Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden
Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden
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DOI：
10.1212/01.wnl.0000324997.21272.0c
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发表时间：
2008-08-12
期刊：
影响因子：
9.9
通讯作者：
Rouleau, G. A.
中科院分区：
文献类型：
--
作者：
Valdmanis, P. N.;Kabashi, E.;Rouleau, G. A.
背景资料：7号染色体上的对氧磷酶基因簇包含PON 1 -3基因，鉴于对氧磷酶基因在对氧化应激的反应过程中的作用及其对神经毒素酶促分解的贡献，对氧磷酶基因簇是肌萎缩性侧索硬化症（ALS）相关性的有吸引力的候选者。氧化应激被认为是ALS发病机制之一。这方面的证据包括这样一个事实，即通常减少有毒超氧阴离子产生的SOD 1突变占ALS家族病例的12%至23%。此外，PON变异体被证明与几个北美和欧洲人群中ALS的易感性相关。我们扩展了这项分析，以检查20个单核苷酸多态性（SNPs）跨PON基因簇在一组患者来自法国（480例，475例对照），魁北克（159例，95例对照）和瑞典558例，对照506例。虽然单个SNP本身不被认为是相关的，在PON 2的C-末端部分，包括PON 2 C311 S氨基酸改变的单倍型在法国人中是显著的。（p值0.0075）和魁北克（p值0.026）人群以及所有三个人群的组合（p值1.69 x 10（-6））。分层的样品表明，这种变化是相关的ALS易感性作为一个整体，而不是一个特定的子集patient.Conclusions：这些研究结果有助于增加重量的证据表明，对氧磷酶基因簇的遗传变异与肌萎缩侧索硬化症。
Background: The paraoxonase gene cluster on chromosome 7 comprising the PON1-3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS. In addition, PON variants were shown to be associated with susceptibility to ALS in several North American and European populations.Methods: We extended this analysis to examine 20 single nucleotide polymorphisms (SNPs) across the PON gene cluster in a set of patients from France (480 cases, 475 controls), Quebec (159 cases, 95 controls), and Sweden (558 cases, 506 controls).Results: Although individual SNPs were not considered associated on their own, a haplotype of SNPs at the C-terminal portion of PON2 that includes the PON2 C311S amino acid change was significant in the French (p value 0.0075) and Quebec ( p value 0.026) populations as well as all three populations combined (p value 1.69 x 10(-6)). Stratification of the samples showed that this variation was pertinent to ALS susceptibility as a whole, and not to a particular subset of patients.Conclusions: These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.