细胞色素P4501A1基因多态性与帕金森病关系的研究

目的　研究细胞色素P45 0 1A1(CYP1A1)MspⅠ基因型和第 7外显子 4889位异亮氨酸 (Ile) 缬氨酸 (Val)基因型与帕金森病 (PD)的关系。方法　采用PCR RELP和ASA技术检测 78例PD患者和 15 2例健康人CYP1A1MspⅠ和Ile Val基因多态性 ,并分析 2组基因型和等位基因分布频率。结果　CYP1A1基因MspⅠ、Ile Val多态位点 ,各基因型和等位基因频率在PD组和对照组间比较无显著性差异 (P >0 0 5 )。结论　细胞色素P45 0 1A1MspⅠ和Ile Val基因多态性与PD患者的遗传易患性可能无关 ,CYP1A1基因多态并不是PD的遗传易患因子。     

新疆地区帕金森病患者COMT基因多态性与临床症状的关系分析

目的探讨儿茶酚胺氧位甲基转移酶(COMT)基因G1947A多态性与新疆地区帕金森病(PD)的相关性,比较其多态性对PD患者临床症状的影响。方法收集新疆地区231例PD患者(PD组)和248例健康对照者(对照组)为研究对象。PD组按照PD相关评分标准完成统一的调查表、统一帕金森病评定量表(UPDRS)、Hoehn-Yahr(H-Y)分级量表、简易智能状态检查(MMSE)量表、日常生活能力问卷(ADL)和神经精神问卷(NPI)评分。应用聚合酶链反应-限制性片段长度多态性分析法(PCR-RFLP)分析COMT-G1947A多态性,比较新疆地区COMT-G1947A多态性对PD临床症状的影响。结果 (1)在年龄≤61岁研究对象中,PD组COMT-G1947A基因型分布与对照组比较,差异有统计学意义(P=0.031);PD组G/A基因型频率(52.6%)高于对照组(36.0%)。(2)总体样本中,COMT-G1947A不同基因型间的PD患者是否"N"字型进展,差异有统计学意义(P=0.023);进一步按性别、民族、年龄进行分层分析,女性、维吾尔族、年龄61岁群体中PD患者3种COMT基因型间是否"N"字型进展,差异有统计学意义(分别为P=0.032、P=0.034、P=0.032)。(3)总体样本中,COMT-G1947A的A等位基因对PD组临床症状的影响差异无显著性(均P0.05);进一步按性别、民族、年龄进行分层分析,女性PD患者COMT-G1947A的A等位基因对其首发部位的影响差异有显著性(P=0.018),汉族、年龄61岁PD患者COMT-G1947A的A等位基因对PD患者是否为单侧起病的影响差异有显著性(分别为P=0.045、P=0.038)。结论 (1)COMT-G1947A多态性可能是新疆地区年龄≤61岁PD患者的潜在易感位点,G/A基因型是其易感基因型;(2)新疆地区PD患者携带COMT基因A/A基因型者"N"字型进展的发生率可能较高,这种趋势主要在女性、维吾尔族、年龄61岁PD患者中存在;(3)COMT-G1947A多态性A等位基因对女性PD患者首发部位、汉族、年龄61岁是否单侧起病可能有影响。     

新疆地区维吾尔族、汉族单胺氧化酶B基因多态性与帕金森病的相关性研究

目的探讨中国新疆地区维吾尔族、汉族人群多巴胺代谢酶-单胺氧化酶B(MAO-B)基因内含子13 G/A多态性与帕金森病(PD)遗传易感性的关系,以及PD患者基因型与临床特点的关系。方法研究对象为中国新疆地区241例PD患者(PD组),其中维吾尔族95例(维吾尔族PD组)、汉族146例(汉族PD组);另选择247名健康对照者(对照组),其中维吾尔族104例、汉族143例。收集并分析PD患者临床资料;采用聚合酶链反应-限制性片段长度多态性分析法(PCR-RLFP)进行MAO-B基因多态性分析,研究基因型和等位基因频率分布情况。结果①PD组与对照组MAO-B基因G/A基因型及等位基因频率差异无统计学意义。②维吾尔族PD组和汉族PD组与对照组的基因型及等位基因频率差异无统计学意义。③男性PD组和女性PD组与相同性别对照组的基因型及等位基因频率分布差异无统计学意义。④发病年龄≤70岁PD患者与对照组基因型频率、等位基因频率差异无统计学意义;>70岁的PD患者与对照组基因型频率、等位基因频率差异有统计学意义。⑤新疆地区维吾尔族、汉族PD患者的3种基因型的临床特点差异无统计学意义。结论MAO-B基因的AA基因型与A等位基因频率增高是发病年龄>70岁新疆维吾尔族和汉族PD患者的危险因素。PD患者MAO-B基因3种基因型的临床特点无差别。     

