GSTA1、GSTO2、和NQO1基因多态性和肌萎缩侧索硬化遗传易感性的研究
|
摘要
目的:肌萎缩侧索硬化(amyotrophic lateral sclerosis,ALS)为成年起病的神经系统变性疾病,发病率为1-2/10万。其特点是选择性的大脑和脊髓上下运动神经元的缺失。大约90%的病例为散发型ALS(sporadic amyotrophic lateral sclerosis,SALS),5-10%的病例为家族型ALS ( familial amyotrophic lateral sclerosis,FALS)。FALS和SALS在临床特点和病理表现方面并无明显区别,这说明它们在运动神经元变性方面有共同的机制。引起ALS的病因和确切发病机制目前尚不明确,只在15-20%的FALS中发现有编码Cu-Zn超氧化物歧化酶(Cu /Zn superoxide dismutase, Cu /ZnSOD1)基因的突变。有证据表明,在FALS和SALS中氧化应激会导致运动神经元损伤;且在SALS病人中枢神经组织中发现氧化应激的的标志物含量增加,这表明氧化应激在ALS中起重要作用。因此,寻找潜在的和ALS相关的抗氧化防御系统的基因变异就很有必要。
近来文献报道,Nrf2/ARE信号通路的激活可在多种组织中诱导一系列内源性的细胞保护基因上调,其中包括抗氧化酶、抗氧化蛋白、抗炎和解毒的蛋白。这些抗氧化酶在神经组织中的表达增加,可对抗氧化应激。谷胱甘肽硫转移酶(GSTs)和醌氧化还原酶1(NQO1)是其中的两种Nrf2/ARE通路下游经典的抗氧化酶。
GSTs在哺乳动物细胞中有七种(Alpha、Mu、Omega、Pi、Sigma、Theta和Zeta)。GSTA1和GSTO2分别是最近定义的GSTs一个亚型。最近研究表明,GSTA1基因启动子临近区域存在C69T多态性位点,等位基因的变化会引起GSTA1的表达下降。在人类,GSTO2存在编码区N142D多态性,这会使GSTO2活力下降。NQO1基因多态性最常见的是其第6外显子609碱基对C→T的点突变,此位点多态性导致其编码蛋白质脯氨酸/丝氨酸的改变,这一突变会使该酶活性减弱。本研究旨在探讨GSTA1、GSTO2和NQO1基因多态性与ALS遗传易感性的关系,从分子水平为ALS的预防和诊治提供依据。
方法:采用病例-对照研究方法,以143例SALS和210例健康对照为研究对象。采集外周静脉血5ml,参照血液基因组DNA提取试剂盒说明书提取外周血白细胞DNA。用聚合酶链式反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)方法对GSTA1、GSTO2和NQO1 3个单核苷酸多态性(single nucleotide polymorphism ,SNP)位点进行基因分型。
数据统计分析采用SPSS11.5版软件包(SPSS Company, Chicago,Illinois,USA)进行处理。正常对照组与ALS组基因型频率分布行χ2检验做Hardy-Weinberg平衡分析。ALS组与对照组的年龄差异采用t检验。基因型和等位基因频率分布比较采用χ2检验,以非条件logistic回归方法计算表示相对风险度的比值比(odds ratio,OR)及其95%可信区间(confidence interval,CI)。P<0.05作为差异有显著性的标准。
结果:1.健康对照组GSTA1、GSTO2、NQO1各基因型实际数与预期数比较,均没有显著性差异(分别为P =0.74,P =0.42,P=0.10),符合Hardy-Weinberg平衡,说明健康对照组样本具有群体代表性。SALS组GSTA1、GSTO2、NQO1位点各基因型实际数与预期数比较,也符合Hardy-Weinberg平衡,也均没有显著性差异(分别为P=0.78,P=0.10,P=0.82),说明样本具有群体代表性。
2. GSTA1基因的三种基因型频率(CC、CT、TT)在ALS组和健康对照组中分布分别是:79.72%、18.88%、1.40%和76.19%、21.90%、1.91%,结果显示两组之间比较无统计学意义(P =0.44)。GSTA1C69T多态的C和T等位基因在ALS组和健康对照组中的频率分布分别为89.16%、10.84%和87.14%、12.86%,两组间比较无显著性差异(P =0.42)。与CC基因型比较, CT基因型并不增加患ALS的风险(OR=0.82,95%CI=0.48～1.40),TT基因型也不增加患病风险(OR=0.70,95%CI=0.13～3.90),CT+TT基因型的结果与此一致(OR=0.81,95%CI=0.49～1.37)。
3. GSTO2基因的三种基因型频率(NN、ND、DD)在ALS组和健康对照组中分布分别是:47.55%、46.85%、5.60%和66.67%、30.95%、2.38%,结果显示两组之间比较有显著性差异(P =0.001),ALS组中ND基因型和DD基因型频率(52.45%)明显高于对照组(33.33%)。GSTO2N142D多态的N和D等位基因在ALS组和健康对照组中的频率分布分别为70.97%、29.03%和82.14%、17.86%,两组间比较差异有显著性(P =0.000) ;ALS组中,D等位基因频率明显高于健康对照组(29.03%比17.86%)。与NN基因型比较,ND+DD基因型亦增加患病风险(OR=2.21,95%CI=1.43～3.41),分别计算ND基因型和DD基因型后发现,携带ND基因型可以增加ALS的患病风险(OR=2.12,95%CI=1.36～3.32),而携带DD基因型则更容易增加ALS的患病风险(OR=3.30, 95%CI= 1.04～10.45)。
4. NQO1基因的三种基因型频率(CC、CT、TT)在ALS组和健康对照组中分布分别是:27.97%、48.95%、23.08%和22.86%、55.71%、21.43%,统计结果显示两组之间比较无统计学意义(P =0.42)。NQO1C609T多态的C和T等位基因在ALS组和健康对照组中的频率分布分别为52.45%、47.55%和50.71%、49.29%,两组间比较无显著性差异(P =0.65)。与CC基因型比较,CT基因型、TT基因型和CT+TT基因型均不增加患ALS的风险,分别为OR=0.72, 95%CI=0.43～1.20;OR=0.88,95%CI=0.48～1.63;OR=0.76,95%CI=0.47～1.24。
5. GSTA1、GSTO2和NQO1各基因型在SALS各分层亚组之间分布的比较
GSTA1基因,以疾病首发部位分层,CC基因型和CT+TT基因型在球部起病和脊髓起病之间比较分布无区别(P =0.78);以病程分层,在小于等于36月组和大于36月组中,CC基因型和CT+TT基因型的分布无差异(P =0.21);以首发年龄分层,在小于等于45岁组和大于45岁组中,CC基因型和CT+TT基因型的分布也无差异(P =0.90);以性别分层,在男女性别之间,CC基因型和CT+TT基因型的分布也无差异(P =0.73)。
GSTO2基因,在以疾病首发部位、病程分层和首发年龄分层中,NN基因型、ND基因型和DD基因型在各亚组间分布无差别(分别为P =0.77、P =0.23、P =0.54);以性别分层中,NN基因型和ND+DD基因型在两亚组间分布无差别(P=0.24)。
NQO1基因,在以疾病首发部位、病程分层、首发年龄分层和性别分层后,CC基因型、CT基因型和TT基因型在各亚组间分布无差别(分别为P =0.81、P =0.27、P =0.99、P =0.31)。
结论:
1.携带GSTO2N142D基因ND基因型、DD基因型、尤其是DD基因型可能增加SALS的发病危险性,因此,ND基因型和DD基因型可能为ALS的潜在危险因素。
2.NQO1C609T和GSTA1C69T的基因多态性可能和SALS的遗传易感性无关。
3.GSTA1C69T基因、GSTO2N142D基因和NQO1C609T各基因型分布与ALS的首发部位、病程、首发年龄和性别之间无相关性。
Objective: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder, with an incidence of 1- 2 per 100 000. It is characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Approximately the 90% of cases are sporadic (SALS),the others are the familial cases (FALS).FALS are clinically and pathologically indistinguishable from SALS, suggesting a common mechanism of motor neuron degeneration. Until now,the etiopathogenisis and exact mechanisms underlying ALS are still less clear. In 15-20% of familial cases, mutations have been found in the gene encoding Cu-Zn superoxide dismutase (SOD1). In both FALS and SALS there is evidence that oxidative stress contributes to motor neuron injury, several studies revealed a significant increase in markers of oxidative stress in CNS tissue in SALS cases, so oxidative stress may play an important role in the pathology of ALS. Thus it is worthwhile screening for defective function in components of the anti-oxidant defense system for potential associations with ALS.
