Molecular genetic study of TNF-α and IL-1α promoter polymorphisms in Parkinson's disease in Taiwan

[[abstract]]Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorder. The hallmarks of PD are death of dopamine neurons in substantia nigra pars compacta and eosinophilic inclusions around the nucleus of neuron from PD patients. The etiology of PD is still not fully understood, but environmental toxicants, oxidative stress, inflammation, and gene dysfunction have thought to evoke PD. The focus of the study is to investigate the association of tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1α) promoter polymorphisms with the risk of PD. The overall genotype distribution at T-1031C and C-857T sites showed significant difference between PD cases and controls (P=0.0062 and 0.0035, respectively). However, only the more frequent -1031 CC genotype was evidently associated with PD (Odds ratio: 2.96, 95% CI: 1.38-7.09, P=0.0085). Using SNPSpD method showed that -1031 and -863 are in strong linkage disequilibrium (D'=0.93, Δ2=0.80). Pairwise Haplotype analysis among the four sites showed that -1031C-863A may act as a risk haplotype among PD cases (Odds ratio=2.18, 95% CI: 1.33-3.69, P=0.0028). Functional study revealed that -1031C allele drove greater transcriptional activity than common allele in Raji cell line. After stimulation with Concanavalin A (ConA), -1031C promoter activity was promoted to a significantly higher level than that of no stimulation. Using lymphoblastoid cells carrying -1031 CC/-863 AA genotype resulted in higher expression of TNF-α compared to cells carrying -1031 TT/-863 CC genotype. For IL-1α gene, the overall genotype distribution was not significantly different at C-889T site. However, when PD and control groups were stratified into >70 years subgroup the CT genotype frequency in PD was significantly less than controls (Odds ratio: 0.31, 95% CI: 0.13-0.71, P=0.0071). It suggested that people carrying -889 CT genotype reduced the probability of PD emergence, even aged. Multivariate analysis demonstrated the possible synergistic effect of the TNF-α promoter common alleles (-1031T, -863C, -857C) to IL-1α CT genotype in control group. In summary, the study demonstrated the association between the TNF-α -1301CC genotype, -1031C/-863A haplotype and susceptibility to PD. In Raji cell line, after stimulation with ConA -1031C allele drove significantly higher transcriptional activity than common allele, even before stimulation. In the onset age > 70 years subgroup, PD carrying IL-1α promoter CT genotype frequency was significantly less than controls, and the synergistic effect of the TNF-α promoter common alleles (-1031T, -863C, -857C) to IL-1α CT genotype in control group.