Analysis of heat-shock protein�70 gene polymorphisms and the risk of Parkinson?s disease

Abstract

Parkinson's disease (PD) involves several genetic and environmental components. Heat-shock protein 70, a chaperone that is up-regulated in stress responses and that refolds protein, may be involved in the pathogenesis of PD. We have investigated the association of polymorphisms -110 A/C, +190 G/C, +1267 A/G, +2074 G/C, and +2437 G/C in the 5' and coding regions of the HSP70-1, HSP70-2, and HSP70-hom genes with the risk of PD by screening DNA samples from 274 PD patients and 183 controls in assays based on the polymerase chain reaction. There was no statistically significant difference in genotype distribution between patients and controls for the three coding-region polymorphisms in HSP70-2 and HSP70-hom. However, for HSP70-1, the overall genotype distribution was significantly different at the -110 site (P=0.004) and tended to be different at the +190 site (P=0.012) between patients and controls. The frequencies of the -110 CC and +190 CC genotypes were significantly higher in PD patients than in controls (P=0.001 and 0.006, respectively). Both -110 CC (odds ratio: 2.91; 95% CI: 1.51-5.96; P=0.002) and +190 CC (odds ratio: 3.59; 95% CI: 1.53-9.88; P=0.006) genotypes were significantly associated with PD. Reporter constructs containing the -110 A allele cloned into a luciferase reporter plasmid drove marginally higher transcriptional activity of HSP70-1 compared with the -110 C allele in both control and heat-shocked IMR32 and 293 cells. Therefore, -110 A/C may be a functional polymorphism in the 5' promoter region of HSP70-1 and may affect susceptibility to PD.

HSP70 (HSPA1) polymorphisms for former workers with chronic mercury vapor exposure

“…In particular, we found the OR adj = 5.58 (p = 0.026) for carriers of CC minor homozygote for the locus HSPA1A (+190G/C) and almost 4-fold statistically significant higher frequency of that genotype in individuals with the CMI diagnoses in combined group (groups 2 and 3) (16.2%) compared with the individuals from the group 1 without that diagnosis (4.3%). These findings are in accordance with the data by Wu et al [25], who reported a significant higher frequency of genotypes -110 CC and 190 CC at HSPA1A in individuals with Parkinson's syndrome vs. control group and suggested their association with neurodegenerative diseases. Moreover, in our study, the high ORs (OR adj = 14.7, p = 0.0015 and OR = 12.41, p = 0.0009) for GG-HSPA1B (+1267A/G) genotype between the combined group (groups 2 and 3) of individuals with the CMI where found, when compared with the group of workers without the disease.…”

Interacting contribution of the five polymorphisms in three genes of Hsp70 family to essential hypertension in Uygur ethnicity

“…In our study, the frequency of −110C allele in control group was 33.6%, which was almost equal to that identified in other areas in Taiwanese at 33.2% (Wu et al 2004). In contrast, the identification in France by Bolla et al (1998) yielded an exceedingly high frequency of 61.6%.…”

“…After restriction enzyme treatment, the reaction mixture was separated on 2% agarose gels. The primers and amplification conditions for the other polymorphisms were according to a report of Wu et al (2004). The accuracy of our screening method was confirmed by direct sequencing of amplified DNA from randomly selected samples (10%), with no difference observed in results between the two methods (data not shown).…”

“…Promoter −110A/C polymorphism in HSPA1A ranks high among the genetic variation most frequently studied in relation to a wide range of clinical endpoints such as Parkinson's disease (Wu et al 2004). In our study, the frequency of −110C allele in control group was 33.6%, which was almost equal to that identified in other areas in Taiwanese at 33.2% (Wu et al 2004).…”

“…As a dominant chaperone, Hsp70 plays an important role in the assembly and transport of newly synthesized proteins within cells, as well as in the removal of denatured proteins. Evidence is accumulating suggesting the involvement of Hsp70 in the pathogenesis of many clinical endpoints, including, for example, atherosclerosis (Xu 2002), Parkinson's disease (Wu et al 2004), high altitude illness (Zhou et al 2005), aging (Singh et al 2006), ischemic stroke (Liu et al 2007), and so on. Moreover, a series of biological or clinical results support the hypothesis that induction of Hsp70 expression in the arterial wall occurs as a physiological response to acute hypertension, i.e., hemodynamic stress or biomechanical stress (Xu et al 1996;House et al 2001;Chang et al 2001).…”