Rodríguez-Rodríguez Eloy, Mateo Ignacio, Infante Jon, Llorca Javier, García-Gorostiaga Inés, Vázquez-Higuera José Luis, Sánchez-Juan Pascual, Berciano José, Combarros Onofre
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla University Hospital, University of Cantabria, Santander, Spain.
Brain Res. 2009 Jul 14;1280:166-71. doi: 10.1016/j.brainres.2009.05.019. Epub 2009 May 14.
A number of studies suggest that increased cellular cholesterol levels induce high amyloid beta (Abeta) production, which is central to the pathogenesis of Alzheimer's disease (AD). In the brain, glial cells have hydroxy-methylglutaryl-coenzyme A reductase (HMGCR) as the major rate-limiting enzyme in the novo synthesis of cholesterol, which once synthesized, is secreted via the cholesterol transporter ABCA1. Overexpression of HMGCR in concert with underexpression of ABCA1 would result in increased cholesterol accumulation, induction of Abeta production, and increased AD risk. We examined two HMGCR polymorphisms located in 5'-UTR (rs3931914) and promoter (-911, rs3761740) regions of the gene, and two ABCA1 polymorphisms (-14, rs1800977; and -477, rs2422493) located in promoter region of the gene, in a group of 325 Spanish AD patients and 383 controls. Subjects carrying both the HMGCR (5'-UTR) GG genotype and the ABCA1 (-14) TT genotype (adjusted by age, sex and APOE status OR=2.77; 95% CI=1.16-6.61; p=0.02), or the ABCA1 (-477) TT genotype (adjusted by age, sex and APOE status OR=2.07; 95% CI=1.14-3.78; p=0.02) had a higher risk of developing AD than subjects without these risk genotypes, and this genetic interaction was observed in either the presence or the absence of the APOE epsilon4 allele. Considering synergistic effects between polymorphisms in synthesis and secretion cholesterol-related genes may help in determining the risk profile for AD.
多项研究表明，细胞内胆固醇水平升高会诱导高淀粉样β蛋白（Aβ）生成，而这是阿尔茨海默病（AD）发病机制的核心。在大脑中，胶质细胞具有羟甲基戊二酰辅酶A还原酶（HMGCR），它是胆固醇从头合成过程中的主要限速酶，胆固醇一旦合成，便通过胆固醇转运蛋白ABCA1分泌出去。HMGCR过表达与ABCA1低表达共同作用会导致胆固醇积累增加、Aβ生成诱导以及AD风险增加。我们在325名西班牙AD患者和383名对照组成的群体中，检测了该基因位于5'-UTR（rs3931914）和启动子（-911，rs3761740）区域的两个HMGCR多态性位点，以及位于该基因启动子区域的两个ABCA1多态性位点（-14，rs1800977；和-477，rs2422493）。携带HMGCR（5'-UTR）GG基因型和ABCA1（-14）TT基因型（经年龄、性别和APOE状态调整后OR = 2.77；95% CI = 1.16 - 6.61；p = 0.02），或ABCA1（-477）TT基因型（经年龄、性别和APOE状态调整后OR = 2.07；95% CI = 1.14 - 3.78；p = 0.02）的受试者患AD的风险高于没有这些风险基因型的受试者，并且无论是否存在APOE ε4等位基因，均观察到这种基因相互作用。考虑到胆固醇合成和分泌相关基因多态性之间的协同效应可能有助于确定AD的风险特征。
