Bandmann O, Vaughan J, Holmans P, Marsden C D, Wood N W
University Department of Clinical Neurology, Institute of Neurology, London, UK.
Lancet. 1997 Oct 18;350(9085):1136-9. doi: 10.1016/s0140-6736(97)03495-8.
Epidemiological studies have identified positive family history and exposure to environmental toxins as risk factors for Parkinson's disease (PD). An inherited defect of xenobiotic metabolism could result in increased susceptibility to such toxins. We investigated the frequency of functionally relevant polymorphisms in six detoxification enzymes among patients with PD to elucidate the relation between these polymorphisms and the disease.
We obtained brain-tissue samples from 100 patients with apparently sporadic PD and blood samples from 100 living patients with familial PD. For the control group, we extracted DNA from the tissue of 100 pathologically normal brains. The six enzymes analysed in these three groups were: CYP2D6, CYP2E1, NAD(P)H-menadione reductase, glutathione transferases M1 and T1, and N-acetyltransferase 2. We also investigated N-acetyltransferase 2 in 100 blood samples from patients with genetically proven Huntington's disease. We used PCR-based methods and restriction-enzyme analysis to detect polymorphisms.
The slow acetylator genotype for N-acetyltransferase 2 was more common in the familial PD group (69%) than in all controls (37%). Even after correction for multiple comparisons, this result remained highly significant (p = 0.002) for familial PD compared with normal controls (odds ratio 3.79 [95% CI 2.08-6.90]) and compared with Huntington's disease (2.45 [1.37-4.38], p = 0.004). The slow acetylator frequency for N-acetyltransferase 2 for sporadic PD was between that for Huntington's disease and familial PD. The frequencies of all the other polymorphisms were similar in the two study groups and the normal control group.
We found an association between the slow acetylator genotype for N-acetyltransferase 2 and familial PD. Further studies are needed to investigate the biological relevance of these findings, but slow acetylation could lead to impaired ability of patients with familial PD to handle neurotoxic substances.
流行病学研究已确定家族病史和接触环境毒素是帕金森病（PD）的风险因素。外源性物质代谢的遗传缺陷可能导致对这类毒素的易感性增加。我们调查了PD患者中六种解毒酶功能相关多态性的频率，以阐明这些多态性与疾病之间的关系。
我们从100例明显散发型PD患者中获取脑组织样本，并从100例家族性PD在世患者中获取血液样本。对于对照组，我们从100例病理正常的脑组织中提取DNA。在这三组中分析的六种酶分别是：细胞色素P450 2D6（CYP2D6）、细胞色素P450 2E1（CYP2E1）、NAD（P）H-甲萘醌还原酶、谷胱甘肽转移酶M1和T1以及N-乙酰转移酶2。我们还在100例基因确诊的亨廷顿病患者的血液样本中研究了N-乙酰转移酶2。我们使用基于聚合酶链反应（PCR）的方法和限制性酶切分析来检测多态性。
家族性PD组中N-乙酰转移酶2的慢乙酰化基因型（69%）比所有对照组（37%）更常见。即使在进行多重比较校正后，与正常对照组相比，家族性PD的这一结果仍具有高度显著性（p = 0.002）（比值比3.79 [95%可信区间2.08 - 6.90]），与亨廷顿病相比也具有显著性（2.45 [1.37 - 4.38]，p = 0.004）。散发型PD中N-乙酰转移酶2的慢乙酰化频率介于亨廷顿病和家族性PD之间。两个研究组和正常对照组中所有其他多态性的频率相似。
我们发现N-乙酰转移酶2的慢乙酰化基因型与家族性PD之间存在关联。需要进一步研究来调查这些发现的生物学相关性，但慢乙酰化可能导致家族性PD患者处理神经毒性物质的能力受损。
