帕金森病相关基因研究
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摘要
【背景】帕金森病(Parkinson disease，PD)是一种以黑质多巴胺能神经元丢失为特征的中枢神经系统变性疾病，病因不清。流行病学调查显示农药，杀虫剂，除草剂等环境毒素可能增加PD的发病危险。不同个体对毒物的反应大小不同与个体的毒物代谢酶的活性高低有关，而后者是由编码这些酶的基因多态性决定的。因此，毒物代谢酶的基因多态性可能与PD的遗传易患性有关。N-乙酰基转移酶(N-acetyltransferase，NAT)催化许多芳香胺类和肼类物质的乙酰化反应，这些物质存在于某些药物，杀虫剂，染料中。因此N-乙酰基转移酶的基因多态性可能与PD的遗传易患性有关。
【目的】探讨N-乙酰基转移酶(NAT2)慢乙酰化等位基因和慢乙酰化基因型与帕金森病的关系。
【方法】采取PCR-RFLP的方法，比较各100名原发性PD患者和健康人NAT2三个慢乙酰化等位基因M1，M2和M3的频率分布以及慢乙酰化基因型的的频率分布差异。
【结果】在全部PD患者和健康对照组之间，NAT2慢乙酰化等位基
天津医科大学博士学位论文
论文一
因和慢乙酞化基因型频率分布无显著差异。而在54名早发性PD患者(发
病年龄<55岁)，Ml，MZ和M3的频率分布为6.5%，26.9%和22.2%，对
照组为4%，16%和16%，两组差异显著(P<0.05)。早发性PD患者和对
照组慢乙酞化基因型的频率分布分别为24.1%和11%，两组差异显著
(P<0.05)。
【结论】NATZ慢乙酞化等位基因和慢乙酞化基因型增加早发性PD
患病危险。
[Background] Parkinson disease (PD) is a neurodegenerative disorder, whose Pathological hallmark is prominent loss of doparminergic neurons in the substantia nigra. The pathogenesis of PD is unknown. Epidemiological studies have identified exposure to environmental toxins, such as pesticide, insecticide and herbicide as risk factors for PD. The ability to inactivate toxins of individuals correlates with different levels of detoxification enzymes, which is determined by polymorphisms of genes encoding those enzymes. So genetic polymorphisms of detoxification enzymes may be associated with genetic
susceptibility to Parkinson disease. N-acetyltransferase(NAT) acetylate numerous chemicals containing aromatic amine or hydrazine groups, which are often found in herbicide, insecticide and dyes. So genetic polymorphism of N-acetyltransferase may have related with genetic susceptibility to Parkinson disease.
[ Objectives ] To investigate the relationship between Parkinson disease(PD) and slow acetylator alleles and slow acetylator genotype of N-acetyltransferase.
[Methods] Using PCR-RFLP, we compare the difference of three slow acetylator alleles Ml, M2 , M3 and slow acetylator genotype between 100 idiopathic PD and controls.
[Results] Between whole PD and controls, the difference in frequency of slow acetylator alleles and genotypes wasn't significant(P>0.05)0 But for 54 early-onset Parkinson disease(onset<55y), the frequency of alleles Ml, M2, M3 were 6.5%, 26.9% and 22.2% respectively, while 4%, 16% and 16% in controls. The differences were statistically significant(P<0.05). The frequency of slow acetylator genotypes were 24.1% and 11% respectively for early-onset Parkinson disease and controls. The differences were statistically significant(P<0.05) too.
[Conclusions] NAT2 Slow acetylator alleles and slow acetylator genotype of N-acetyltransferase might at higher risk to develop early-onset Parkinon disease.
【目的】探讨N-乙酰基转移酶(NAT2)慢乙酰化等位基因和慢乙酰化基因型与帕金森病的关系。
【方法】采取PCR-RFLP的方法，比较各100名原发性PD患者和健康人NAT2三个慢乙酰化等位基因M1，M2和M3的频率分布以及慢乙酰化基因型的的频率分布差异。
【结果】在全部PD患者和健康对照组之间，NAT2慢乙酰化等位基
天津医科大学博士学位论文
论文一
因和慢乙酞化基因型频率分布无显著差异。而在54名早发性PD患者(发
病年龄<55岁)，Ml，MZ和M3的频率分布为6.5%，26.9%和22.2%，对
照组为4%，16%和16%，两组差异显著(P<0.05)。早发性PD患者和对
照组慢乙酞化基因型的频率分布分别为24.1%和11%，两组差异显著
(P<0.05)。
【结论】NATZ慢乙酞化等位基因和慢乙酞化基因型增加早发性PD
患病危险。
[Background] Parkinson disease (PD) is a neurodegenerative disorder, whose Pathological hallmark is prominent loss of doparminergic neurons in the substantia nigra. The pathogenesis of PD is unknown. Epidemiological studies have identified exposure to environmental toxins, such as pesticide, insecticide and herbicide as risk factors for PD. The ability to inactivate toxins of individuals correlates with different levels of detoxification enzymes, which is determined by polymorphisms of genes encoding those enzymes. So genetic polymorphisms of detoxification enzymes may be associated with genetic
susceptibility to Parkinson disease. N-acetyltransferase(NAT) acetylate numerous chemicals containing aromatic amine or hydrazine groups, which are often found in herbicide, insecticide and dyes. So genetic polymorphism of N-acetyltransferase may have related with genetic susceptibility to Parkinson disease.
