Reynolds Chandra A, Hong Mun-Gwan, Eriksson Ulrika K, Blennow Kaj, Bennet Anna M, Johansson Boo, Malmberg Bo, Berg Stig, Wiklund Fredrik, Gatz Margaret, Pedersen Nancy L, Prince Jonathan A
Department of Psychology, University of California at Riverside, Riverside, California, USA.
Hum Mutat. 2009 Sep;30(9):1348-54. doi: 10.1002/humu.21076.
We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.23-1.57, p=7.7x10(-8)). Haplotype-based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of beta-amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease.
我们和其他研究人员已针对ABCA1与阿尔茨海默病风险进行了靶向基因关联分析，结果既有支持也有反驳，但之前所有研究都仅基于少数几个标记物。在此，我们对总共1567例瑞典痴呆症病例（包括1275例阿尔茨海默病患者）和2203例对照进行了ABCA1区域遗传变异的详细调查，结果表明在标记物rs2230805处存在显著关联（优势比[OR]=1.39；95%置信区间[CI]为1.23 - 1.57，p = 7.7×10⁻⁸）。基于单倍型的检验在排除rs2230805后证实了该基因组区域的关联，且通过推断未发现有更多支持的其他标记物。显著关联的标记物位于两个不同的连锁不平衡区域，其峰值分别靠近启动子以及截短的ABCA1剪接形式的末端外显子。还发现rs2230805的假定风险等位基因与脑脊液中β - 淀粉样蛋白水平降低有关。当将所有形式的痴呆症综合考虑时获得了最强的关联证据，但仅评估确诊的阿尔茨海默病病例时效应大小相似。结果进一步表明ABCA1与痴呆症有关，强化了脂质转运在神经退行性疾病中可能的作用。
