载脂蛋白 E ε4 表达增加与不同祖先背景的阿尔茨海默病风险差异有关。
Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds.
机构信息
John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA.
Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.
出版信息
Alzheimers Dement. 2021 Jul;17(7):1179-1188. doi: 10.1002/alz.12287. Epub 2021 Feb 1.
INTRODUCTION
Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4 carriers with European local ancestry (ELA). Cell type specific transcriptional variation between the two local ancestries (LAs) could contribute to this disease risk differences.
METHODS
Single-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE ε4/ε4 AD patients: seven with ELA, four with ALA.
RESULTS
A total of 60,908 nuclei were sequenced. Within the LA region (chr19:44-46Mb), APOE was the gene most differentially expressed, with ELA carriers having significantly more expression (overall P < 1.8E ) in 24 of 32 cell clusters. The transcriptome of one astrocyte cluster, with high APOE ε4 expression and specific to ELA, is suggestive of A1 reactive astrocytes.
DISCUSSION
AD patients with ELA expressed significantly greater levels of APOE than ALA APOE ε4 carriers. These differences in APOE expression could contribute to the reduced risk for AD seen in African APOE ε4 carriers.
简介
载脂蛋白 E（APOE）ε4 等位基因使具有非洲局部遗传背景（ALA）的阿尔茨海默病（AD）携带者的发病风险低于具有欧洲局部遗传背景（ELA）的 APOE ε4 携带者。两种局部遗传背景（LAs）之间的细胞类型特异性转录变异可能导致这种疾病风险差异。
方法
对纯合 APOE ε4/ε4 AD 患者的冷冻额皮质进行单细胞 RNA 测序：7 名具有 ELA，4 名具有 ALA。
结果
共测序了 60908 个核。在 LA 区域（chr19：44-46Mb）中，APOE 是表达差异最显著的基因，在 32 个细胞簇中的 24 个中，ELA 携带者的表达显著更高（总体 P<1.8E-）。一个具有高 APOE ε4 表达且特异性为 ELA 的星形胶质细胞簇的转录组提示 A1 反应性星形胶质细胞。
讨论
具有 ELA 的 AD 患者的 APOE 表达水平明显高于 ALA APOE ε4 携带者。APOE 表达的这些差异可能导致非洲 APOE ε4 携带者 AD 发病风险降低。
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