Strong Association of Lipid Metabolism Related MicroRNA Binding Sites Polymorphisms with the Risk of Late Onset Alzheimer's Disease.
Strong Association of Lipid Metabolism Related MicroRNA Binding Sites Polymorphisms with the Risk of Late Onset Alzheimer's Disease.
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DOI：
10.2174/1567202613666161027101100
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发表时间：
2017-01
影响因子：
2.1
通讯作者：
Lin Tan;A. Xing;Dan Zhao;Fu-Rong Sun;M. Tan;Yu Wan;Chen‐Chen Tan;Wei Zhang;Dan Miao;Jin-Tai Yu;L. Tan
中科院分区：
文献类型：
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作者：
Lin Tan;A. Xing;Dan Zhao;Fu-Rong Sun;M. Tan;Yu Wan;Chen‐Chen Tan;Wei Zhang;Dan Miao;Jin-Tai Yu;L. Tan
尽管细胞生物学和流行病学研究表明脂代谢异常与晚发性阿尔茨海默病(LOAD)的发病机制密切相关，但将脂代谢与LOAD联系起来的遗传学研究仍不是很清楚。MicroRNAs(MiRNAs)在转录后下调，其3‘非翻译区(3’UTR)的靶序列可被单核苷酸多态(SNPs)改变。因此，我们探讨聚集素基因(CLU)(Rs9331949)、脂蛋白脂酶基因(Lpl)(rs1059507、rs3200218、rs3208305、rs3735964)和低密度脂蛋白受体相关蛋白6(LRP6)(Rs2160525)的6个基因座是否通过改变miRNA结合位点来调节负荷风险。我们对中国北方汉族2338例无血缘关系的受试者(984例和1354例年龄和性别匹配的对照)进行了病例对照研究。我们发现，即使在调整多次检测后，rs9331949的微小C等位基因也显著增加了负载风险(P<；0.001，OR=1.31，95%CI=1.14-1.51)。Logistic回归分析表明，即使在载脂蛋白E(ApoE)ε4等位基因非携带者亚组中，rs9331949基因多态性仍与LOAD密切相关。然而，在Bonferroni调整后，其他5个基因座与负荷没有显著关联。综上所述，我们在LPL和LRP6中发现了位于CLU 3‘非编码区结合位点处的基因座(Rs9331949)与LPL和LRP6中的LOAD有很强的相关性。但是，需要额外的独立复制才能进一步验证。
Although altered lipid metabolism has been extensively implicated in the pathogenesis of late onset Alzheimer's disease (LOAD) through cell biological and epidemiological studies, genetic studies linking lipid metabolism and LOAD are still not well understood. MicroRNAs (miRNAs) exert posttranscriptional down-regulation and their target sequence on the 3' untranslated regions (3'UTR) may be altered by single nucleotide polymorphisms (SNPs). We therefore explore whether the six loci in Clusterin gene (CLU) (rs9331949), Lipoprotein lipase gene (LPL) (rs1059507, rs3200218, rs3208305, rs3735964) and Low-density lipoprotein receptor related protein 6 (LRP6) (rs2160525) could modulate LOAD risk through the alteration of miRNA binding sites. We performed a case-control study of 2338 unrelated subjects (984 cases and 1354 age- and gender-matched controls) in the Northern Han Chinese. We found that the minor C allele in rs9331949 significantly increased the risk of LOAD (P<0.001, OR=1.31, 95% CI=1.14-1.51), even after adjusting for multiple testing. Logistic analysis identified the rs9331949 polymorphism was still strongly associated with LOAD, even in Apolipoprotein E (APOE) ε4 allele noncarrier subgroups. However, the other five loci were not significantly associated with LOAD after Bonferroni adjustment. In conclusion, we have identified that the locus (rs9331949) located in the binding site of 3' UTR of CLU has a strong association with LOAD rather than loci in LPL and LRP6. However, additional independent replication is required for further validation.