PINK1基因T313M多态性与新疆维吾尔族帕金森病的关系研究

目的探讨PINK1基因第4外显子T313M的多态性与新疆维吾尔族(维族)帕金森病(PD)的关系。方法对175例维族原发性PD患者(PD组)及163例维族健康体检者(对照组)提取基因组DNA,采用PCR扩增所需PINK1基因第4外显子T313M基因片段,用限制性内切酶酶切技术测定其基因型和等位基因,再进行测序分析验证。结果 PD组PINK1基因T313M的T/T基因型频率为2.9%,C/C基因型频率为97.1%,T等位基因频率为2.9%,C等位基因频率为97.1%;对照组PINK1基因T313M的T/T基因型频率为1.2%,C/C基因型频率为98.8%,T等位基因频率为1.2%,C等位基因频率为98.8%。两组间PINK1基因T313M多态性的比较差异无统计学意义(P0.05)。结论 PINK1基因第4外显子T313M多态性与新疆维族PD患者的遗传易感性无关。     

儿茶酚胺氧位甲基转移酶-287A/G基因多态性与精神分裂症的关联性研究

目的 探讨儿茶酚胺氧位甲基转移酶(COMT)基因-287A/G多态性与精神分裂症的关系.方法 纳入232例符合美国精神障碍诊断与统计手册第四版(DSM-Ⅳ)诊断标准的精神分裂症患者和141名正常对照,采用限制性片段长度多态技术测定受试者的COMT基因-287A/G多态性.结果 COMT基因-287A/G多态性突变率为10%,患者组和正常对照组间该多态性基因型及基因频率差异无统计学意义(P＞0.05),按性别分层后比较结果仍同前;不同家族史患者组间的上述差异也无统计学意义;该多态性基因型在精神分裂症阳性亚型、阴性亚型、混合型和对照组中分布差异具有统计学意义(P＜0.05),各亚型与对照组比较差异无统计学意义,但G/G基因型在阴性亚型出现的频率是混合型的6.30倍(OR=6.300),G等位基因在阴性亚型出现的频率是混合型的1.859倍(OR=1.859).结论 COMT基因-287A/C多态性在不同亚型精神分裂症患者中存在差异,G/G基因型和G等位基因可能是精神分裂症阴性亚型的危险因素.     

基因多态性与山东临沂地区激素性股骨头坏死遗传易感性的关联*

背景：近年来有研究表明激素性股骨头坏死患者的发病与遗传易感因素有关。 目的：探讨临沂地区人群中候选基因单核苷酸多态性与激素性股骨头坏死的关联。 方法：纳入分析63例激素性股骨头坏死患者和71例使用激素无股骨头坏死的对照组患者的激素总剂量并测定两组ApoB基因C7623T，G12619A，CYP1A2基因G2964A共3个位点的基因多态性，分析它们的基因型与等位基因频率的分布。 结果与结论：两组激素治疗的总剂量比较差异无显著性意义，ApoB C7623T位点TT基因型和T等位基因出现的频率在激素性股骨头坏死组明显高于对照组(P < 0.05)。提示CYP1A2G2964A与ApoB C7623T的基因多态性可能与激素性股骨头坏死的遗传易感性有关。CYP1A2G2964A与ApoB C7623T的基因多态性的协同作用与激素性股骨头坏死相关联。     