[ Objectives ] To investigate the relationship between Parkinson disease(PD) and slow acetylator alleles and slow acetylator genotype of N-acetyltransferase.
[Methods] Using PCR-RFLP, we compare the difference of three slow acetylator alleles Ml, M2 , M3 and slow acetylator genotype between 100 idiopathic PD and controls.
[Results] Between whole PD and controls, the difference in frequency of slow acetylator alleles and genotypes wasn't significant(P>0.05)0 But for 54 early-onset Parkinson disease(onset<55y), the frequency of alleles Ml, M2, M3 were 6.5%, 26.9% and 22.2% respectively, while 4%, 16% and 16% in controls. The differences were statistically significant(P<0.05). The frequency of slow acetylator genotypes were 24.1% and 11% respectively for early-onset Parkinson disease and controls. The differences were statistically significant(P<0.05) too.
[Conclusions] NAT2 Slow acetylator alleles and slow acetylator genotype of N-acetyltransferase might at higher risk to develop early-onset Parkinon disease.
引文
Agundez JAG, Jimenez-Jimenez FJ , Luengo A, et al. Slow allotypic variants of the NAT2 gene and susceptibility to early-onset Parkinson's disease. Neurology, 1998;51:1587-1592
Bandmann O, Vaughan J , Holmans P, etal. Association of slow acetylator genotype for N-acetyltransferase 2 with familial Parkinson's disease. Lancet, 1997;350:1136-1139
Bandmann O, Vaughan JR, Holmans P,et. Detailed genotyping demonstrates association between the slow acetylator genotype for N-acetyltransferase 2 (NAT2) and familial Parkinson's disease. Mov Disord,2000;15:30-5
Blum M, Demierre A, Grant DM, et al. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc.Natl.Acad.Sci.USA, 1991;88:5237-5241
Cascorbi I , Drakoulis N , Brockmoller J , et al . Arylamine N-acetyltransferase(NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity. Am J Hum Gener, 1995;57: 581-592
Daly AK,Cholerton S,Gregory W, et al. Metabolic polymorphisms. Pharmac Ther,1993;57:129-160
Maraganore DM, Farrer MJ, Hardy JA,ET. Case-control study of debrisoquine 4-hydroxylase, N-acetyltransferase 2,and apolipoprotein E gene polymorphisms in Parkinson's disease. Mov Disord, 2000; 15:714-9
Meyer UA,Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabolism., Annu Rev Pharmacol Toxicol,1997;37:269-96
Bandmann O, Vaughan J , Holmans P, etal. Association of slow acetylator genotype for N-acetyltransferase 2 with familial Parkinson's disease. Lancet, 1997;350:1136-1139
Bandmann O, Vaughan JR, Holmans P,et. Detailed genotyping demonstrates association between the slow acetylator genotype for N-acetyltransferase 2 (NAT2) and familial Parkinson's disease. Mov Disord,2000;15:30-5
Blum M, Demierre A, Grant DM, et al. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proc.Natl.Acad.Sci.USA, 1991;88:5237-5241
Cascorbi I , Drakoulis N , Brockmoller J , et al . Arylamine N-acetyltransferase(NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity. Am J Hum Gener, 1995;57: 581-592
Daly AK,Cholerton S,Gregory W, et al. Metabolic polymorphisms. Pharmac Ther,1993;57:129-160
Maraganore DM, Farrer MJ, Hardy JA,ET. Case-control study of debrisoquine 4-hydroxylase, N-acetyltransferase 2,and apolipoprotein E gene polymorphisms in Parkinson's disease. Mov Disord, 2000; 15:714-9
Meyer UA,Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabolism., Annu Rev Pharmacol Toxicol,1997;37:269-96
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