Recently, it is reported that the activation of Nrf2/ARE signaling pathway could induce a series of antioxidant enzyme, antioxidant protein, anti-inflammatory and antitoxic protein. The expression of those antioxidant enzymes in nervous system exhibited broad neuroprotection against oxidative stress. The classic antioxidant enzyme glutathione S-transferases (GSTs) and NADPH quinone oxidoreductase 1 (NQO1) were two kinds of a series of downstream protein of Nrf2/ARE pathway.
There are seven isoforms of GST (Alpha, Mu, Omega, Pi, Sigma, Theta and Zeta) in mammalian cells. The GSTA1 and GSTO2 are two new identified subgroups of GSTs. There is polymorphism nearby the promoter of GSTA1 (C69T), and the variant allele is associated with decreased expression of GSTA1 proteins. In human, the GSTO2 is polymorphic with an N142D substitution in the coding region, it is reported that the variant would decrease the activity of GSTO2.
The common genetic polymorphism of NQO1 is a C to T point mutation at base pair 609 of exon 6, which codes for a proline to serine substitution in NQO1 protein. This mutation results in a loss of NQO1 activity.
This study was designed to investigate the association between polymorphisms of GSTA1、GSTO2 and NQO1and the risk of ALS. By this way, we hope to offer some evidence for the prevention and therapy of ALS at molecular level.
Methods: This case-control study included 143 ALS patients and 210 healthy controls. Five milliliter of venous blood from each subject was drawn and genomic DNA was extracted. Single nucleotide polymorphisms (SNPs) of GSTA1、GSTO2 and NQO1 were genotyped by polymerase chain reaction- restrictive fragment length polymorphism (PCR-RFLP) analysis.
Statistical analysis was performed using SPSS11.5 software package. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in each groups using Chi-square test. Between cases and controls, the t test was used to examine the difference of age. The comparison of genotype and allele frequency was performed by Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model. P <0.05 was considered significant for all statistical analyses.
Result:
1 The distributions of GSTA1、GSTO2 and NQO1 genotypes among healthy controls were compatible with those expected genotype frequencies from Hardy-Weinberg equilibrium (P =0.74,P =0.42,P =0.10,respectively). The distributions of GSTA1、GSTO2 and NQO1 genotypes among patients cases were compatible with those expected genotype frequencies from Hardy-Weinberg equilibrium, too (P=0.78, P=0.10, P=0.82, respectively), suggesting that sample could represent groups.
2 The frequencies of three genotypes (CC, CT and TT) of GSTA1 C69T in ALS group and healthy controls were 79.72%、18.88%、1.40% and 76.19%、21.90%、1.91% respectively. The distributions of genotype were not significantly different in the ALS group compared to those in the control group (P=0.44). The frequencies of allele (C and T) of GSTA1 C69T in ALS patients and healthy controls were 89.16%、10.84% and 87.14%、12.86% respectively. The frequencies of allele were not significantly different in the ALS group compared to the control group (P=0.42). Compared with the CC genotypes, the CT genotype did not significantly increased the risk of ALS.(OR=0.82, 95%CI=0.48～1.40),so did the TT and CT+TT genotype(OR=0.70, 95%CI=0.13～3.90; OR=0.81, 95%CI=0.49～1.37, respectively).
3 The frequencies of three genotypes (NN, ND and DD) of GSTO2 N142D in ALS patients and healthy controls were 47.55%、46.85%、5.60% and 66.67%、30.95%、2.38% respectively. The distributions of genotype were significantly different in ALS group compared to the control group (P=0.001). The frequencies of the genotype ND and DD of the GSTO2 N142D were significantly higher in ALS patients (52.45%) than those in healthy controls (33.33%). The frequencies of allele (N and D) of GSTO2 N142D in ALS patients and healthy controls were 70.97%、29.03% and 82.14%、17.86% respectively. The frequencies of allele were significantly different in the ALS group compared to the control group (P=0.000). The frequencies of the D allele of the GSTO2 N142D were significantly higher in ALS group (29.03%) than those in healthy controls (17.86%). Compared with the NN genotypes, the NN+ND genotype significantly increased the risk of ALS(OR=2.21, 95%CI=1.43～3.41).When calculated respectively, both NN and ND genotype could significantly increased the risk of ALS(OR=2.12, 95%CI=1.36～3.32;OR=3.30, 95%CI=1.04～10.45, respectively).
4 The frequencies of three genotypes (CC, CT and TT) of NQO1C609T in ALS patients and healthy controls were 27.97%、48.95%、23.08% and 22.86%、55.71%、21.43% respectively, but there was no statistic difference (P =0.42). The frequencies of allele (C and T) of NQO1C609T in ALS patients and healthy controls were 52.45%、47.55% and 50.71%、49.29% respectively. The distributions of genotype were not significantly different in the ALS group compared to the control group (P=0.65). Compared with the CC genotypes, the CT genotype、TT genotype and CT plus TT genotype did not significantly increased the risk of ALS: OR=0.72, 95%CI=0.43～1.20 ; OR=0.88, 95%CI= 0.48～1.63 ; OR=0.76, 95%CI=0.47～1.24, respectively .
5 The distributions of GSTA1、GSTO2 and NQO1 genotypes among each stratified subgroup according to clinical stage
For GSTA1 gene, stratification analysis showed no significant difference between the bulbar onset group and the spinal onset group in genotype distributions according to the disease onset location (P=0.78). Stratification analysis showed no significant difference between the≦36 months group and >36 months group in genotype distributions according to the symptom duration (P=0.21). Stratification analysis by age at onset and gender, there was no significant difference yet (P=0.90; P=0.73, respectively). (The CC genotype relative to the CT and TT genotypes).
For GSTO2 gene, stratification analysis by disease onset location、symptom duration and age at onset, there was no significant difference in genotype distributions (P =0.77、P =0.23、P =0.54, respectively); stratification analysis showed no significant difference between the male group and female group in genotype distributions according to gender(P=0.24). ( the NN genotype relative to the ND and DD genotypes). For NQO1 gene, stratification analysis by disease onset location,symptom duration, age at onset and gender, there was no significant difference in genotype distributions (P =0.81、P =0.27、P =0.99、P =0.31, respectively).
Conclusions:
1 The risk of ALS were significantly increased in subjects with GSTO2 N142D ND genotype especially GSTO2N142D DD genotype. Therefore, ND genotype and DD genotype may be a potential risk factor for SALS.
2 The GSTA1 C69T SNP and NQO1C609T SNP may have no association with susceptibility to the SALS.
3 In the ALS patients, GSTA1 gene、GSTO2 gene and NQO1 gene stratification analysis showed no significant difference in genotype distributions according to disease onset location、symptom duration、age at onset and gender.
