Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease
Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease
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DOI：
10.1086/373937
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发表时间：
2003-04-01
影响因子：
9.8
通讯作者：
Vance, JM
中科院分区：
文献类型：
--
作者：
van der Walt, JM;Nicodemus, KK;Vance, JM
线粒体（mt）损伤，特别是电子传递系统复合体I的损伤，与帕金森病（PD）的发病机制有关。超过一半的线粒体编码多肽是还原烟酰胺腺嘌呤二核苷酸脱氢酶（NADH）复合体I酶的一部分。为了验证mtDNA变异有助于PD表达的假设，我们在609名白人PD患者和340名未受影响的白人对照中对10个单核苷酸多态性（snp）进行了基因分型，这些多态性定义了欧洲mtDNA单倍群。总体而言，与携带最常见单倍群h的个体相比，被分类为单倍群J（优势比[OR] 0.55； 95%置信区间[CI] 0.34-0.91; P = 0.02）或K （OR 0.52; 95% CI 0.30-0.90; P = 0.02）的个体患PD的风险显著降低。此外，定义这两个单倍群的特定SNP 10398G与这种保护作用密切相关（OR 0.53; 95% CI 0.39-0.73; P = 0.0001）。SNP 10398G导致复合体i的NADH脱氢酶3 （ND3）中的非保守氨基酸从苏氨酸变为丙氨酸。按性别分层后，这种风险的降低在女性中表现得比男性更强（OR 0.43; 95% CI 0.27-0.71; P = 0.0009）。此外，ATP6的SNP 9055A对女性有保护作用（OR 0.45; 95% CI 0.22-0.93; P = 0.03）。我们的研究结果表明ND3是白人PD易感性的一个重要因素，可以帮助解释复合物I在PD表达中的作用。
Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P = .02) or K (OR 0.52; 95% CI 0.30-0.90; P = .02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P = .0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P = .0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P = .03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.