Genetic risk profiles for Alzheimer's disease: Integration of APOE genotype and variants that up-regulate inflammation
Genetic risk profiles for Alzheimer's disease: Integration of APOE genotype and variants that up-regulate inflammation
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DOI：
10.1016/j.neurobiolaging.2006.07.007
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发表时间：
2007-11-01
影响因子：
4.2
通讯作者：
Corder, Elizabeth H.
中科院分区：
文献类型：
--
作者：
Licastro, Federico;Porcellini, Elisa;Corder, Elizabeth H.
背景：许多研究将阿尔茨海默病与载脂蛋白E基因多态性和等位基因联系起来，这些基因和等位基因有利于细胞因子或急性时相蛋白等免疫介质表达的增加。我们综合了这些信息，以更好地定义风险并确定载脂蛋白E和免疫介质的相对重要性。方法：我们研究了在意大利北部260名AD患者和190名对照中发现的APOE、IL-10(3个座位)、ACT(2个座位)、HMGCR、IL-1α、IL-1β、TNF-α、干扰素-γ和IL-6的功能基因变异。采用一种模糊潜在分类方法，即隶属度分析(GOM)，来识别极端纯型风险集或轮廓。这种方法通过分级的成员分数自动将个人与每个配置文件相关联。发现：识别了四个极端纯型风险集。SET I定义了低内在风险，携带促炎症等位基因或APOE epsilon 4的概率很低。确定了三个充分的危险集：早发性AD(Set II)具有高密度的促炎等位基因，认知功能迅速下降，独立于APOE epsilon 4。晚发性AD这些等位基因的密度较低(65-74岁，Set III)，或亚组纯合子(75岁+，Set IV)，出现一个或两个APOE epsilon 4等位基因的概率很高。共有97%的病例受试者非常相似，即至少有50%的成员属于足够的风险集合，25%的中年对照组受试者也是如此。与载脂蛋白E相比，IL-10、HMGCR、ACT和IL-1β基因变异体在识别风险集合方面的信息量更大。解释：AD可能有许多决定因素，包括载脂蛋白E基因多态性和调节先天免疫的基因变异体。对这些因素的识别、对个人的风险预测以及成功的预防和治疗试验需要整合相关信息。(C)2006 Elsevier Inc.保留所有权利。
Background: A number of studies associate Alzheimer's disease with APOE polymorphism and alleles which favor the increased expression of immunological mediators such as cytokines or acute phase proteins. We integrated this information to better define risk and determine the relative importance of APOE and immunological mediators.Methods: We investigated functional gene variants for APOE, IL-10 (3 loci), ACT (2 loci), HMGCR, IL-1 alpha, IL-1 beta TNF-alpha, IFN-gamma, and IL-6 found for 260 AD patients and 190 controls enrolled in Northern Italy. A fuzzy latent classification approach, namely grade-of-membership analysis (GoM), was taken to identify extreme pure type risk sets, or profiles. This approach automatically relates individuals to each profile via graded membership scores.Findings: Four extreme pure type risk sets were identified. Set I defined low intrinsic risk and had a low probability of carrying proinflammatory alleles or APOE epsilon 4. Three sufficient risk sets were identified: early onset AD (set II) was characterized by a high density of pro-inflammatory alleles, a rapid cognitive decline and independent of APOE epsilon 4. Late onset AD had a lower density (ages 65-74, set III), or a subset homozygous (ages 75+, set IV), for these alleles and a high probability of one or two APOE epsilon 4 alleles. A total of 97% of the subjects who were cases strongly resembled, i.e. had at least 50% membership in, the sufficient risk sets, as did 25% of middle aged control subjects. IL-10, HMGCR, ACT, and IL-1 beta gene variants were each more informative in identifying the risk sets than was APOE.Interpretation: AD likely has many determinants including APOE polymorphism and gene variants that modulate innate immunity. Identification of these factors, risk prediction for individuals, and successful prevention and treatment trials require integration of relevant information. (c) 2006 Elsevier Inc. All rights reserved.