近来文献报道,Nrf2/ARE信号通路的激活可在多种组织中诱导一系列内源性的细胞保护基因上调,其中包括抗氧化酶、抗氧化蛋白、抗炎和解毒的蛋白。这些抗氧化酶在神经组织中的表达增加,可对抗氧化应激。谷胱甘肽硫转移酶(GSTs)和醌氧化还原酶1(NQO1)是其中的两种Nrf2/ARE通路下游经典的抗氧化酶。
GSTs在哺乳动物细胞中有七种(Alpha、Mu、Omega、Pi、Sigma、Theta和Zeta)。GSTA1和GSTO2分别是最近定义的GSTs一个亚型。最近研究表明,GSTA1基因启动子临近区域存在C69T多态性位点,等位基因的变化会引起GSTA1的表达下降。在人类,GSTO2存在编码区N142D多态性,这会使GSTO2活力下降。NQO1基因多态性最常见的是其第6外显子609碱基对C→T的点突变,此位点多态性导致其编码蛋白质脯氨酸/丝氨酸的改变,这一突变会使该酶活性减弱。本研究旨在探讨GSTA1、GSTO2和NQO1基因多态性与ALS遗传易感性的关系,从分子水平为ALS的预防和诊治提供依据。
方法:采用病例-对照研究方法,以143例SALS和210例健康对照为研究对象。采集外周静脉血5ml,参照血液基因组DNA提取试剂盒说明书提取外周血白细胞DNA。用聚合酶链式反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)方法对GSTA1、GSTO2和NQO1 3个单核苷酸多态性(single nucleotide polymorphism ,SNP)位点进行基因分型。
数据统计分析采用SPSS11.5版软件包(SPSS Company, Chicago,Illinois,USA)进行处理。正常对照组与ALS组基因型频率分布行χ2检验做Hardy-Weinberg平衡分析。ALS组与对照组的年龄差异采用t检验。基因型和等位基因频率分布比较采用χ2检验,以非条件logistic回归方法计算表示相对风险度的比值比(odds ratio,OR)及其95%可信区间(confidence interval,CI)。P<0.05作为差异有显著性的标准。
结果:1.健康对照组GSTA1、GSTO2、NQO1各基因型实际数与预期数比较,均没有显著性差异(分别为P =0.74,P =0.42,P=0.10),符合Hardy-Weinberg平衡,说明健康对照组样本具有群体代表性。SALS组GSTA1、GSTO2、NQO1位点各基因型实际数与预期数比较,也符合Hardy-Weinberg平衡,也均没有显著性差异(分别为P=0.78,P=0.10,P=0.82),说明样本具有群体代表性。
2. GSTA1基因的三种基因型频率(CC、CT、TT)在ALS组和健康对照组中分布分别是:79.72%、18.88%、1.40%和76.19%、21.90%、1.91%,结果显示两组之间比较无统计学意义(P =0.44)。GSTA1C69T多态的C和T等位基因在ALS组和健康对照组中的频率分布分别为89.16%、10.84%和87.14%、12.86%,两组间比较无显著性差异(P =0.42)。与CC基因型比较, CT基因型并不增加患ALS的风险(OR=0.82,95%CI=0.48～1.40),TT基因型也不增加患病风险(OR=0.70,95%CI=0.13～3.90),CT+TT基因型的结果与此一致(OR=0.81,95%CI=0.49～1.37)。
3. GSTO2基因的三种基因型频率(NN、ND、DD)在ALS组和健康对照组中分布分别是:47.55%、46.85%、5.60%和66.67%、30.95%、2.38%,结果显示两组之间比较有显著性差异(P =0.001),ALS组中ND基因型和DD基因型频率(52.45%)明显高于对照组(33.33%)。GSTO2N142D多态的N和D等位基因在ALS组和健康对照组中的频率分布分别为70.97%、29.03%和82.14%、17.86%,两组间比较差异有显著性(P =0.000) ;ALS组中,D等位基因频率明显高于健康对照组(29.03%比17.86%)。与NN基因型比较,ND+DD基因型亦增加患病风险(OR=2.21,95%CI=1.43～3.41),分别计算ND基因型和DD基因型后发现,携带ND基因型可以增加ALS的患病风险(OR=2.12,95%CI=1.36～3.32),而携带DD基因型则更容易增加ALS的患病风险(OR=3.30, 95%CI= 1.04～10.45)。
4. NQO1基因的三种基因型频率(CC、CT、TT)在ALS组和健康对照组中分布分别是:27.97%、48.95%、23.08%和22.86%、55.71%、21.43%,统计结果显示两组之间比较无统计学意义(P =0.42)。NQO1C609T多态的C和T等位基因在ALS组和健康对照组中的频率分布分别为52.45%、47.55%和50.71%、49.29%,两组间比较无显著性差异(P =0.65)。与CC基因型比较,CT基因型、TT基因型和CT+TT基因型均不增加患ALS的风险,分别为OR=0.72, 95%CI=0.43～1.20;OR=0.88,95%CI=0.48～1.63;OR=0.76,95%CI=0.47～1.24。
5. GSTA1、GSTO2和NQO1各基因型在SALS各分层亚组之间分布的比较
GSTA1基因,以疾病首发部位分层,CC基因型和CT+TT基因型在球部起病和脊髓起病之间比较分布无区别(P =0.78);以病程分层,在小于等于36月组和大于36月组中,CC基因型和CT+TT基因型的分布无差异(P =0.21);以首发年龄分层,在小于等于45岁组和大于45岁组中,CC基因型和CT+TT基因型的分布也无差异(P =0.90);以性别分层,在男女性别之间,CC基因型和CT+TT基因型的分布也无差异(P =0.73)。
GSTO2基因,在以疾病首发部位、病程分层和首发年龄分层中,NN基因型、ND基因型和DD基因型在各亚组间分布无差别(分别为P =0.77、P =0.23、P =0.54);以性别分层中,NN基因型和ND+DD基因型在两亚组间分布无差别(P=0.24)。
NQO1基因,在以疾病首发部位、病程分层、首发年龄分层和性别分层后,CC基因型、CT基因型和TT基因型在各亚组间分布无差别(分别为P =0.81、P =0.27、P =0.99、P =0.31)。
结论:
1.携带GSTO2N142D基因ND基因型、DD基因型、尤其是DD基因型可能增加SALS的发病危险性,因此,ND基因型和DD基因型可能为ALS的潜在危险因素。
2.NQO1C609T和GSTA1C69T的基因多态性可能和SALS的遗传易感性无关。
3.GSTA1C69T基因、GSTO2N142D基因和NQO1C609T各基因型分布与ALS的首发部位、病程、首发年龄和性别之间无相关性。
Objective: Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder, with an incidence of 1- 2 per 100 000. It is characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Approximately the 90% of cases are sporadic (SALS),the others are the familial cases (FALS).FALS are clinically and pathologically indistinguishable from SALS, suggesting a common mechanism of motor neuron degeneration. Until now,the etiopathogenisis and exact mechanisms underlying ALS are still less clear. In 15-20% of familial cases, mutations have been found in the gene encoding Cu-Zn superoxide dismutase (SOD1). In both FALS and SALS there is evidence that oxidative stress contributes to motor neuron injury, several studies revealed a significant increase in markers of oxidative stress in CNS tissue in SALS cases, so oxidative stress may play an important role in the pathology of ALS. Thus it is worthwhile screening for defective function in components of the anti-oxidant defense system for potential associations with ALS.
Recently, it is reported that the activation of Nrf2/ARE signaling pathway could induce a series of antioxidant enzyme, antioxidant protein, anti-inflammatory and antitoxic protein. The expression of those antioxidant enzymes in nervous system exhibited broad neuroprotection against oxidative stress. The classic antioxidant enzyme glutathione S-transferases (GSTs) and NADPH quinone oxidoreductase 1 (NQO1) were two kinds of a series of downstream protein of Nrf2/ARE pathway.
There are seven isoforms of GST (Alpha, Mu, Omega, Pi, Sigma, Theta and Zeta) in mammalian cells. The GSTA1 and GSTO2 are two new identified subgroups of GSTs. There is polymorphism nearby the promoter of GSTA1 (C69T), and the variant allele is associated with decreased expression of GSTA1 proteins. In human, the GSTO2 is polymorphic with an N142D substitution in the coding region, it is reported that the variant would decrease the activity of GSTO2.
The common genetic polymorphism of NQO1 is a C to T point mutation at base pair 609 of exon 6, which codes for a proline to serine substitution in NQO1 protein. This mutation results in a loss of NQO1 activity.
This study was designed to investigate the association between polymorphisms of GSTA1、GSTO2 and NQO1and the risk of ALS. By this way, we hope to offer some evidence for the prevention and therapy of ALS at molecular level.
Methods: This case-control study included 143 ALS patients and 210 healthy controls. Five milliliter of venous blood from each subject was drawn and genomic DNA was extracted. Single nucleotide polymorphisms (SNPs) of GSTA1、GSTO2 and NQO1 were genotyped by polymerase chain reaction- restrictive fragment length polymorphism (PCR-RFLP) analysis.
Statistical analysis was performed using SPSS11.5 software package. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in each groups using Chi-square test. Between cases and controls, the t test was used to examine the difference of age. The comparison of genotype and allele frequency was performed by Chi-square test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model. P <0.05 was considered significant for all statistical analyses.
Result:
1 The distributions of GSTA1、GSTO2 and NQO1 genotypes among healthy controls were compatible with those expected genotype frequencies from Hardy-Weinberg equilibrium (P =0.74,P =0.42,P =0.10,respectively). The distributions of GSTA1、GSTO2 and NQO1 genotypes among patients cases were compatible with those expected genotype frequencies from Hardy-Weinberg equilibrium, too (P=0.78, P=0.10, P=0.82, respectively), suggesting that sample could represent groups.
2 The frequencies of three genotypes (CC, CT and TT) of GSTA1 C69T in ALS group and healthy controls were 79.72%、18.88%、1.40% and 76.19%、21.90%、1.91% respectively. The distributions of genotype were not significantly different in the ALS group compared to those in the control group (P=0.44). The frequencies of allele (C and T) of GSTA1 C69T in ALS patients and healthy controls were 89.16%、10.84% and 87.14%、12.86% respectively. The frequencies of allele were not significantly different in the ALS group compared to the control group (P=0.42). Compared with the CC genotypes, the CT genotype did not significantly increased the risk of ALS.(OR=0.82, 95%CI=0.48～1.40),so did the TT and CT+TT genotype(OR=0.70, 95%CI=0.13～3.90; OR=0.81, 95%CI=0.49～1.37, respectively).
3 The frequencies of three genotypes (NN, ND and DD) of GSTO2 N142D in ALS patients and healthy controls were 47.55%、46.85%、5.60% and 66.67%、30.95%、2.38% respectively. The distributions of genotype were significantly different in ALS group compared to the control group (P=0.001). The frequencies of the genotype ND and DD of the GSTO2 N142D were significantly higher in ALS patients (52.45%) than those in healthy controls (33.33%). The frequencies of allele (N and D) of GSTO2 N142D in ALS patients and healthy controls were 70.97%、29.03% and 82.14%、17.86% respectively. The frequencies of allele were significantly different in the ALS group compared to the control group (P=0.000). The frequencies of the D allele of the GSTO2 N142D were significantly higher in ALS group (29.03%) than those in healthy controls (17.86%). Compared with the NN genotypes, the NN+ND genotype significantly increased the risk of ALS(OR=2.21, 95%CI=1.43～3.41).When calculated respectively, both NN and ND genotype could significantly increased the risk of ALS(OR=2.12, 95%CI=1.36～3.32;OR=3.30, 95%CI=1.04～10.45, respectively).
