ATXN8 −62 G/A promoter polymorphism and risk of Taiwanese Parkinson's disease

Background and purpose We recently reported a novel −62 G/A polymorphism within ataxin 8 (ATXN8) gene promoter region, with −62 G displaying significantly higher luciferase activity compared with −62 A. Phenotypic variability in spinocerebellar ataxia type 8 (SCA8) has been suggested, and large SCA8 repeats were found in patients with Parkinson's disease (PD). We aimed to investigate the association of ATXN8 −62 G/A polymorphism with the risk of Taiwanese PD, and identify the trans‐acting factor modulating the ATXN8 promoter activity. Methods A case–control study in a cohort of 569 PD cases and 547 ethnically matched controls was conducted by polymerase chain reaction (PCR) and restriction enzyme analysis. The trans‐acting factor binding to the ATXN8 promoter was examined by chromatin immunoprecipitation (ChIP)‐PCR assay, cDNA co‐transfection and luciferase reporter assay. Results When genotype distribution was calculated by comparing the rare AA genotype with the GG + GA genotypes (recessive model), a significant difference was found (P = 0.035, 1 df). Individuals carrying AA genotype exhibited a decreased risk of developing PD (odds ratio: 0.73; 95% CI: 0.55–0.98, P = 0.035). After stratification by age, individuals over 60 years of age carrying AA genotype demonstrated a further decrease in the risk of developing PD (odds ratio: 0.64; 95% CI: 0.43–0.96, P = 0.030). ChIP‐PCR and cDNA over‐expression revealed that CCAAT/enhancer‐binding protein alpha binds to the ATXN8 proximal promoter to upregulate ATXN8 expression in neuroblastoma SK‐N‐SH cells. Conclusions Our data suggest that ATXN8 −62 G/A polymorphism plays a role in Taiwanese PD susceptibility.