subjects from Spain. Set-association analysis did not reveal an independent or an interactive effect of these inflammatory genes on the PD risk.

Common genetic variants (rs5848 and rs646776) have been reported as regulators of blood progranulin (GRN) levels in healthy individuals.To assess the influence of rs5848 and rs646776 polymorphisms in both serum GRN level and risk for common neurodegenerative diseases, we studied 304 patients with Parkinson's disease (PD), 217 individuals with Alzheimer's disease, 131 subjects with mild cognitive impairment, and 126 controls.The mean concentration of GRN in the serum of patients with PD (319.6 ng/ml) was significantly lower than that of controls (371.5 ng/ml; P = 0.009), whereas there were no significant differences between other groups. Rs646776 minor allele carriers had lower serum GRN levels in each of the four subgroups. There was no correlation between rs5848 genotypes and serum GRN concentrations. Genotype frequencies of both polymorphisms did not differ between groups.Reduced circulating GRN levels might be associated with PD risk by pathogenic factors different from rs5848 and rs646776 polymorphisms.

A loss in the regulatory mechanism that controls tau phosphorylation in normal brain is suggested to cause tau hyperphosphorylation in Alzheimer's disease (AD) brain and the development of neurofibrillary tangles (NFT). 14-3-3 zeta protein and butyrylcholinesterase (BCHE) are associated with NFT in AD brain and stimulate tau phosphorylation. In a case-control study in 231 AD patients and 221 healthy controls, we examined whether the combined effects between 14-3-3 zeta (rs964917 and rs983583) and BCHE (K variant) polymorphisms might be responsible for susceptibility to AD. Subjects carrying both the BCHE K allele and the 14-3-3 zeta rs964917 G/G genotype (OR = 0.44, 95% CI = 0.20-0.95, P = 0.03), or 14-3-3 zeta rs983583 G/G genotype (OR = 0.46, 95% CI = 0.21-1.00, P = 0.05) had a lower risk of developing AD than subjects without these risk genotypes. Considering synergistic effects between polymorphisms in tau phosphorylation relate-genes may help in determining the risk profile for AD.