4 The frequencies of three genotypes (CC, CT and TT) of NQO1C609T in ALS patients and healthy controls were 27.97%、48.95%、23.08% and 22.86%、55.71%、21.43% respectively, but there was no statistic difference (P =0.42). The frequencies of allele (C and T) of NQO1C609T in ALS patients and healthy controls were 52.45%、47.55% and 50.71%、49.29% respectively. The distributions of genotype were not significantly different in the ALS group compared to the control group (P=0.65). Compared with the CC genotypes, the CT genotype、TT genotype and CT plus TT genotype did not significantly increased the risk of ALS: OR=0.72, 95%CI=0.43～1.20 ; OR=0.88, 95%CI= 0.48～1.63 ; OR=0.76, 95%CI=0.47～1.24, respectively .
5 The distributions of GSTA1、GSTO2 and NQO1 genotypes among each stratified subgroup according to clinical stage
For GSTA1 gene, stratification analysis showed no significant difference between the bulbar onset group and the spinal onset group in genotype distributions according to the disease onset location (P=0.78). Stratification analysis showed no significant difference between the≦36 months group and >36 months group in genotype distributions according to the symptom duration (P=0.21). Stratification analysis by age at onset and gender, there was no significant difference yet (P=0.90; P=0.73, respectively). (The CC genotype relative to the CT and TT genotypes).
For GSTO2 gene, stratification analysis by disease onset location、symptom duration and age at onset, there was no significant difference in genotype distributions (P =0.77、P =0.23、P =0.54, respectively); stratification analysis showed no significant difference between the male group and female group in genotype distributions according to gender(P=0.24). ( the NN genotype relative to the ND and DD genotypes). For NQO1 gene, stratification analysis by disease onset location,symptom duration, age at onset and gender, there was no significant difference in genotype distributions (P =0.81、P =0.27、P =0.99、P =0.31, respectively).
Conclusions:
1 The risk of ALS were significantly increased in subjects with GSTO2 N142D ND genotype especially GSTO2N142D DD genotype. Therefore, ND genotype and DD genotype may be a potential risk factor for SALS.
2 The GSTA1 C69T SNP and NQO1C609T SNP may have no association with susceptibility to the SALS.
3 In the ALS patients, GSTA1 gene、GSTO2 gene and NQO1 gene stratification analysis showed no significant difference in genotype distributions according to disease onset location、symptom duration、age at onset and gender.
引文
1 S?rensen M, Autrup H, Tj?nneland A, et al. Genetic polymorphisms in CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer. Cancer Letters,2005, 221 185–190
2 Masoudi M, Saadat I, Omidvari S,et al.Genetic polymorphisms of GSTO2, GSTM1, and GSTT1 and risk of gastric cancer. Mol Biol Rep,2009,36(4): 781-784
3 Traver R D, Siegel D,Beall H D, et al. Characterization of a polymorphism in NAD ( P) H: quinone oxidoreductase (DT-diaphorase). Br J Cancer, 1997, 75: 69 - 75
4 Rowland LP, Shneider NA. Medical progress: amyotrophic lateral sclerosis. N Eng J Med, 2001, 344:1689-1695
5 Figlewicz DA, Orrell RW, The genetics of motor neuron diseases.Amyotroph Lateral Scler, Other Mot. NeuronDisord,2003,4:225-231
6李焰生,黄坚,庄建华.运动神经元疾病.第二军医大学出版社,2002,60-98
7 Simonian N A,Coyle J T. Oxidative stress in neurodegenerative diseases.Annu Rev Pharmacol Toxicol,1996,36:83 -106
8阿部康三.氧化应激与神经系统疾病.日本医学介绍,2006,27(12): 556-558
9 Shibata N,Nagai R,Miyata S,et al. Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase 1 mutation. Acta Neuropathol,2000,100(3):275-284
10张远锦,张俊,张楠,等.新型自由基清除剂依达拉奉治疗肌萎缩侧索硬化的随机开放临床试验.中国现代神经疾病杂志,2007,7(2):121-124
11 Gu Z, Kaul M, Yan B, et al. S-nitrosylation of matrix metalloproteinases:signaling pathway to neuronal cell death. Science, 2002, 297:1186-1190
12 Maria Teresa Carr`, Alberto Ferri , Mauro Cozzolino et al.Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals.Brain Research Bulletin,2003,61:365-374
13 Moi P, Chan K, Asunis I, et al. Isolation of NF-E2-related factor 2(Nrf2), aNF-E2- like basic leucine zipper transcriptional activator that binds to the tandem NF - E2/ AP1 repeat of the beta-globin locus control region. Proc NatlAcad Sci USA, 1994, 91(21): 9926-9930
14 Talalay P, Dinkova-Kostova A T, Holtzclaw W D.Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Adv Enzyme Regul, 2003, 43:121-134
15 Giudice A, Montella M. Activation of the Nrf2/ARE signaling pathway: a promising strategy in cancer prevention. Bioessays, 2006, 28(2):169-181
16李煌元,石年.Keap1-Nrf2/ARE通路在分子毒理学中的研究进展.国外医学卫生学分册,2006,33(3 ):129-135
17 Vargas MR, Johnson DA, Sirkis DW, et al. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci, 2008,28(50):13574-81
18刘晓云,卜晖,李哲,等.二相酶诱导剂D3T对运动神经元的保护作用.细胞生物学杂志, 2007, 29: 135-139
19 Andrew D. Kraft a, Jon M . et al.Activation of the Nrf2/ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1 . Experimental Neurology ,2007, 207:107-117
20 Johnson JA, Johnson DA, Kraft AD. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration.Ann N Y Acad Sci,2008,1147:61-69
21王亚林,江军.谷胱甘肽巯基转移酶基因多态性与前列腺癌风险相关性.临床泌尿外科杂志(综述),2005,20(2):123-126
22 Board P, Coggan M, Johnston P, et al. Genetic heterogeneity of the human glutathione S-transferases: a complex gene families. Pharmacol Ther ,1990,48:357–369
23 Theodore C, Singh SV, Hong TD, et al. Glutathione Stransferases of human brain Evidence for two immunologically distinct types of 26500-Mr subunits. Biochem ,1985;225:375–82
24 Tetlow N, Liu D, Board P.Polymorphism of human Alpha class glutathione transferases. Pharmacogenetics ,2001, 11:609-617
25梁冰,张爱华,奚绪光,等. GSTO基因多态性与燃煤污染型砷中毒易感性的关系研究.环境与职业医学,2007,24(2):129-132
26欧阳晓春,刘振华,吴多斌.NQO1基因多态性与阿尔茨海默病的相关研究.实用医学杂志,2006,20: 1269-1270
27陈赛娟,黄薇,樊绮诗.人类基因组研究基本技术.人民卫生出版社,2002,155-159
28韦薇,李瑗,苏建家,等.谷胱甘肽S-转移酶A1在肝癌中的异常表达.肿瘤防治研究,2006,33(9): 623-625
29 van de Giessen E, Fogh I, Gopinath S, et al. Association study on glutathione S-transferase omega 1 and 2 and familial ALS.Amyotrophic Lateral Sclerosis, 2008; 9: 81–84
30 Raina A K,Templeton D J,Deak J C,et al. quinone oxidoreductase(NQO1), a sensitive red oxindicator,is increased in Alzheimer’s disease. Redox Rep,1999,4(1/2):23-27
31马秋兰,陈彪,邵明.NAD(P)H:醌氧化还原酶基因多态性与阿尔茨海默病遗传易感性的关系.中华老年医学杂志,2001,20(2):93-95
1 Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Eng J Med, 2001, 344(22):1689-1700
2王维治,罗祖明,等.神经病学.人民卫生出版社,2004,221-224
3 CarríMT, Ferri A, Cozzolino M,et al.Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals. Brain Res Bull,2003 ,61(4):365-374
4 Tandan R, Bradley WG. Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management.Ann Neurol, 1985 ,18(3):271-280
5 Mulder DW, Kurland LT, Offord KP,et al. Familial adult motor neuron disease: amyotrophic lateral sclerosis. Neurology, 1986,36(4):511–517
6 CoppedèF, Mancuso M, Lo Gerfo A ,et al. Association of the hOGG1 Ser326Cys polymorphism with sporadic amyotrophic lateral sclerosis. Neuroscience Letters,2007,420(2):163–168
7 Al-Chalabi A, Leigh PN. Recent advances in amyotrophic lateral Sclerosis. Curr Opin Neurol, 2000 ,13(4):397-405
8 Cluskey S, Ramsden DB. Mechanisms of neurodegeneration in amyotrophic lateral sclerosis. Mol Pathol, 2001, 54 (6):386-392
9李焰生,黄坚,庄建华.运动神经元疾病.第二军医大学出版社,2002, 60-98
10 Cozzolino M, Ferri A, CarrìMT. Amyotrophic lateral sclerosis: from current developments in the laboratory to clinical implications. Antioxid Redox Signal, 2008 ,10(3):405-443
