GSK3B基因3'-UTR多态性与阿尔茨海默病发病风险的相关性分析

目的研究中国汉族人群中糖原合成酶激酶3β基因(GSK3B)3'端非翻译区(3'-UTR)基因多态性与阿尔茨海默病(AD)发病风险的相关性。方法采用直接测序的方法,对535例AD病例及464例正常对照的GSK3B基因3'-UTR单核苷酸多态性(SNPs)位点进行基因分型。结果 GSK3B基因3'-UTR各SNPs位点的等位基因频率和基因型分布在AD组和正常对照组之间的差异无统计学意义(P0.05)。其中rs60393216、rs56728675和rs3732361存在强连锁不平衡,其构成的三种单体型的频率在AD组和正常对照组之间的差异无统计学意义(P0.05)。结论 GSK3B基因3'-UTR多态性与中国汉族人群AD发病风险无关。     

单胺氧化酶B基因多态与早发帕金森病的相关性

Objective To investigate the association between polymorphisms in monoamine oxidase B (MAO-B)and early-onset Parkinson's disease(EOPD).Methods Polymerase chsin reactionrestriction fragment length polymorphism was used to identify the genotypes of polymorphisms in MAO-B in 65 patients in EOPD group(early-onset age<50 years),60 in late-onset Parkinson's disease(LOPD) group(late-onset age≥160 years)and 66 healthy controls(<50 years).Results The frequency of AA genotype was higher in EOPD groups(49/65,75.4%)than in healthy controls(34/66,51.5%),and the difference between them was statistically significant(x2=8.075,P=0.018).The frequency of AA genotype between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance.The frequency of AA genotype between male in EOPD group and male healthy controls,between female in EOPD group and female healthy controls had no statistical significance.The frequencies of AA genotype between male in EOPD group and LOPD group,between female in EOPD group and in LOPD group had no statistical significance.The frequency of AA genotype between male in LOPD group and in healthy controls,between female in LOPD group and female healthy controls had no statistical significance.The frequency of A alleles was higher in EOPD group(107/130,82.3%)than in healthy controls(87/132,65.9%)and the difierence between them was statistical significant(x2=9.165,P=0.002).The frequency of A allele between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance. The frequency of A allele was higher in male EOPD group (60/70,85.7%) than in male healthy controls(51/72,70. 8% ), the difference between them was statistically significant (X2 =4. 606, P=0. 032) ;the frequency of A alleles was higher in female in EOPD group (47/60,78. 3% ) than in female healthy controls(36/60,60. 0% ), the difference between them was statistical significance( x2 =4. 728, P = 0. 030). The frequency of A alleles between male EOPD group and male LOPD group, between female EOPD group and female LOPD group had no statistical significance. The frequency of A allele between male LOPD group and male healthy controls, between female LOPD group and female healthy controls had no statistical significance. Conclusions The AA genotype of MAO-B is the risk factor of EOPD. The A allele of MAO-B is a risk factor of EOPD group for both male and female.     

单胺氧化酶B基因多态与早发帕金森病的相关性

Objective To investigate the association between polymorphisms in monoamine oxidase B (MAO-B)and early-onset Parkinson's disease(EOPD).Methods Polymerase chsin reactionrestriction fragment length polymorphism was used to identify the genotypes of polymorphisms in MAO-B in 65 patients in EOPD group(early-onset age<50 years),60 in late-onset Parkinson's disease(LOPD) group(late-onset age≥160 years)and 66 healthy controls(<50 years).Results The frequency of AA genotype was higher in EOPD groups(49/65,75.4%)than in healthy controls(34/66,51.5%),and the difference between them was statistically significant(x2=8.075,P=0.018).The frequency of AA genotype between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance.The frequency of AA genotype between male in EOPD group and male healthy controls,between female in EOPD group and female healthy controls had no statistical significance.The frequencies of AA genotype between male in EOPD group and LOPD group,between female in EOPD group and in LOPD group had no statistical significance.The frequency of AA genotype between male in LOPD group and in healthy controls,between female in LOPD group and female healthy controls had no statistical significance.The frequency of A alleles was higher in EOPD group(107/130,82.3%)than in healthy controls(87/132,65.9%)and the difierence between them was statistical significant(x2=9.165,P=0.002).The frequency of A allele between EOPD group and LOPD group,between LOPD group and healthy controls had no statistical significance. The frequency of A allele was higher in male EOPD group (60/70,85.7%) than in male healthy controls(51/72,70. 8% ), the difference between them was statistically significant (X2 =4. 606, P=0. 032) ;the frequency of A alleles was higher in female in EOPD group (47/60,78. 3% ) than in female healthy controls(36/60,60. 0% ), the difference between them was statistical significance( x2 =4. 728, P = 0. 030). The frequency of A alleles between male EOPD group and male LOPD group, between female EOPD group and female LOPD group had no statistical significance. The frequency of A allele between male LOPD group and male healthy controls, between female LOPD group and female healthy controls had no statistical significance. Conclusions The AA genotype of MAO-B is the risk factor of EOPD. The A allele of MAO-B is a risk factor of EOPD group for both male and female.     

