APP and BACE1 miRNA Genetic Variability Has No Major Role in Risk for Alzheimer Disease
APP and BACE1 miRNA Genetic Variability Has No Major Role in Risk for Alzheimer Disease
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DOI：
10.1002/humu.21027
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发表时间：
2009-08-01
期刊：
影响因子：
3.9
通讯作者：
Van Broeckhoven, Christine
中科院分区：
文献类型：
--
作者：
Bettens, Karolien;Brouwers, Nathalie;Van Broeckhoven, Christine
淀粉样前体蛋白（APP）和β位点淀粉样蛋白（A β）裂解酶1（BACE 1）的表达水平与阿尔茨海默病（AD）进展有关。在一个由358名AD患者和462名对照组成的比利时组中，我们研究了APP和BACE 1的microRNA（miPNA）结合位点或相关miRNAs的遗传变异性是否影响AD的风险。直接测序鉴定了APP 3'非翻译区（UTR）中的6个变体和BACE 1 3' UTR中的29个变体，其中少数变体仅限于患者：APP中，6名患者中的4个变体（类似于2%）和BACE 1中，11名患者中的7个变体（类似于3.5%）。对编码miR-29 a/B-1基因的miR-29簇的进一步遗传筛选显示了与该簇非常接近的10种变体。使用在BACE 1的3' UTR和miR-29基因簇中检测到的所有常见变异的关联研究没有确定与AD风险的关联。然而，我们确实观察到rs 535860（BACE 1 3' UTR）和rs34772568之间的统计学相互作用（接近miR 29 a;比值比[OR]（相互作用），0.4; 95%置信区间[CI] 0.17-0.96; P = 0.033）。虽然在APP和BACE 1的3' UTR区域内的患者特异性miRNA变体的确切作用需要进一步分析，但本研究不支持miRNA遗传变异对AD发病机制的主要贡献。《Mutat》30，1207-1213，2009年。(C)2009威利-利斯公司
Expression levels of the amyloid precursor protein (APP) and beta-site amyloid (A beta) cleaving enzyme 1 (BACE1) have been implicated in Alzheimer disease (AD) progression. In a well-characterized Belgian group of 358 AD patients and 462 controls, we examined whether genetic variability in microRNA (miPNA) binding sites of APP and BACE1 or in associated miRNAs influenced risk for AD. Direct sequencing identified six variant, in the 3' untranslated region (UTR) of APP and 29 variants in the 3' UTR of BACE1, of which few variants were restricted to patients: in APP, 4 variants in 6 patients (similar to 2%) and in BACE1; 7 variants in 11 patients (similar to 3.5%). Further genetic screening of the miR-29 cluster encoding the miR-29a/b-1 genes showed 10 variants in close proximity of this cluster. Association studies using all common variants detected in the 3' UTR of BACE1 and the miR-29 gene cluster did not identify an association,with AD risk. However, we did observe statistical interaction between rs535860 (BACE1 3' UTR) and rs34772568 (near miR29a; odds ratio [OR](interaction), 0.4; 95% confidence interval [CI] 0.17-0.96; P = 0.033). While the exact role of the patient, specific miRNA variants within the 3' UTR region of APP and BACE1 demands further analyses, this study does not support a major contribution of miRNA genetic variability to AD pathogenesis. Hum Mutat 30, 1207-1213, 2009. (C) 2009 Wiley-Liss, Inc.