DLST对极高龄人群阿尔茨海默病遗传风险的调节作用。

Modulation by DLST of the genetic risk of Alzheimer's disease in a very elderly population.

作者信息

Sheu K F, Brown A M, Haroutunian V, Kristal B S, Thaler H, Lesser M, Kalaria R N, Relkin N R, Mohs R C, Lilius L, Lannfelt L, Blass J P

机构信息

Burke Medical Research Institute, White Plains, NY 10605, USA.

出版信息

Ann Neurol. 1999 Jan;45(1):48-53.

PMID:9894876

Abstract

The mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC) is deficient in Alzheimer's disease (AD). The DLST gene encodes the core, dihydrolipoyl succinyltransferase (DLST) component of KGDHC, and recent reports indicate an association between polymorphisms of DLST and AD in both white and Japanese patients. We therefore examined the relationship between AD and the DLST and apolipoprotein E (APOE) genes in elderly (89 +/- 7 years) AD patients, in whom the epsilon4 allele of APOE (APOE4) is a weak risk factor for AD. Polymorphisms of DLST (A19,117G and T19,183C), shown to be of interest in previous studies, were analyzed by restriction fragment length polymorphism analysis after polymerase chain reaction amplification. In a series of 429 white subjects from two Jewish nursing homes, an association of APOE4 with AD was found only in patients homozygous for the G,C allele of DLST. Similar relationships occurred in the "very elderly" (> or =85 years, n = 302) subgroup of this series, and also in an autopsy series (n = 225) that included white subjects from the Jewish nursing homes as well as other white subjects. These findings suggest a relationship between APOE4 and a DLST locus in the pathogenesis of AD in very elderly subjects.

摘要

线粒体α-酮戊二酸脱氢酶复合体（KGDHC）在阿尔茨海默病（AD）中存在缺陷。DLST基因编码KGDHC的核心成分二氢硫辛酰胺琥珀酰转移酶（DLST），最近的报告表明，在白种人和日本患者中，DLST的多态性与AD之间存在关联。因此，我们研究了老年（89±7岁）AD患者中AD与DLST和载脂蛋白E（APOE）基因之间的关系，在这些患者中，APOE的ε4等位基因（APOE4）是AD的一个弱风险因素。通过聚合酶链反应扩增后，采用限制性片段长度多态性分析方法，分析了先前研究中显示有意义的DLST多态性（A19117G和T19183C）。在来自两家犹太养老院的429名白人受试者中，仅在DLST的G、C等位基因纯合的患者中发现APOE4与AD有关联。在该系列的“非常老年”（≥85岁，n = 302）亚组中以及在一个尸检系列（n = 225）中也出现了类似的关系，尸检系列包括来自犹太养老院的白人受试者以及其他白人受试者。这些发现表明，在非常老年受试者的AD发病机制中，APOE4与一个DLST基因座之间存在关联。