新疆维吾尔族、汉族帕金森病患者α-突触核蛋白SNCA基因多态性与临床症状的关系

目的探讨新疆维吾尔族、汉族帕金森病(PD)患者α-突触核蛋白SNCA基因多态性与临床症状的关系。方法应用PCR-限制性片段长度多态性分析法对新疆地区的90例维吾尔族和135例汉族PD患者进行SNCA基因rs3822086位点多态性分析。采集相关临床资料;采用H-Y分期法判断PD严重程度;采用统一PD评定量表(UPDRS)、日常生活能力问卷(ADL)、MMSE和神经精神问卷(NPI)进行评分。比较SNCA基因rs3822086位点不同基因型PD患者间临床症状的差异。结果基因检测结果显示,SNCA基因rs3822086位点C/T基因型111例,T/T基因型61例,C/C基因型53例;不同基因型PD患者间年龄、性别、民族及病程的差异均无统计学意义。不同基因型PD患者间H-Y分期的差异无统计学意义(P=0.237);PD严重程度的差异无统计学意义(P=0.068);首发症状的差异无统计学意义(P=0.746);UPDRSⅡ评分的差异无统计学意义(P=0.598);UPDRSⅢ评分的差异无统计学意义(P=0.815);UPDRSⅣ评分的差异无统计学意义(P=0.096);ADL评分的差异无统计学意义(P=0.464);MMSE评分的差异无统计学意义(P=0.475)。SNCA基因rs3822086位点T/T基因型PD患者NPI评分明显高于C/C基因型PD患者(P0.05)。结论新疆维吾尔族、汉族PD患者SNCA基因T/T基因型在神经精神症状方面的风险要高于C/C基因型,其他临床症状与SNCA基因多态性无关。     

Omi/Htra2基因1195G/A多态性与帕金森病的相关性研究

目的 探讨中国汉族人群Omi/Htra2基因编码区1195G/A 位点的单核苷酸多态性(SNP)与帕金森病(PD)发病的关系.方法 采用聚合酶链反应-限制性酶切片段长度多态性(PCR-RFLP)技术,检测56例PD患者和109例健康人的Omi/Htra2基因编码区1195G/A位点多态性的基因型及等位基因频率.结果 56例PD病例中Omi/Htra2基因1195G/G基因型55例,G/A杂合子1例；对照组中109例全部为G/G基因型.结论 中国汉族人群Omi/Htra2基因编码区1195G/A杂合子可能是PD的患病因素.     

parkin基因启动子区-258T/G多态性增加晚发帕金森病的发病风险

目的探讨parkin基因启动子区-258T／G多态性位点与帕金森病(Parkinson’s disease，PD)的相关性，尤其是该多态与PD发病年龄的关系。方法应用聚合酶链反应(PCR)、变性高效液相和测序等方法分析parkin基因-258T／G多态性位点在PD患者和健康对照间分布频率的差异。结果检测了299例PD患者和156名健康对照。总体分析发现，PD组G等位基因频率和T／G G／G基因型频率高于对照组，但差异无显著意义。将PD组按年龄分层后，60岁以上PD患者parkin基因-258T／G多态G等位基因频率(56．6％)明显高于健康对照组(42．6％)，OR=1．76，95％CI为1．15-2．69(P=0．0064)，而60岁以下发病者与对照相比差异无显著意义。相应的基因型频率(T／G G／G)在60岁以上发病PD组为80．9％，对照组为69．9％，两者虽未达统计学差异，但PD组明显高于对照组。OR=1．82，95％CI为0．87-3．88。年龄分层后的趋势分析显示相对危险度与PD发病年龄间存在正相关联系。结论研究结果证实-258T／G多态可能是中国人晚发PD的一个危险因素。     

谷胱甘肽S-转移酶P1~105基因多态性与高原环境下人体运动能力的关系

背景: 谷胱甘肽S-转移酶具有清除活性氧、提高机体抗氧化能力的作用。 目的：分析谷胱甘肽S-转移酶P1~105基因多态性与高原环境下人体运动能力的关联性。 设计、时间及地点：对照比较分析,于2007年在解放军体育进修学院完成。 对象：实验组86名高原登山运动员为在高原环境下具有较强的作业能力的特定人群,对照组为解放军体育学院随机选取的90名健康学员。 方法：采集86名高原登山运动员及90名健康学员的血样,提取基因组DNA,采用PCR-RFLP技术检测谷胱甘肽S-转移酶P1~105基因多态性,分别比较高原登山运动员与平原汉族对照人群间谷胱甘肽S-转移酶P1~105等位基因和基因型的分布。 主要观察指标：谷胱甘肽S-转移酶P1~105基因型的分布。 结果：共检测到谷胱甘肽S-转移酶P1~105基因3种基因型：变异杂合型(A/G)、变异纯合型(G/G)、野生基因型(A/A)。实验组谷胱甘肽S-转移酶P1~105的G等位基因、变异基因型(A/G+G/G)的频率皆明显低于对照组(P < 0.01)。以变异基因型作为暴露因素,求得OR＝2.19 ,95% CI=1.16~4.13,提示在高原环境下,与具有谷胱甘肽S-转移酶P1~105野生基因型人的运功能力比较,具有谷胱甘肽S-转移酶P1~105变异基因型人的运动能力下降了1.19倍。 结论：谷胱甘肽S-转移酶P1~105基因多态性与高原环境下人体运动能力相关,野生基因型表现出明显的运动优势。     