11吴文斌,郑永玲,胡常林.肌萎缩侧索硬化的治疗.河南实用神经疾病杂志,2002 ,5 (2):30-31
12 Aqqarwal S,Cudkowicz M. ALS drug development: reflections from the past and a way forward. Neurotherapeutics,2008 ,5(4):516-527
13 Turner MR, Kiernan MC, Leigh PN, et al. Biomarkers in amyotrophic lateral sclerosis.Lancet Neurol,2009 ,8(1):94-109
14 Majoor-Krakauer D, Willems P J, Hofman A. Genetic epidemiology of amyotrophic lateral sclerosis. Clin Genet,2003,63(2):83-101
15 Gros-Louis F, Gaspar C, Rouleau GA. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta, 2006,1762(11-12):956-972
16 Pardo CA, Xu Z, Borchelt DR, et al. Superoxide dismutaseis an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons. Proc Natl Acad Sci USA, 1995, 92:954-958
17卢锡林,姚晓黎,张成,等.肌萎缩侧索硬化症SOD1基因突变特点.中山大学学报(医学科学版), 2006, 27(1):80- 82
18郑永玲,吴文斌,胡常林.肌萎缩侧索硬化发病机制的研究进展.脑与神经疾病杂,2002,10(2):128-130
19徐仁伵,陶玉慧,吴成斯,等.肌萎缩侧索硬化的病因研究进展.临床荟萃,2007,22(1):69-70
20 Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation . Science, 1994, 264(5166): 1772-1775
21 Jaarsma D, Haasdijk ED, Grashorn JA,et al. Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Neurobiol Dis,2000,7(6 Pt B):623-643
22黄慧,张成,席静,等.家族性肌萎缩侧索硬化症转基因鼠的繁殖和鉴定.南方医科大学学报, 2006;26(3),258-265
23 Strey CW,Spellman D,Stieber A ,et al . Dysregulation of Stathmin, a Microtubule-Destabilizing Protein, and Up-Regulation of Hsp25,Hsp27, and the AntioxidantPeroxiredoxin 6 in a Mouse Model of Familial Amyotrophic Lateral Sclerosis. Am J Pathol ,2004, 165:1701-1718
24 Yamanaka K. Animal models of amyotrophic lateral sclerosis. Rinsho Shinkeigaku, 2007 ,47(11):934-937
25 Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol, 2008,85(1):94-134
26 Bruijn LI, Becher MW, Lee MK, et al.ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions.Neuron ,1997,18(2): 327–338
27 Wong PC, Pardo CA, Borchelt DR,et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.Neuron, 1995 ,14(6):1105-16
28 Ripps ME, Huntley GW, Hof PR, et al.Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis.Proc Natl Acad Sci U S A, 1995,92(3):689–693
29 Wang J, Xu G, Gonzales V,et al. Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site. Neurobiol Dis, 2002,10(2):128-38
30 Wang J, Slunt H, Gonzales V, et al.Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature. Hum MolGenet,2003, 12 (21): 2753–2764
31 Talalay P, Dinkova-Kostova AT, Holtzclaw WD.Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Adv Enzyme Regul, 2003, 43:121-134
32 Valentine JS. Do oxidatively modified proteins cause ALS? Free Radic Biol Med, 2002,33: 1314-1320
33 Shibata N.Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. Neuropathology, 2001,21(1):82-92
34 Kunst CB.Complex Genetics of Amyotrophic Lateral Sclerosis . Am J Hum Genet, 2004,75(6):933-947
35 Watanabe Y, Morita E, Fukada Y, et al. Adherent monomer-misfolded SOD1. PloS ONE, 2008,3(10):e3497
36 Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet, 2001, 29: 166~173
37 Hadano S, Yanagisawa Y, Skaug J et al. Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33~q34: candidate genes for ALS2. Genomics, 2001,71: 200~213
38 Yang Y, Hentati A, Deng HX, et al. The gene encoding alsin, a protein with three guanine~nucleotide exchange factor domains, is mutated in a form of recessive amyotrophiclateral sclerosis. Nat Genet, 2001,29: 160-165
39 Hentati A, Bejaoui K, Pericak-Vance MA, et al.Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33–q35. Nat Genet, 1994,7:425-428
40 Hadano S, Kunita R, Otomo A, et al. Molecular and cellular function of ALS2/alsin: Implication of membrane dynamics in neuronal development and degeneration .Neurochemistry International, 2007, 51:74–84
41 Kress JA, Kühnlein P, Winter P,et al. Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Ann Neurol,2005,58(5):800-803
42 Y. Yang, A. Hentati, H.X. Deng, et al.The gene encoding alsin, a protein with three guanine–nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.Nat Genet,2001, 29:160–165
43 Cai H, Shim H, Lai C. ALS2/Alsin Knockout Mice and Motor Neuron Diseases. Neurodegener Dis,2008,5(6):359-366
44 Paul N. Valdmanis,Guy A. Rouleau. Genetics of familial amyotrophic lateral Sclerosis. Neurology,2008,70:144–152
45 Siddique T, Figlewicz DA, Pericak-Vance MA, et al.Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N Engl J Med,1991, 324(20):1381–1384
46 Hand CK, Khoris J, Salachas F, et al. A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q.Am J Hum Genet,2002,70(1):251-256
47 Siddique N, Siddique T. Genetics of amyotrophic lateral sclerosis. Phys Med Rehabil Clin N Am,2008,19(3):429-39
48 Chen, Y.-Z, Bennett, C. L, Huynh, H. M,et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet,2004 ,74(6):1128-35
49 Chance PF, Rabin BA, Ryan SG, et al.Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet, 1998,62(3):633-640
50 Blair IP, Bennett CL, Abel A,et al. A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34. Neurogenetics, 2000 ,3(1):1-6
51 De Jonghe P, Auer-Grumbach M, Irobi J. Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain, 2002,125(Pt 6):1320-1325
52 Chen, Y.-Z, Bennett, C. L, Huynh, H. M, et al.DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet,2004,74: 1128-1135
53 Grohmann K, Schuelke M, Diers A, et al.Mutations in the gene encoding immunoglobulin mu-binding protein 2 causespinal muscular atrophy with respiratory distress type 1.Nat Genet,2001, 29:75–77
54 Arning L, Sch?ls L, Cin H, et al.Identification and characterisation of a large Senataxin (SETX) gene duplication in ataxia with ocular apraxia type 2 (AOA2). Neurogenetics,2008 ,9(4):295-299
55 Hentati A, Ouahchi K, Pericak-Vance MA,et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome15q15-q22markers.Neurogenetics,1998,2(1):55-60
56 Sapp PC, Hosler BA, McKenna-Yasek D,et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis.Am J Hum Genet,2003 ,73(2):397-403
57 Abalkhail H, Mitchell J, Habgood J,et al.A new familial amyotrophic lateral sclerosis locus on chromosome 16q12.1-16q12.2. Am J Hum Genet,2003 ,73(2):383-389
58 Ruddy DM, Parton MJ, Al-Chalabi A,et al. Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. Am J Hum Genet, 2003,73(2):390-396
59 Nishimura AL, Mitne-Neto M, Silva HC,et al. A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13. J Med Genet, 2004 ,41(4):315-20
60 Nishimura AL, Mitne-Neto M, Silva HC,et al. A mutation in the vesicle-trafficking protein VAPB causes late-onsetspinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet,2004 ,75(5):822-831
61 Kirby J,Hewamadduma C A A, Hartley J A,et al.Mutations in VAPB are not associated with sporadic ALS. Neurology, 2007,68: 1951-1953
62 Landers J E, Leclerc A L, Shi L,et al.New VAPB deletion variant and exclusion of VAPB mutations in familial ALS. Neurology, 2008,70: 1179-1185
63 Teuling E, Ahmed S, Haasdijk E,et al.Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. Neurosci, 2007, 27: 9801-9815
64 Foster LJ, Weir ML, Lim DY et al.A functional role for VAP-33 in insulin-stimulated GLUT4 traffic.Traffic, 2000,1(6):512–521
65 Greenway MJ, Alexander MD, Ennis S , et al.A novel candidate region for ALS on chromosome 14q11.2.Neurology,2004, 63: 1936-1938
66 Greenway M J, Andersen P M, Russ C,et al.ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature Genet,2006, 38: 411-413
67 Wu D, Yu W, Kishikawa H,et al.Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol,2007, 62: 609-617
