Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina, USA.
Alzheimers Dement. 2022 Nov;18(11):2067-2078. doi: 10.1002/alz.12540. Epub 2022 Jan 3.
The apolipoprotein E (APOE) ε2 and ε4 alleles have beneficial and adverse impacts on Alzheimer's disease (AD), respectively, with incomplete penetrance, which may be modulated by other genetic variants.
We examined whether the associations of the APOE alleles with other polymorphisms in the genome can be sensitive to AD-affection status.
We identified associations of the ε2 and ε4 alleles with 314 and 232 polymorphisms, respectively. Of them, 35 and 31 polymorphisms had significantly different effects in AD-affected and -unaffected groups, suggesting their potential involvement in the AD pathogenesis by modulating the effects of the ε2 and ε4 alleles, respectively. Our survival-type analysis of the AD risk supported modulating roles of multiple group-specific polymorphisms. Our functional analysis identified gene enrichment in multiple immune-related biological processes, for example, B cell function.
These findings suggest involvement of local and inter-chromosomal modulators of the effects of the APOE alleles on the AD risk.
载脂蛋白 E (APOE) ε2 和 ε4 等位基因分别对阿尔茨海默病 (AD) 具有有益和不利的影响，但存在不完全外显率，这可能受到其他遗传变异的调节。
我们研究了 APOE 等位基因与基因组中其他多态性之间的关联是否能敏感地反映 AD 发病情况。
我们鉴定了 ε2 和 ε4 等位基因与 314 个和 232 个多态性分别相关。其中，35 个和 31 个多态性在受 AD 影响和不受影响的组之间有显著不同的作用，提示它们可能通过调节 ε2 和 ε4 等位基因的作用，参与 AD 的发病机制。我们对 AD 风险的生存型分析支持多个组特异性多态性的调节作用。我们的功能分析确定了多个免疫相关生物学过程的基因富集，例如 B 细胞功能。
这些发现提示了 APOE 等位基因对 AD 风险影响的局部和染色体间调节因子的参与。