Genetics of neurofibromatosis 1 and the NF1 gene

Neurofibromatosis 1 serves as a paradigm for understanding the principles of human genetics. The concepts of gene mutation, penetrance of the condition, variable clinical expressivity, mosaicism, age-dependent expression of clinical manifestations, and pleiotropy are evident in this autosomal dominant condition. The lack of genotype-phenotype correlation, except the whole-gene deletion phenotype, leads to speculation on modifiers of the haploinsufficient state of the NF1 gene product neurofibromin. The variant form of neurofibromatosis, neurofibromatosis Noonan's syndrome, suggests potential interaction of independent biochemical pathways. Identification of the NF1 gene led to the discovery of its role in ras signal transduction. Neurofibromin is a negative regulator of intracellular ras signaling. This observation now provides the framework for the development of rational medical therapies. In addition, knowledge of the molecular basis of the variable expression of clinical manifestations could provide better anticipatory guidance and more effective management of the medical complications that are associated with this condition.     

The PON1 gene and detoxication

It has been assumed since its discovery that serum paraoxonase (PON1) plays a major role in the detoxication of specific organophosphorus compounds. It was also assumed that individuals with low PON1 activity would be more susceptible to paraoxon/parathion poisoning than individuals with higher PON1 activity. Evidence supporting this hypothesis was provided by injection of rabbit PON1 into rodents. Injected PON1 protected against paraoxon toxicity in rats and chlorpyrifos oxon toxicity in mice. The recent availability of PON1 knockout mice has provided an in vivo system with which one can more closely examine the role of PON1 in detoxication. PON1 knockout mice demonstrated dramatically increased sensitivity to chlorpyrifos oxon and diazoxon and moderately increased sensitivity to the respective parent compounds. The PON1 knockout mutation also resulted in the elimination of liver PON1 activity, accounting for the dramatic increase in sensitivity to chlorpyrifos oxon and diazoxon. Totally unexpected was our finding that the PON1 knockout mice were not more sensitive to paraoxon. This was particularly surprising in light of the earlier enzyme injection experiments. Differences in the relative catalytic efficiencies of rabbit vs. mouse PON1 for the specific oxon forms explain these observations. Mouse PON1 has good catalytic efficiency for the hydrolysis of diazoxon and chlorpyrifos oxon, but a poor efficiency for paraoxon hydrolysis relative to rabbit PON1. The human PON1Q192 isoform has a catalytic efficiency similar to that of mice, whereas the human PON1R192 isoform has a much better catalytic efficiency, predicting that individuals expressing high levels of the PONIR192 isoform may have increased resistance to paraoxon toxicity.     

Akt1 gene deletion and stroke

Activation of Akt has been implicated as a major contributor to neuronal survival after an ischemic insult. Numerous neuroprotective agents have been shown to augment Akt activity, suggesting that this protein represents a major mechanism of cellular salvage after injury. Estrogen is known to augment Akt, but the possibility that Akt plays a differential role in the male and female brain has yet to be evaluated. In this study, we employed both pharmacological and genetic approaches to investigate the role of Akt in stroke. Utilizing a focal stroke model we show that deletion of the Akt1 isoform does not affect stroke outcome in either male or female mice. Akt1 deficient mice had equivalent levels of phosphorylated Akt (p-Akt) when compared to their WT controls following stroke suggesting that alternative isoforms can compensate for Akt1 loss. Secondly, estrogen's neuroprotective effect is maintained in Akt1^−/− mice and estrogen exposure did not enhance p-Akt levels in WT female mice. Thirdly, we show that inhibiting Akt using the direct pan-Akt inhibitor triciribine has no effect on stroke outcome despite dramatic reductions in p-Akt. Our study demonstrates the limitations of genetic mouse models and suggests that the importance of Akt to ischemic outcome remains unclear.     

Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia

Interleukin-1β (IL-1β) and neuregulin-1 (NRG-1) have an important role in development of the central nervous system. Several recent studies suggest that their genetic polymorphisms are associated with schizophrenia. We studied the effects of the IL-1β gene (IL-1B) -511 and NRG-1 SNP8NRG221533 polymorphisms and their interactions on the risk and age of onset of schizophrenia in 113 Finnish schizophrenic patients and 393 healthy controls. The allele and genotype frequencies of IL-1B and NRG-1 did not differ between schizophrenic patients and healthy controls, but the risk of schizophrenia was more than 10 times higher (odds ratio 10.20, 95% CI 2.53–41.09, p = 0.001) among subjects with the IL-1B 2.2, NRG-1 CC genotypes compared to subjects with the IL-1B 2.2, NRG-1 T-allele carriage. There was also a trend for an association between the interaction between IL-1B and NRG-1 polymorphisms and the age at onset of schizophrenia (χ² = 2.80; df = 1; p = 0.09, log rank test). IL-1B-511 allele 1 homozygotes had a significantly higher age of onset than allele 2 carriers (mean age of onset 25.9 ± 7.7 and 22.7 ± 5.4 years, t-test: t = 2.46; p = 0.032). Our results suggest that there is an interaction between the IL-1B and NRG-1 genes in schizophrenia. In addition, the IL-1B-511 polymorphism seems to be associated with the age at onset of schizophrenia.     

Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia

Interleukin-1beta (IL-1beta) and neuregulin-1 (NRG-1) have an important role in development of the central nervous system. Several recent studies suggest that their genetic polymorphisms are associated with schizophrenia. We studied the effects of the IL-1beta gene (IL-1B) -511 and NRG-1 SNP8NRG221533 polymorphisms and their interactions on the risk and age of onset of schizophrenia in 113 Finnish schizophrenic patients and 393 healthy controls. The allele and genotype frequencies of IL-1B and NRG-1 did not differ between schizophrenic patients and healthy controls, but the risk of schizophrenia was more than 10 times higher (odds ratio 10.20, 95% CI 2.53-41.09, p = 0.001) among subjects with the IL-1B 2.2, NRG-1 CC genotypes compared to subjects with the IL-1B 2.2, NRG-1 T-allele carriage. There was also a trend for an association between the interaction between IL-1B and NRG-1 polymorphisms and the age at onset of schizophrenia (chi(2) = 2.80; df = 1; p = 0.09, log rank test). IL-1B-511 allele 1 homozygotes had a significantly higher age of onset than allele 2 carriers (mean age of onset 25.9 +/- 7.7 and 22.7 +/- 5.4 years, t-test: t = 2.46; p = 0.032). Our results suggest that there is an interaction between the IL-1B and NRG-1 genes in schizophrenia. In addition, the IL-1B-511 polymorphism seems to be associated with the age at onset of schizophrenia.     

遗传性痉挛性截瘫患者ERDA1和SEF2-1基因三核苷酸重复序列的研究

目的对ERDA1基因CAG/CTG和SEF2-1基因CTG重复序列数目的遗传性痉挛性截瘫(HSP)患者及正常人群中的分布和二者在逐代传递中的动态变化进行研究.方法采用PCR扩增,聚丙烯酰胺凝胶电泳,GeneS-can和Genotype软件分析的方法,对7个有2～3代样本的HSP家系中的62名HSP患者和家系中105名表型正常的患者亲属,22名散发患者和31名散发患者的一级亲属,以及116名无血缘关系的正常人检测ERDA1基因CAG/CTG和SEF2-1基因CTG重复序列的数目.结果ERDA1基因CAG/CTG重复序列的数目在正常人中范围为9～82(平均26.35±20.35),HSP患者为9～85(平均28.35±23.41),患者亲属为9～87(平均26.36±22.06).SEF2-1基因CTG重复序列的数目在正常人中范围为23～49(平均30.90±6.95),HSP患者为24～57(平均31.17±7.99),患者亲属为18～53(平均30.37±7.02).两种三核甘酸重复序列数目在HSP患者与患者亲属之间,以及患者与无关正常人群之间比较均无显著性差异.尽管在逐代传递中ERDA1基因CAG/CTG重复序列数目有一定的动态变化,但与发病年龄和疾病的严重程度无关.而SEF2-1基因CTG重复序列数目在各代间稳定传递.结论ERDA1基因CAG/CTG和SEF2-1基因CTG重复序列数目与HSP表型无相关关系.