68 Gellera C, Colombrita C, Ticozzi N,et al.Identification ofnew ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis. Neurogenetics,2008,9: 33-40
69 Tagawa A, Tan C F, Kikugawa K,et al. Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons. Acta Neuropath,2007,113: 205-211
70 Van Deerlin V M, Leverenz J B, Bekris L M,et al.TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet,2008,7: 409-416
71 Sreedharan J, Blair I P, Tripathi V B,et al.TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science,2008,319: 1668-1672
72 Gitcho M A, Baloh R H, Chakraverty S, et al.TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol,2008,63: 535-538
73 Kabashi E,Valdmanis P N,Dion P,et al.TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nature Genet,2008,40: 572-574
74 Luquin N, Yu B, Trent RJ, et al. An analysis of the entire SOD1 gene in sporadic ALS. Neuromuscular Disorders,2008,8:545–552
75 Suthers G, Laing N, Wilton S,et al.“Sporadic”motoneuron disease due to familial SOD1 mutation with lowpenetrance.Lancet,1994, 344: 1773
76 R.W. Orrell, J. Habgood, P. Rudge,et al.Difficulties in distinguishing sporadic from familial amyotrophic lateral sclerosis. Ann Neurol,1996,39:810–812
77刘岩峰,黄平,何欣,等. ApoE的研究进展及其在脑外伤发生中的意义.法律与医学杂志,2007,14(1):72-75
78马玉梅,张振馨. APOE基因多态性与阿尔茨海默病关系研究的进展.基础医学与临床, 2007,27 (7):739-744
79 Bedlack RS, Strittmatter WJ, Morgenlander JC. Apolipoprotein E and neuromuscular disease: a critical review of the literature. Arch Neurol,2000,57(11):1561-1565
80 Mui S, Rebeck GW, McKenna-Yasek D,et al. Apolipoprotein E epsilon 4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis. Ann Neurol,1995,38:460-463
81 Siddique T, Pericak-Vance MA, Caliendo J, et al. Lack of association between apolipoprotein E genotype and sporadic amyotrophic lateral sclerosis. Neurogenetics 1998,1:213–216
82 Lacomblez L, Doppler V, Beucler I,et al.APOE: A potential marker of disease progression in ALS.Neurology, 2002,58:1112–1114
83 Drory VE, Birnbaum M, Korczyn AD, et al. Association of APOE epsilon4 allele with survival in amyotrophic lateral sclerosis. J Neurol Sci,2001,190:17–20
84 Li YJ, Pericak-Vance MA, Haines JL, et al. ApolipoproteinE is associated with age at onset of amyotrophic lateral sclerosis.Neurogenetics,2004,5:209–13
85 Henrik Zetterberg , Johan Jacobsson , Lars Rosengren , et al.Association of APOE with age at onset of sporadic amyotrophic lateral sclerosis.Journal of the Neurological Sciences,2008,273:67–69
86 Saeed M, Siddique N, Hung WY, et al. Paraoxonase cluster polymorphisms are associated with sporadic ALS. Neurology,2006, 67(5):771-776
87 Slowik A, Tomik B, Wolkow PP, et al.Paraoxonase gene polymorphisms and sporadic ALS.Neurology, 2006,67(5):766-770
88 Cronin S, Greenway MJ, Prehn JH, et al. Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry,2007,78(9):984-986
89 Landers JE, Shi L, Cho TJ,et al.A common haplotype within the PON1 promoter region is associated with sporadic ALS.Amyotroph Lateral Scler,2008 ,9(5):306-314
90 Wills AM, Landers JE, Zhang H, et al. Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS. Neurology,2008,70(12):929-934
91齐琰,鲁莹,钟延强.血管内皮生长因子及其可降解性控释系统研究进展.中国药学杂志,2007,42(1):2-5
92 Lambrechts D, Storkebaum E, Morimoto M, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice andhumans and protects motoneurons against ischemic death. Nature Genet,2003,34: 383-394
93 Terry PD, Kamel F, Umbach DM,et al.VEGF promoter haplotype and amyotrophic lateral sclerosis (ALS). J Neurogenet,2004,18(2):429–434
94 Brockington A, Kirby J, Eggitt D,et al. Screening of the regulatory and coding regions of vascular endothelial growth factor in amyotrophic lateral sclerosis.Neurogenetics,2005,6:101–104
95 Gros-Louis F, Laurent S, Lopes AA,et al. Absence of mutations in the hypoxia response element of VEGF in ALS.Muscle Nerve,2003,28:774–775
96 Holzbaur E L F, Tokito M K.Localization of the DCTN1 gene encoding p150(Glued) to human chromosome 2p13 by fluorescence in situ hybridization.Genomics,1996,31: 398-399
97 Munch C,Rosenbohm A,Sperfeld A D,et al. Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and FTD. Ann Neurol,2005,777-780
98 Puls I, Jonnakuty C, LaMonte BH,et al. Mutant dynactin in motor neuron disease. Nat Genet, 2003 ,33(4):455-456
99 Münch C, Sedlmeier R, Meyer T, et al. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.Neurology, 2004,63:724–726
100 Collard JF, C?téF, Julien JP.Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis.Nature,1995, 375(6526):61-64
101 Figlewicz DA, Krizus A, Martinoli MG ,et al . Variants of the heavy neurofilament subunit areassociated with the development of amyotrophic lateral sclerosis. Hum Mol Genet,1994,3(10):1757-1761
102 Al-Chalabi A, Andersen PM, Nilsson P,et al.Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet,1999,(2):157-164
103 Tomkins J, Usher P, Slade JY,et al.Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). NeuroReport ,1998,(9):3967-3970
104 Rooke K, Figlewicz DA, Han FY, et al.Analysis of the KSP repeat of the neurofilament heavy subunit in familial amyotrophiclateral sclerosis.Neurology,1996 ,46(3):789-90
2 Masoudi M, Saadat I, Omidvari S,et al.Genetic polymorphisms of GSTO2, GSTM1, and GSTT1 and risk of gastric cancer. Mol Biol Rep,2009,36(4): 781-784
3 Traver R D, Siegel D,Beall H D, et al. Characterization of a polymorphism in NAD ( P) H: quinone oxidoreductase (DT-diaphorase). Br J Cancer, 1997, 75: 69 - 75
4 Rowland LP, Shneider NA. Medical progress: amyotrophic lateral sclerosis. N Eng J Med, 2001, 344:1689-1695
5 Figlewicz DA, Orrell RW, The genetics of motor neuron diseases.Amyotroph Lateral Scler, Other Mot. NeuronDisord,2003,4:225-231
6李焰生,黄坚,庄建华.运动神经元疾病.第二军医大学出版社,2002,60-98
7 Simonian N A,Coyle J T. Oxidative stress in neurodegenerative diseases.Annu Rev Pharmacol Toxicol,1996,36:83 -106
8阿部康三.氧化应激与神经系统疾病.日本医学介绍,2006,27(12): 556-558
9 Shibata N,Nagai R,Miyata S,et al. Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase 1 mutation. Acta Neuropathol,2000,100(3):275-284
10张远锦,张俊,张楠,等.新型自由基清除剂依达拉奉治疗肌萎缩侧索硬化的随机开放临床试验.中国现代神经疾病杂志,2007,7(2):121-124
11 Gu Z, Kaul M, Yan B, et al. S-nitrosylation of matrix metalloproteinases:signaling pathway to neuronal cell death. Science, 2002, 297:1186-1190
12 Maria Teresa Carr`, Alberto Ferri , Mauro Cozzolino et al.Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals.Brain Research Bulletin,2003,61:365-374
13 Moi P, Chan K, Asunis I, et al. Isolation of NF-E2-related factor 2(Nrf2), aNF-E2- like basic leucine zipper transcriptional activator that binds to the tandem NF - E2/ AP1 repeat of the beta-globin locus control region. Proc NatlAcad Sci USA, 1994, 91(21): 9926-9930
14 Talalay P, Dinkova-Kostova A T, Holtzclaw W D.Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Adv Enzyme Regul, 2003, 43:121-134
15 Giudice A, Montella M. Activation of the Nrf2/ARE signaling pathway: a promising strategy in cancer prevention. Bioessays, 2006, 28(2):169-181
16李煌元,石年.Keap1-Nrf2/ARE通路在分子毒理学中的研究进展.国外医学卫生学分册,2006,33(3 ):129-135
17 Vargas MR, Johnson DA, Sirkis DW, et al. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci, 2008,28(50):13574-81
18刘晓云,卜晖,李哲,等.二相酶诱导剂D3T对运动神经元的保护作用.细胞生物学杂志, 2007, 29: 135-139
19 Andrew D. Kraft a, Jon M . et al.Activation of the Nrf2/ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1 . Experimental Neurology ,2007, 207:107-117
20 Johnson JA, Johnson DA, Kraft AD. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration.Ann N Y Acad Sci,2008,1147:61-69
