Abondio Paolo, Bruno Francesco, Luiselli Donata
Laboratory of Ancient DNA, Department of Cultural Heritage, University of Bologna, Via degli Ariani 1, 48121 Ravenna, Italy.
Laboratory of Molecular Anthropology and Center for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.
Curr Issues Mol Biol. 2023 Mar 31;45(4):2817-2831. doi: 10.3390/cimb45040184.
Human APOE is a 299-amino acid long protein expressed and secreted in several tissues and body districts, where it exerts different functions mainly related to lipid metabolism, with specific activities around cholesterol transport and absorption/elimination. It has three main isoforms, determined by the pair of mutations rs7412-C/T and rs429358-C/T, which gives rise to the functionally different APOE variants ε2, ε3, and ε4. These have a distinct impact on lipid metabolism and are differentially implicated in Alzheimer's disease and neurodegeneration, cardiovascular disease, and dyslipidemia. A plethora of other single nucleotide variants along the sequence of the APOE gene have been studied in cohorts of affected individuals, where they also modulate the influence of the three main isoforms to determine the risk of developing the disease. However, no contextual analysis of gene-long haplotypes has been carried out so far, and never extensively in cohorts of healthy individuals from different worldwide populations. Leveraging a rich population genomics dataset, this study elucidates the distribution of APOE variants and haplotypes that are shared across populations and to specific macroareas, revealing a variety of risk-allele associations that distinguish specific ancestral backgrounds and can be leveraged for specific ancestry-informed screenings in medicine and public health.
人类载脂蛋白E（APOE）是一种由299个氨基酸组成的蛋白质，在多个组织和身体部位表达并分泌，在这些部位发挥主要与脂质代谢相关的不同功能，在胆固醇运输以及吸收/清除方面具有特定活性。它有三种主要的异构体，由rs7412-C/T和rs429358-C/T这一对突变决定，这产生了功能不同的APOE变体ε2、ε3和ε4。这些异构体对脂质代谢有不同影响，并在阿尔茨海默病和神经退行性变、心血管疾病以及血脂异常中有着不同程度的关联。在受影响个体队列中，人们研究了载脂蛋白E基因序列上大量的其他单核苷酸变体，它们也调节三种主要异构体的影响，以确定患疾病的风险。然而，到目前为止尚未对基因全长单倍型进行背景分析，在来自世界各地不同人群的健康个体队列中也从未进行过广泛分析。利用丰富的群体基因组学数据集，本研究阐明了在不同人群以及特定宏观区域中共享的APOE变体和单倍型的分布，揭示了多种风险等位基因关联，这些关联区分了特定的祖先背景，并可用于医学和公共卫生领域特定的祖先信息筛查。