单胺氧化酶B基因多态与早发帕金森病的相关性

目的 探讨单胺氧化酶B(MAO-B)基因型和等位基因与早发帕金森病(early-onset Parkinson's disease,EOPD)的关系.方法 采取聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法,研究65例EOPD患者(<50岁)、60例晚发PD(late-onset Parkinson's disease,LOPD)患者(≥60岁)和66名健康对照者(<50岁)的基因型频率和等位基因频率的分布差异.结果 EOPD组的AA基因型频率(49/65,75.4%)高于健康对照组(34/66,51.5%),差异有统计学意义(x2=8.075,P=0.018);LOPD组分别与EOPD组、健康对照组的从基因型频率比较,差异无统计学意义;男性EOPD组分别与男性健康对照组、男性LOPD组,女性EOPD组分别与女性健康对照组、女性LOPD组的AA基因型频率比较,差异无统计学意义;男性LOPD组与男性健康对照组、女性LOPD组与女性健康对照组的AA基因型频率比较,差异无统计学意义.EOPD组的A等位基因频率(107/130,82.3%)高于健康对照组(87/132,65.9%),差异有统计学意义(X2=9.165,P=0.002);LOPD组分别与EOPD组、健康对照组的A等位基因频率比较,差异无统计学意义;男性EOPD组的A等位基因频率(60/70,85.7%)高于男性健康对照组(51/72,70.8%),差异有统计学意义(x2=4.606,P=0.032);女性EOPD组的A等位基因频率(47/60,78.3%)高于女性健康对照组(36/60,60.0%),差异有统计学意义(x2=4.728,P=0.030);男性LOPD组分别与男性EOPD组、男性健康对照组,女性LOPD组分别与女性EOPD组、女性健康对照组的A等位基因频率比较,差异均无统计学意义.结论 MAO-B的从基因型频率增高是EOPD组发病的危险因素;MAO-B的A等位基因频率增高是EOPD组、男性EOPD组及女性EOPD组发病的危险因素.     

Genetic polymorphisms of superoxide dismutase in Parkinson's disease.

Oxidative stress reactions may contribute to the pathogenesis of Parkinson's disease (PD). The superoxide dismutases potentially play significant roles in PD by detoxifying superoxide radical. We developed genomic DNA and cDNA-based sequencing assays to identify genetic variants in the copper/zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes. No genetic variants were detected in the gene encoding SOD1 in DNA from 45 idiopathic PD cases and 49 controls from a population-based case-control study. However, we identified a previously described polymorphism of the mitochondrial targeting sequence consisting of a C47T in exon 2 of SOD2, which results in an alanine to valine substitution. We analyzed this SOD2 variant in DNA from 155 cases and 231 controls from the same study, using an allele-specific fluorogenic 5' nuclease assay, and found no differences in the distributions of allelic frequencies. These results indicate that SOD gene variants do not contribute to PD pathogenesis.     

