一种触珠蛋白（HP）结构变体改变了载脂蛋白 E 等位基因对阿尔茨海默病的影响。
A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease.
机构信息
Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, USA.
Systems Biology and Bioinformatics, Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
出版信息
Alzheimers Dement. 2023 Nov;19(11):4886-4895. doi: 10.1002/alz.13050. Epub 2023 Apr 12.
BACKGROUND
Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2.
METHODS
HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N = 20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models.
RESULTS
The HP polymorphism significantly impacts AD risk in European-descent individuals (and in meta-analysis with African-descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers.
DISCUSSION
The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.
背景
触珠蛋白（HP）是载脂蛋白 E（APOE）的抗氧化剂，先前的报告表明 HP 与 APOE 和淀粉样蛋白β（Aβ）结合以帮助其清除。HP 基因的一个常见结构变体将其区分成两个等位基因：HP1 和 HP2。
方法
在来自阿尔茨海默病遗传学联合会（ADGC）的 29 个队列中对 HP 基因型进行了推断（N=20512）。通过回归模型研究了 HP 多态性与 APOE 相互作用对阿尔茨海默病（AD）风险和发病年龄的关联。
结果
HP 多态性通过改变 APOE ε2 的保护作用和 APOE ε4 的有害作用，显著影响了欧洲血统个体的 AD 风险（并与非洲血统个体的荟萃分析中得到了证实）。这种影响在 APOE ε4 携带者中尤为显著。
讨论
HP 对 APOE 的作用修饰表明，在考虑 APOE 风险时，有必要对 HP 基因型进行调整和/或分层。我们的研究结果还为进一步研究这种关联背后的潜在机制提供了方向。
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