Rodríguez-Rodríguez Eloy, Mateo Ignacio, Llorca Javier, Sánchez-Quintana Coro, Infante Jon, García-Gorostiaga Inés, Sánchez-Juan Pascual, Berciano José, Combarros Onofre
Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria), 39008 Santander, Spain.
Am J Med Genet B Neuropsychiatr Genet. 2007 Oct 5;144B(7):964-8. doi: 10.1002/ajmg.b.30552.
ABCA1 plays key roles in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain. To evaluate the relationship between ABCA1 genetic variants and Alzheimer's disease (AD), independently or in concert with the APOE epsilon4 allele, we examined three ABCA1 polymorphisms located in the coding region (R219K, I883M, and R1587K) and two ABCA1 polymorphisms in the promoter region (C-14T and C-477T) in a group of 372 Spanish AD patients and 440 controls. The ABCA1 219K, 883I, 1587R haplotype was significantly associated with AD, conferring a risk of 1.78 (P = 0.007). The ABCA1 C-14T polymorphism modified the risk of AD in an APOE epsilon4 allele-dependent fashion: in APOE epsilon4 carriers, homozygous for the ABCA1 -14T allele had 3.7 times higher risk of developing AD (OR = 13.99) than carriers of the ABCA1 -14CC and CT genotypes (OR = 3.79). These data suggest that the development of AD might be influenced by either a qualitative change of the ABCA1 protein caused by coding region variants (219K, 883I, and 1587R), or by a quantitative change in ABCA1 expression caused by promoter region variant (-14T) in concert with the APOE epsilon4 allele.
ABCA1在大脑中的胆固醇转运和载脂蛋白E（APOE）代谢中起关键作用。为了评估ABCA1基因变异与阿尔茨海默病（AD）之间的关系，无论是独立作用还是与APOE ε4等位基因协同作用，我们检测了一组372名西班牙AD患者和440名对照中位于编码区的三个ABCA1多态性位点（R219K、I883M和R1587K）以及启动子区的两个ABCA1多态性位点（C-14T和C-477T）。ABCA1 219K、883I、1587R单倍型与AD显著相关，风险比为1.78（P = 0.007）。ABCA1 C-14T多态性以APOE ε4等位基因依赖的方式改变AD风险：在APOE ε4携带者中，ABCA1 -14T等位基因纯合子患AD的风险比ABCA1 -14CC和CT基因型携带者高3.7倍（OR = 13.99）（OR = 3.79）。这些数据表明，AD的发生可能受编码区变异（219K、883I和1587R）导致的ABCA1蛋白质量变化影响，或者受启动子区变异（-14T）与APOE ε4等位基因协同作用导致的ABCA1表达量变化影响。