Association study between iron-related genes polymorphisms and Parkinson's disease

We have conducted a case-control study in order to test for an association between 8 intragenic polymorphisms of 5 iron-related genes (transferrin, transferrin receptor1, HFE, frataxin and lactoferrin) and Parkinson disease. Comparison of genotypes and allele frequencies did not differ significantly between cases and controls for all studied polymorphisms except the G258S transferrin polymorphism, for which a higher frequency of the G allele was found among cases (p=0.033), particularly among cases with onset older than 60 (p=0.0017) and with negative family history (p=0.022). This finding suggests that genetic variations in the control of iron metabolism may contribute to the pathogenesis of the disease. Received: 23 July 2001, Received in revised form: 8 November 2001, Accepted: 14 November 2001     

铁相关基因多态性与帕金森病的关联分析

目的 探讨铁相关基因转铁蛋白(Tf)258 G/S及转铁蛋白受体(TfR)82 S/G多态性与中国华北和西北地区帕金森病(PD)间的关联. 方法 应用聚合酶链反应-限制性片段长度多态性方法对61例华北地区PD患者(华北PD组)、56例西北地区PD患者(西北PD组)及两地各70名健康对照者之间的Tf258 G/S和TfR 82 S/G的基因型和等位基因分布频率进行检测. 结果 (1)Tf258G/S位点:两PD组的G等位基因和GS基因型均明显高于相应对照组,差异有统计学意义(P＜0.05);而两PD之间、两对照组之间各基因型和等位基因分布差异均无统计学意义(m0.05).(2)TfR 82 S/G位点:两PD组、两对照组之间各基因型和等位基因分布差异均无统计学意义(P＞0.05). 结论 (1)TfG/S位点多态性与华北、西北地区PD的发病可能存在关联,等位基因G、杂合基因型GS增加了PD的易患性.(2)TfR S/G位点多态性与中国华北、西北地区PD患者患病率无关.     

Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer’s disease

The disruption of glycogen synthase kinase 3-beta (GSK3B) homeostasis has implications in the pathophysiology of neuropsychiatric disorders, namely Alzheimer’s disease (AD). GSK3B activity is increased within the AD brain, favoring the hyperphosphorylation of microtubule-associated protein Tau and the formation of neurofibrillary tangles. Such abnormality has also been detected in leukocytes of patients with cognitive disorders. The aim of the present study was to determine the expression of total and phosphorylated GSK3B at protein level in platelets of older adults with varying degrees of cognitive impairment, and to compare GSK3B activity in patients with AD, mild cognitive impairment (MCI) and healthy controls. Sixty-nine older adults were included (24 patients with mild to moderate AD, 22 patients with amnestic MCI and 23 elderly controls). The expression of platelet GSK3B (total- and Ser-9 phosphorylated GSK3B) was determined by Western blot. GSK3B activity was indirectly assessed by means of the proportion between phospho-GSK3B to total GSK3B (GSK3B ratio), the former representing the inactive form of the enzyme. Ser-9 phosphorylated GSK3B was significantly reduced in patients with MCI and AD as compared to controls (p = 0.04). Platelet GSK3B ratio was significantly decreased in patients with MCI and AD (p = 0.04), and positively correlated with scores on memory tests (r = 0.298, p = 0.01). In conclusion, we corroborate previous evidence of increased GSK activity in peripheral tissues of patients with MCI and AD, and further propose that platelet GSK may be an alternative peripheral biomarker of this abnormality, provided samples are adequately handled in order to preclude platelet activation.     

SNCA polymorphisms, smoking, and sporadic Parkinson's disease in Japanese

Several case-control studies and genome-wide association studies have examined the relationships between single nucleotide polymorphisms (SNPs) in the SNCA gene and Parkinson's disease (PD), and have provided inconsistent results. We investigated the relationships between SNPs rs356229, rs356219, rs356220, rs7684318, and rs2736990 and the risk of sporadic PD in Japan using data from a multicenter hospital-based case-control study. Included were 229 cases within 6 years of onset of PD as defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, and smoking. Based on the recessive model, compared with subjects with the CC or CT genotype of SNP rs356220, those with the TT genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.42 (95% CI: 1.002-2.02). In the additive model, SNP rs2736990 was significantly related to the risk of sporadic PD: the adjusted OR was 1.30 (95% CI: 1.002-1.68). There were no significant relationships between SNP rs356229, rs356219, or rs7684318 and the risk of sporadic PD in any genetic model. The additive interactions between SNPs rs356219 and rs356220 and smoking with respect to sporadic PD were significant although the multiplicative interactions were not significant. This study suggests that SNCA SNPs rs356220 and rs2736990 are significantly associated with the risk of sporadic PD in Japanese. We also present new evidence for biological interactions between SNPs rs356219 and rs356220 and smoking that affect sporadic PD.