Paraoxonase cluster polymorphisms are associated with sporadic ALS
Paraoxonase cluster polymorphisms are associated with sporadic ALS
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DOI：
10.1212/01.wnl.0000227187.52002.88
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发表时间：
2006-09-12
期刊：
影响因子：
9.9
通讯作者：
Siddique, T.
中科院分区：
文献类型：
--
作者：
Saeed, M.;Siddique, N.;Siddique, T.
背景：对氧磷酶（脑桥）参与有机磷农药和化学神经毒剂的解毒。由于海湾战争退伍军人中ALS的风险可能增加两倍，以及PON1多态性与海湾战争综合征的神经系统症状综合征的相关性，作者在一个大型的北美白人家族和病例对照队列（N = 1，891）中调查了散发性ALS（SALS）和PON基因簇变异之间的关联。研究方法：根据修订后的埃尔埃斯科里亚标准，排除ALS家族史和SOD 1突变分析，诊断临床明确和可能的ALS。使用TaqMan分析在ABI7900HT上进行单核苷酸多态性（SNP）基因分型。数据分析采用SPSS、Haploview、FBAT和THESIAS。结果：一个跨越PON2和PON3的高度连锁不平衡（LD）单块与SALS相关。SNPs rs10487132和rs11981433处于强LD中，并且在三人组（父母影响的孩子三人组）模型中与SALS相关。rs10487132的关联在450个包括三人组和不一致同胞对的核家系中被复制。在病例对照模型中未发现相关性，其单倍结构与总体LD降低的三人组不同。重测序确定了一个内含子变异（rs17876088），区分有害和保护SALS单倍型。总结：这项研究证明了对氧磷酶基因簇中的变异体与散发性ALS显著相关的证据，并且与易感宿主中的环境毒性可能沉淀ALS的假设相容。
Background: Paraoxonases (PONs) are involved in the detoxification of organophosphate pesticides and chemical nerve agents. Due to a reported possible twofold increased risk of ALS in Gulf War veterans and the associations of PON1 polymorphisms with the neurologic symptom complex of the Gulf War syndrome, the authors investigated the association between sporadic ALS (SALS) and PON gene cluster variants in a large North American Caucasian family based and case-control cohort (N = 1,891). Methods: Clinically definite and probable ALS was diagnosed according to the revised El Escorial criteria, exclusion of family history of ALS, and SOD1 mutation analysis. Single nucleotide polymorphism (SNP) genotyping was done using TaqMan assays on ABI7900HT. Data were analyzed using SPSS, Haploview, FBAT, and THESIAS. Results: A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. The SNPs rs10487132 and rs11981433 were in strong LD and associated with SALS in the trio (parents-affected child triad) model. The association of rs10487132 was replicated in 450 nuclear pedigrees comprising trios and discordant sibpairs. No association was found in case-control models, and their haplostructure was different from that of the trios with overall reduced LD. Resequencing identified an intronic variant (rs17876088) that differentiated between detrimental and protective SALS haplotypes. Conclusion: This study demonstrates evidence of significant association of variants in the Paraoxonase gene cluster with sporadic ALS and is compatible with the hypothesis that environmental toxicity in a susceptible host may precipitate ALS.