21王亚林,江军.谷胱甘肽巯基转移酶基因多态性与前列腺癌风险相关性.临床泌尿外科杂志(综述),2005,20(2):123-126
22 Board P, Coggan M, Johnston P, et al. Genetic heterogeneity of the human glutathione S-transferases: a complex gene families. Pharmacol Ther ,1990,48:357–369
23 Theodore C, Singh SV, Hong TD, et al. Glutathione Stransferases of human brain Evidence for two immunologically distinct types of 26500-Mr subunits. Biochem ,1985;225:375–82
24 Tetlow N, Liu D, Board P.Polymorphism of human Alpha class glutathione transferases. Pharmacogenetics ,2001, 11:609-617
25梁冰,张爱华,奚绪光,等. GSTO基因多态性与燃煤污染型砷中毒易感性的关系研究.环境与职业医学,2007,24(2):129-132
26欧阳晓春,刘振华,吴多斌.NQO1基因多态性与阿尔茨海默病的相关研究.实用医学杂志,2006,20: 1269-1270
27陈赛娟,黄薇,樊绮诗.人类基因组研究基本技术.人民卫生出版社,2002,155-159
28韦薇,李瑗,苏建家,等.谷胱甘肽S-转移酶A1在肝癌中的异常表达.肿瘤防治研究,2006,33(9): 623-625
29 van de Giessen E, Fogh I, Gopinath S, et al. Association study on glutathione S-transferase omega 1 and 2 and familial ALS.Amyotrophic Lateral Sclerosis, 2008; 9: 81–84
30 Raina A K,Templeton D J,Deak J C,et al. quinone oxidoreductase(NQO1), a sensitive red oxindicator,is increased in Alzheimer’s disease. Redox Rep,1999,4(1/2):23-27
31马秋兰,陈彪,邵明.NAD(P)H:醌氧化还原酶基因多态性与阿尔茨海默病遗传易感性的关系.中华老年医学杂志,2001,20(2):93-95
1 Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Eng J Med, 2001, 344(22):1689-1700
2王维治,罗祖明,等.神经病学.人民卫生出版社,2004,221-224
3 CarríMT, Ferri A, Cozzolino M,et al.Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals. Brain Res Bull,2003 ,61(4):365-374
4 Tandan R, Bradley WG. Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management.Ann Neurol, 1985 ,18(3):271-280
5 Mulder DW, Kurland LT, Offord KP,et al. Familial adult motor neuron disease: amyotrophic lateral sclerosis. Neurology, 1986,36(4):511–517
6 CoppedèF, Mancuso M, Lo Gerfo A ,et al. Association of the hOGG1 Ser326Cys polymorphism with sporadic amyotrophic lateral sclerosis. Neuroscience Letters,2007,420(2):163–168
7 Al-Chalabi A, Leigh PN. Recent advances in amyotrophic lateral Sclerosis. Curr Opin Neurol, 2000 ,13(4):397-405
8 Cluskey S, Ramsden DB. Mechanisms of neurodegeneration in amyotrophic lateral sclerosis. Mol Pathol, 2001, 54 (6):386-392
9李焰生,黄坚,庄建华.运动神经元疾病.第二军医大学出版社,2002, 60-98
10 Cozzolino M, Ferri A, CarrìMT. Amyotrophic lateral sclerosis: from current developments in the laboratory to clinical implications. Antioxid Redox Signal, 2008 ,10(3):405-443
11吴文斌,郑永玲,胡常林.肌萎缩侧索硬化的治疗.河南实用神经疾病杂志,2002 ,5 (2):30-31
12 Aqqarwal S,Cudkowicz M. ALS drug development: reflections from the past and a way forward. Neurotherapeutics,2008 ,5(4):516-527
13 Turner MR, Kiernan MC, Leigh PN, et al. Biomarkers in amyotrophic lateral sclerosis.Lancet Neurol,2009 ,8(1):94-109
14 Majoor-Krakauer D, Willems P J, Hofman A. Genetic epidemiology of amyotrophic lateral sclerosis. Clin Genet,2003,63(2):83-101
15 Gros-Louis F, Gaspar C, Rouleau GA. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta, 2006,1762(11-12):956-972
16 Pardo CA, Xu Z, Borchelt DR, et al. Superoxide dismutaseis an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons. Proc Natl Acad Sci USA, 1995, 92:954-958
17卢锡林,姚晓黎,张成,等.肌萎缩侧索硬化症SOD1基因突变特点.中山大学学报(医学科学版), 2006, 27(1):80- 82
18郑永玲,吴文斌,胡常林.肌萎缩侧索硬化发病机制的研究进展.脑与神经疾病杂,2002,10(2):128-130
19徐仁伵,陶玉慧,吴成斯,等.肌萎缩侧索硬化的病因研究进展.临床荟萃,2007,22(1):69-70
20 Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation . Science, 1994, 264(5166): 1772-1775
21 Jaarsma D, Haasdijk ED, Grashorn JA,et al. Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Neurobiol Dis,2000,7(6 Pt B):623-643
22黄慧,张成,席静,等.家族性肌萎缩侧索硬化症转基因鼠的繁殖和鉴定.南方医科大学学报, 2006;26(3),258-265
23 Strey CW,Spellman D,Stieber A ,et al . Dysregulation of Stathmin, a Microtubule-Destabilizing Protein, and Up-Regulation of Hsp25,Hsp27, and the AntioxidantPeroxiredoxin 6 in a Mouse Model of Familial Amyotrophic Lateral Sclerosis. Am J Pathol ,2004, 165:1701-1718
24 Yamanaka K. Animal models of amyotrophic lateral sclerosis. Rinsho Shinkeigaku, 2007 ,47(11):934-937
25 Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol, 2008,85(1):94-134
26 Bruijn LI, Becher MW, Lee MK, et al.ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions.Neuron ,1997,18(2): 327–338
27 Wong PC, Pardo CA, Borchelt DR,et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.Neuron, 1995 ,14(6):1105-16
28 Ripps ME, Huntley GW, Hof PR, et al.Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis.Proc Natl Acad Sci U S A, 1995,92(3):689–693
29 Wang J, Xu G, Gonzales V,et al. Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site. Neurobiol Dis, 2002,10(2):128-38
30 Wang J, Slunt H, Gonzales V, et al.Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature. Hum MolGenet,2003, 12 (21): 2753–2764
31 Talalay P, Dinkova-Kostova AT, Holtzclaw WD.Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Adv Enzyme Regul, 2003, 43:121-134
32 Valentine JS. Do oxidatively modified proteins cause ALS? Free Radic Biol Med, 2002,33: 1314-1320
33 Shibata N.Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. Neuropathology, 2001,21(1):82-92
34 Kunst CB.Complex Genetics of Amyotrophic Lateral Sclerosis . Am J Hum Genet, 2004,75(6):933-947
35 Watanabe Y, Morita E, Fukada Y, et al. Adherent monomer-misfolded SOD1. PloS ONE, 2008,3(10):e3497
36 Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet, 2001, 29: 166~173
37 Hadano S, Yanagisawa Y, Skaug J et al. Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33~q34: candidate genes for ALS2. Genomics, 2001,71: 200~213
38 Yang Y, Hentati A, Deng HX, et al. The gene encoding alsin, a protein with three guanine~nucleotide exchange factor domains, is mutated in a form of recessive amyotrophiclateral sclerosis. Nat Genet, 2001,29: 160-165
39 Hentati A, Bejaoui K, Pericak-Vance MA, et al.Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33–q35. Nat Genet, 1994,7:425-428
40 Hadano S, Kunita R, Otomo A, et al. Molecular and cellular function of ALS2/alsin: Implication of membrane dynamics in neuronal development and degeneration .Neurochemistry International, 2007, 51:74–84
41 Kress JA, Kühnlein P, Winter P,et al. Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Ann Neurol,2005,58(5):800-803
42 Y. Yang, A. Hentati, H.X. Deng, et al.The gene encoding alsin, a protein with three guanine–nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.Nat Genet,2001, 29:160–165
43 Cai H, Shim H, Lai C. ALS2/Alsin Knockout Mice and Motor Neuron Diseases. Neurodegener Dis,2008,5(6):359-366
44 Paul N. Valdmanis,Guy A. Rouleau. Genetics of familial amyotrophic lateral Sclerosis. Neurology,2008,70:144–152
45 Siddique T, Figlewicz DA, Pericak-Vance MA, et al.Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N Engl J Med,1991, 324(20):1381–1384
46 Hand CK, Khoris J, Salachas F, et al. A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q.Am J Hum Genet,2002,70(1):251-256
47 Siddique N, Siddique T. Genetics of amyotrophic lateral sclerosis. Phys Med Rehabil Clin N Am,2008,19(3):429-39
48 Chen, Y.-Z, Bennett, C. L, Huynh, H. M,et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet,2004 ,74(6):1128-35
49 Chance PF, Rabin BA, Ryan SG, et al.Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet, 1998,62(3):633-640
50 Blair IP, Bennett CL, Abel A,et al. A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34. Neurogenetics, 2000 ,3(1):1-6
51 De Jonghe P, Auer-Grumbach M, Irobi J. Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain, 2002,125(Pt 6):1320-1325
52 Chen, Y.-Z, Bennett, C. L, Huynh, H. M, et al.DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet,2004,74: 1128-1135
