We found that the allele A of -1279G/A was significantly associated with PD risk in a northern Chinese population. Subgroup analysis showed that both − 1279G/A and rs1801282 were associated with EOPD and both A allele of -1279G/A polymorphism and G allele of rs1801282 polymorphism within PPARγ gene might be a risk factor for EOPD in a northern Chinese population. In addition, our finding showed that A allele of -1279G/A may increase the risk of male PD and AG + AA genotype may increase the susceptibility of PD in the dominant model. However, there was no mutual effect between the rs3856806 polymorphism and PD in the dominant and recessive model.
PPARγ has been reported to be associated with the development of numerous degenerative diseases. Additionally, an association of the rs1801282 genotype with early-onset AD has been reported in the Finnish population . In the absence of the APOEε4 subgroup with PPARγ Pro12Ala polymorphism (rs1801282), the onset age of AD patients with the Pro/Ala genotype was found 4.6 years earlier than Pro/Pro genotype carriers in northeast China. Another study on Italians reported that the risk of developing AD in Ala carriers was twice as high as that of octogenarian controls. Interestingly, analysis after gender stratification showed that the G allele of rs1801282 played a protective role in females but had an opposite effect in male Caucasians from the UK. Tanner CM et al demonstrated the effect of genetic factors was more obvious in the EOPD subgroup than it in the LOPD subgroup . In a certain sense, above studies seems to tell us rs1801282 is more likely a age-related mutation after so many different racial analysis.
A previous association study on PPARγ gene polymorphism in Japanese patients with Parkinson’s disease with dementia (PDD) (n = 171) and controls (n = 136) reported no significant between-group differences in the genotypic frequencies of the SNPs (rs3856806 and rs1801282) or the haplotype analysis for the 2 PPARγ- SNPs. Yang investigated the PPARγ gene polymorphism (rs3856806 and rs1801282) in a Southern Chinese cohort comprising patients with PD (n = 206) and controls (n = 210) and reported no significant between-group difference in the genotype distribution . Our results are clearly consistent with those of the aforementioned studies; however, we performed further subgroup analysis based on age and sex using a larger sample size from a different geographical area. This is the first study to provide evidence that the A allele of -1279G/A SNP may contribute to increasing PD risk in northern Chinese population. Our findings might contribute toward developing a novel therapy and a feasible means of predicting the risk for PD.
To date, the pathophysiology of PD remains elusive. A review reported that the most probable nosogenesis involves lesions of the ubiquitin-proteasome system (UPS), oxidative stress anomaly, and mitochondrial deficiency. UPS dysfunction might result in excess or misfolded proteins in the brain, in turn resulting in PD development. Rosiglitazone, a PPARγ agonist, not only reduces mHtt aggregates containing ubiquitin and heat shock factor1 (HSF1) but also enhance the function of the UPS, HSF1, and heat shock protein27/70 (HSP27/70) in N2A cells . Moreover, in human neuroblastoma SH-SY5Y cells, rosiglitazone improves the expression of SOD, catalase, Bcl-2, and Bax, which might attribute to the prevention of mitochondrial impairment induced by the 1-methyl-4-phenylpyridinium ion (MPP+). In addition, ciglitazone, a PPARγ agonist, plays a role in protecting neurons from oxidative stress by regulating mitochondrial fusion and fission in hippocampal neurons . Overall, PPARγ play a protective role in the development of PD.
To our knowledge, the rs1801282 G allele variation shows decreased transcriptional activity of PPARγ in vitro, suggesting potential association with PD. -1279G/A is located in the promoter region of PPARγ and the polymorphism of the promoter region tends to affect gene expression and contribute to the occurrence of disease. The ENCODE project and bioinfomatics approaches identified the − 1279G/A(rs7647481) as the cis-regulatory vabriant which exerts the effect of regulating transranscriptional activity, and ultimately contributes to different sensitivity of insulin in primary adipose cells. In addition, Yin Yang 1(YY1) has been confirmed as an allele-specific transcription factor for − 1279G/A (rs7647481) A allele, which may affects the level of PPARγ. Taken together, the − 1279G/A polymorphism is a cis-regulatory vabrian, which may play a role in decreasing transcriptional activity of PPARγ, leading to the low expression level of PPARγ which confers to susceptibility for the development of PD. In fact, the precise molecular mechanism is more complicated than we expect, and hence, further research is required to elucidate the underlying mechanism between variants and disease risk.
Our study had several limitations, such as limited sample size, race, and mutational sites. Therefore, there is a need for more studies with more ethnicities and larger cohorts to assess the association of PPARγ polymorphism with PD susceptibility.