Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Int J Geriatr Psychiatry. 2019 May;34(5):692-699. doi: 10.1002/gps.5068. Epub 2019 Mar 7.
While a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) or cognitive impairment have been identified, independent replications remain the only way to validate proposed signals. We investigated SNPs in candidate genes associated with either cognitive impairment or AD pathogenesis and their relationships with probable dementia (PD) in the Women's Health Initiative Memory Study (WHIMS).
We analyzed 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, and KIBRA) in 2857 women (ages ≥65) from the WHIMS randomized trials of hormone therapy using a custom Illumina GoldenGate assay; 19% of the sample were MCI (N = 165) or PD (N = 387), and the remaining 81% were free of cognitive impairment. SNP associations were evaluated for PD in non-Hispanic whites adjusting for age and HT using logistic regression under an additive genetic model.
One SNP (rs157582), located in the TOMM40 gene nearby APOE, was associated with the PD phenotype based on a P value accounting for multiple comparisons. An additional 12 SNPs were associated with the PD phenotype at P ≤ 0.05 (APOE: rs405509, rs439401; TOMM40: rs8106922, and KIBRA: rs4320284, rs11740112, rs10040267, rs13171394, rs6555802, rs2241368, rs244904, rs6555805, and rs10475878). Results of the sensitivity analyes excluding MCI were similar, with addition of COMT rs737865 and BDNF rs1491850 (P ≤ 0.05).
Our results in older women provide supporting evidence that the APOE/TOMM40 genes confer dementia risk and extend these findings to COMT, BDNF, and KIBRA. Our findings may lead to a better understanding of the role these genes play in cognition and cognitive impairment.
尽管已经发现了许多与阿尔茨海默病（AD）或认知障碍相关的单核苷酸多态性（SNP），但独立的重复验证仍然是验证所提出信号的唯一方法。我们在妇女健康倡议记忆研究（WHIMS）中调查了与认知障碍或 AD 发病机制相关的候选基因中的 SNP 及其与可能的痴呆（PD）的关系。
我们使用定制的 Illumina GoldenGate 测定法分析了来自 WHIMS 激素治疗随机试验的 2857 名年龄≥65 岁的女性中的五个基因（APOE/TOMM40、BDNF、COMT、SORL1 和 KIBRA）中的 96 个 SNP；19%的样本为 MCI（N=165）或 PD（N=387），其余 81%无认知障碍。使用 logistic 回归在加性遗传模型下，根据年龄和 HT 调整，对非西班牙裔白人的 PD 进行 SNP 关联评估。
位于 APOE 附近的 TOMM40 基因中的一个 SNP（rs157582），基于考虑到多次比较的 P 值，与 PD 表型相关。另外 12 个 SNP 与 PD 表型相关，P 值≤0.05（APOE：rs405509、rs439401；TOMM40：rs8106922 和 KIBRA：rs4320284、rs11740112、rs10040267、rs13171394、rs6555802、rs2241368、rs244904、rs6555805 和 rs10475878）。排除 MCI 的敏感性分析结果相似，增加了 COMT rs737865 和 BDNF rs1491850（P≤0.05）。
我们在老年女性中的研究结果提供了支持性证据，表明 APOE/TOMM40 基因导致痴呆风险，并将这些发现扩展到 COMT、BDNF 和 KIBRA。我们的发现可能有助于更好地理解这些基因在认知和认知障碍中的作用。