53 Grohmann K, Schuelke M, Diers A, et al.Mutations in the gene encoding immunoglobulin mu-binding protein 2 causespinal muscular atrophy with respiratory distress type 1.Nat Genet,2001, 29:75–77
54 Arning L, Sch?ls L, Cin H, et al.Identification and characterisation of a large Senataxin (SETX) gene duplication in ataxia with ocular apraxia type 2 (AOA2). Neurogenetics,2008 ,9(4):295-299
55 Hentati A, Ouahchi K, Pericak-Vance MA,et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome15q15-q22markers.Neurogenetics,1998,2(1):55-60
56 Sapp PC, Hosler BA, McKenna-Yasek D,et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis.Am J Hum Genet,2003 ,73(2):397-403
57 Abalkhail H, Mitchell J, Habgood J,et al.A new familial amyotrophic lateral sclerosis locus on chromosome 16q12.1-16q12.2. Am J Hum Genet,2003 ,73(2):383-389
58 Ruddy DM, Parton MJ, Al-Chalabi A,et al. Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. Am J Hum Genet, 2003,73(2):390-396
59 Nishimura AL, Mitne-Neto M, Silva HC,et al. A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13. J Med Genet, 2004 ,41(4):315-20
60 Nishimura AL, Mitne-Neto M, Silva HC,et al. A mutation in the vesicle-trafficking protein VAPB causes late-onsetspinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet,2004 ,75(5):822-831
61 Kirby J,Hewamadduma C A A, Hartley J A,et al.Mutations in VAPB are not associated with sporadic ALS. Neurology, 2007,68: 1951-1953
62 Landers J E, Leclerc A L, Shi L,et al.New VAPB deletion variant and exclusion of VAPB mutations in familial ALS. Neurology, 2008,70: 1179-1185
63 Teuling E, Ahmed S, Haasdijk E,et al.Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates. Neurosci, 2007, 27: 9801-9815
64 Foster LJ, Weir ML, Lim DY et al.A functional role for VAP-33 in insulin-stimulated GLUT4 traffic.Traffic, 2000,1(6):512–521
65 Greenway MJ, Alexander MD, Ennis S , et al.A novel candidate region for ALS on chromosome 14q11.2.Neurology,2004, 63: 1936-1938
66 Greenway M J, Andersen P M, Russ C,et al.ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature Genet,2006, 38: 411-413
67 Wu D, Yu W, Kishikawa H,et al.Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol,2007, 62: 609-617
68 Gellera C, Colombrita C, Ticozzi N,et al.Identification ofnew ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis. Neurogenetics,2008,9: 33-40
69 Tagawa A, Tan C F, Kikugawa K,et al. Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons. Acta Neuropath,2007,113: 205-211
70 Van Deerlin V M, Leverenz J B, Bekris L M,et al.TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet,2008,7: 409-416
71 Sreedharan J, Blair I P, Tripathi V B,et al.TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science,2008,319: 1668-1672
72 Gitcho M A, Baloh R H, Chakraverty S, et al.TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol,2008,63: 535-538
73 Kabashi E,Valdmanis P N,Dion P,et al.TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nature Genet,2008,40: 572-574
74 Luquin N, Yu B, Trent RJ, et al. An analysis of the entire SOD1 gene in sporadic ALS. Neuromuscular Disorders,2008,8:545–552
75 Suthers G, Laing N, Wilton S,et al.“Sporadic”motoneuron disease due to familial SOD1 mutation with lowpenetrance.Lancet,1994, 344: 1773
76 R.W. Orrell, J. Habgood, P. Rudge,et al.Difficulties in distinguishing sporadic from familial amyotrophic lateral sclerosis. Ann Neurol,1996,39:810–812
77刘岩峰,黄平,何欣,等. ApoE的研究进展及其在脑外伤发生中的意义.法律与医学杂志,2007,14(1):72-75
78马玉梅,张振馨. APOE基因多态性与阿尔茨海默病关系研究的进展.基础医学与临床, 2007,27 (7):739-744
79 Bedlack RS, Strittmatter WJ, Morgenlander JC. Apolipoprotein E and neuromuscular disease: a critical review of the literature. Arch Neurol,2000,57(11):1561-1565
80 Mui S, Rebeck GW, McKenna-Yasek D,et al. Apolipoprotein E epsilon 4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis. Ann Neurol,1995,38:460-463
81 Siddique T, Pericak-Vance MA, Caliendo J, et al. Lack of association between apolipoprotein E genotype and sporadic amyotrophic lateral sclerosis. Neurogenetics 1998,1:213–216
82 Lacomblez L, Doppler V, Beucler I,et al.APOE: A potential marker of disease progression in ALS.Neurology, 2002,58:1112–1114
83 Drory VE, Birnbaum M, Korczyn AD, et al. Association of APOE epsilon4 allele with survival in amyotrophic lateral sclerosis. J Neurol Sci,2001,190:17–20
84 Li YJ, Pericak-Vance MA, Haines JL, et al. ApolipoproteinE is associated with age at onset of amyotrophic lateral sclerosis.Neurogenetics,2004,5:209–13
85 Henrik Zetterberg , Johan Jacobsson , Lars Rosengren , et al.Association of APOE with age at onset of sporadic amyotrophic lateral sclerosis.Journal of the Neurological Sciences,2008,273:67–69
86 Saeed M, Siddique N, Hung WY, et al. Paraoxonase cluster polymorphisms are associated with sporadic ALS. Neurology,2006, 67(5):771-776
87 Slowik A, Tomik B, Wolkow PP, et al.Paraoxonase gene polymorphisms and sporadic ALS.Neurology, 2006,67(5):766-770
88 Cronin S, Greenway MJ, Prehn JH, et al. Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry,2007,78(9):984-986
89 Landers JE, Shi L, Cho TJ,et al.A common haplotype within the PON1 promoter region is associated with sporadic ALS.Amyotroph Lateral Scler,2008 ,9(5):306-314
90 Wills AM, Landers JE, Zhang H, et al. Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS. Neurology,2008,70(12):929-934
91齐琰,鲁莹,钟延强.血管内皮生长因子及其可降解性控释系统研究进展.中国药学杂志,2007,42(1):2-5
92 Lambrechts D, Storkebaum E, Morimoto M, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice andhumans and protects motoneurons against ischemic death. Nature Genet,2003,34: 383-394
93 Terry PD, Kamel F, Umbach DM,et al.VEGF promoter haplotype and amyotrophic lateral sclerosis (ALS). J Neurogenet,2004,18(2):429–434
94 Brockington A, Kirby J, Eggitt D,et al. Screening of the regulatory and coding regions of vascular endothelial growth factor in amyotrophic lateral sclerosis.Neurogenetics,2005,6:101–104
95 Gros-Louis F, Laurent S, Lopes AA,et al. Absence of mutations in the hypoxia response element of VEGF in ALS.Muscle Nerve,2003,28:774–775
96 Holzbaur E L F, Tokito M K.Localization of the DCTN1 gene encoding p150(Glued) to human chromosome 2p13 by fluorescence in situ hybridization.Genomics,1996,31: 398-399
97 Munch C,Rosenbohm A,Sperfeld A D,et al. Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and FTD. Ann Neurol,2005,777-780
98 Puls I, Jonnakuty C, LaMonte BH,et al. Mutant dynactin in motor neuron disease. Nat Genet, 2003 ,33(4):455-456
99 Münch C, Sedlmeier R, Meyer T, et al. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.Neurology, 2004,63:724–726
100 Collard JF, C?téF, Julien JP.Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis.Nature,1995, 375(6526):61-64
101 Figlewicz DA, Krizus A, Martinoli MG ,et al . Variants of the heavy neurofilament subunit areassociated with the development of amyotrophic lateral sclerosis. Hum Mol Genet,1994,3(10):1757-1761
102 Al-Chalabi A, Andersen PM, Nilsson P,et al.Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet,1999,(2):157-164
103 Tomkins J, Usher P, Slade JY,et al.Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). NeuroReport ,1998,(9):3967-3970
104 Rooke K, Figlewicz DA, Han FY, et al.Analysis of the KSP repeat of the neurofilament heavy subunit in familial amyotrophiclateral sclerosis.Neurology,1996 ,46(3):789-90
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |