Valdmanis P N, Kabashi E, Dyck A, Hince P, Lee J, Dion P, D'Amour M, Souchon F, Bouchard J-P, Salachas F, Meininger V, Andersen P M, Camu W, Dupré N, Rouleau G A
Center of Excellence in Neuromics, University of Montreal, CHUM Research Center, Notre-Dame Hospital, Montreal, Quebec, Canada.
Neurology. 2008 Aug 12;71(7):514-20. doi: 10.1212/01.wnl.0000324997.21272.0c.
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.
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).
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.
These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.
鉴于对氧磷酶基因在氧化应激反应中的作用及其对神经毒素酶解的贡献，位于7号染色体上包含PON1 - 3基因的对氧磷酶基因簇是肌萎缩侧索硬化症（ALS）关联研究的一个有吸引力的候选对象。氧化应激被认为是ALS发病机制之一。支持这一观点的证据包括：超氧化物歧化酶1（SOD1）的突变通常会减少有毒超氧阴离子的产生，在ALS的家族性病例中占12%至23%。此外，在北美和欧洲的一些人群中，PON变体被证明与ALS易感性有关。
我们扩大了这项分析，在来自法国（480例患者，475例对照）、魁北克（159例患者，95例对照）和瑞典（558例患者，506例对照）的一组患者中，检测了整个PON基因簇中的20个单核苷酸多态性（SNP）。
尽管单个SNP本身不被认为具有关联性，但包含PON2 C311S氨基酸变化的PON2 C末端部分的SNP单倍型在法国人群（p值0.0075）、魁北克人群（p值0.026）以及所有三个群体合并后的人群中具有显著性（p值1.69×10⁻⁶）。样本分层显示，这种变异与整体ALS易感性相关，而不是与特定患者亚组相关。
这些发现进一步证明了对氧磷酶基因簇中的遗传变异与肌萎缩侧索硬化症相关，证据权重不断增加。
