Multiple LRRK2 Variants Modulate Risk of Parkinson Disease: A Chinese Multicenter Study
Multiple LRRK2 Variants Modulate Risk of Parkinson Disease: A Chinese Multicenter Study
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DOI：
10.1002/humu.21225
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发表时间：
2010-05-01
期刊：
影响因子：
3.9
通讯作者：
Wu, Ruey-Meei
中科院分区：
文献类型：
--
作者：
Tan, Eng-King;Peng, Rong;Wu, Ruey-Meei
我们和其他人发现了两个与中国帕金森病（PD）相关的LRRK 2（富含亮氨酸重复序列激酶2）多态性变体（rs34778348：G > A; p.G2385R和rs33949390：G > C; p.R1628P），但缺乏全球常见的rs34637584：G > A; p.G2019S突变。我们首先对年轻发病和家族性PD患者的编码区进行了测序，并确定了59个变体。然后，我们在250名患者和250名对照受试者中检查了这些变异。在17个多态性变体中，5个在病例与对照中表现出不同的频率，并在1，363名患者和1，251名对照受试者的较大样本中进行了考虑。携带p.G2385R和p.R1628P的个体的相对风险约为1.9，如果个体还携带rs7133914：G > C; p.R1398H或rs7308720：C > A：p.N551K，则风险降低至1.5-1.6。携带p.R1628P的风险在很大程度上是否定的，如果个人也携带p.R1398H或p.N551K。在多巴胺能神经元系中，p.R1398H具有显著较低的激酶活性，而p.G2385R和p.R1628P显示出比野生型更高的激酶活性。我们提供了第一个证据表明，多个LRRK 2变异发挥个体效应，并共同调节中国人的PD风险。Mutat 31：561-568，2010. (C)2010 Wiley-Liss，Inc.
We and others found two polymorphic LRRK2 (leucine-rich repeat kinase 2) variants (rs34778348:G > A; p.G2385R and rs33949390:G > C; p.R1628P) associated with Parkinson disease (PD) among Chinese patients, but the common worldwide rs34637584:G > A; p.G2019S mutation, was absent. Focusing exclusively on Han Chinese, we first sequenced the coding regions in young onset and familial PD patients and identified 59 variants. We then examined these variants in 250 patients and 250 control subjects. Among the 17 polymorphic variants, five demonstrated different frequency in cases versus controls and were considered in a larger sample of 1,363 patients and 1,251 control subjects. The relative risk of an individual with both p.G2385R and p.R1628P is about 1.9, and this is reduced to 1.5-1.6 if the individual also carries rs7133914:G > C; p.R1398H or rs7308720:C > A: p.N551K. The risk of a carrier with p.R1628P is largely negated if the individual also carries p.R1398H or p.N551K. In dopaminergic neuronal lines, p.R1398H had significantly lower kinase activity, whereas p.G2385R and p.R1628P showed higher kinase activity than wild type. We provided the first evidence that multiple LRRK2 variants exert an individual effect and together modulate the risk of PD among Chinese. Hum Mutat 31:561-568, 2010. (C) 2010 Wiley-Liss, Inc.