A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan
A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan
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DOI：
10.1007/s10048-006-0041-5
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发表时间：
2006-07-01
期刊：
影响因子：
2.2
通讯作者：
Bonifati, Vincenzo
中科院分区：
文献类型：
--
作者：
Di Fonzo, Alessio;Wu-Chou, Yah-Huei;Bonifati, Vincenzo
LRRK2基因突变是常染色体显性遗传性帕金森病(PD)的原因之一。LRRK2变异是否影响对普通人的易感性，散发性帕金森病仍在很大程度上尚不清楚。有关亚洲人口的数据尤其有限。为了寻找新的、生物相关的变异，我们对台湾帕金森病患者的LRRK2编码区进行了测序。在608例帕金森病患者和373名种族匹配的对照样本中，对台湾一个帕金森氏症家系中发现的四个新发现的变异体和另一个变异体进行了疾病相关性测试。在PD患者中，Gly2385Arg变异的杂合性频率显著高于对照组(名义p值=0.004，多次比较校正=0.012，性别和年龄调整后的优势比=2.24，95%可信区间：1.29-3.88)；该变异在性别和年龄层中均匀分布。在一例PD病例中分别发现了两个新的变异体Met1869Val和Glu1874Stop；因此，它们的致病作用仍不确定。其余两个新的变异体(Ala419Val和Pro755Leu)在病例和对照中的频率相似，因此被解释为与疾病无关的多态。我们的发现表明，LRRK2 Gly2385Arg是第一个被发现的功能相关的突变，它是中国人散发性帕金森病的共同危险因素。
Mutations in the LRRK2 gene are a cause of autosomal dominant Parkinson's disease (PD). Whether LRRK2 variants influence susceptibility to the commoner, sporadic forms of PD remains largely unknown. Data are particularly limited concerning the Asian population. In search for novel, biologically relevant variants, we sequenced the LRRK2 coding region in Taiwanese patients with PD. Four newly identified variants and another variant recently found in a Taiwanese PD family were tested for association with the disease in a sample of 608 PD cases and 373 ethnically matched controls. Heterozygosity for the Gly2385Arg variant was significantly more frequent among PD patients than controls (nominal p value=0.004, corrected for multiple comparisons=0.012, gender- and age-adjusted odds ratio=2.24, 95% C.I.: 1.29-3.88); this variant was uniformly distributed across genders and age strata. Two novel variants, Met1869Val and Glu1874Stop, were found in one PD case each; their pathogenic role remains, therefore, uncertain. The remaining two novel variants (Ala419Val and Pro755Leu) were present with similar frequency in cases and controls, and were therefore, interpreted as disease-unrelated polymorphisms. Our findings suggest that the LRRK2 Gly2385Arg is the first identified, functionally relevant variant, which acts as common risk factor for sporadic PD in the population of Chinese ethnicity.