Anthropological studies on effects of genetic and environmental factors on lipid metabolism

阿尔茨海默病（AD）是一种中枢神经系统（CNS）进行性神经退行性疾病。载脂蛋白E （apoE）的ε4等位基因APOEε4已被证明是散发性和晚发性家族性AD的遗传易感性危险因素。星形胶质细胞分泌的含apoe的脂蛋白似乎通过受体介导的内吞作用转运到脑内的其他细胞中。因此，含有载脂蛋白e的脂蛋白受体被认为与AD的发病有关。我们之前分离了一个载脂蛋白e受体2 (ApoER2)，它与含载脂蛋白e的脂蛋白具有高亲和力。ApoER2主要在大脑中表达，并与极低密度脂蛋白受体（VLDLR）协同在中枢神经系统（CNS）的发育中起重要作用。我们分析了日本散发性AD患者和正常人ApoER2基因的多态性。我们发现了位于人类ApoER2基因5'- utr的CGG重复长度多态性（6、7和8倍重复等位基因）。我们还发现了由外显子1编码的信号序列中CTG重复序列（10倍和11倍重复等位基因）长度的多态性。这个三联体重复序列编码人类ApoER2信号序列中的聚亮氨酸片段。我们还在配体结合区域发现了替换46和299位氨基酸的两个变体：c.374G>T: E46D在第2外显子和c.1132G>A: C299Y在第6外显子。编码区还有3个不替换氨基酸的变异，分别是第5外显子的977C、977C、977C、977C、977t: R247R。1346C>T: D370D外显子7。和c.3018G>T: P927P在第18外显子。在AD患者和正常人中，E46D变异的等位基因频率分别为52%和53%。AD患者有1个C299Y等位基因，正常人有2个C299Y等位基因。

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system (CNS). The ε4 allele of the apolipoprotein E (apoE), APOEε4, has been shown to be a genetic susceptibility risk factor in both sporadic and late-onset familial AD. The apoE-containing lipoproteins secreted by astrocytes appear to be transported into other cells in the brain via receptor-mediated endocytosis. Therefore, the receptors for apoE-containing lipoproteins have been proposed to be associated with onset of AD. We previously isolated an apoE receptor 2 (ApoER2) that binds apoE-containing lipoproteins with high affinity. ApoER2 is predominantly expressed in the brain, and plays a significant role in development of the central nervous system (CNS) in collaboration with very low density lipoprotein receptor (VLDLR). We analyzed polymorphisms in the ApoER2 genes of Japanese sporadic AD patients and normal subjects. We found polymorphisms in length of CGG repeat (6-, 7- and 8-fold repeated alleles) located at 5'-UTR of the human ApoER2 gene. We also found polymorphisms in length of a CTG repeat (10- and 11-fold repeated alleles) in the signal sequence encoded by exon 1. This triplet repeat encodes a polyleucine stretch in the signal sequence of human ApoER2. We also found two variants in the ligand-binding domain that replace amino acids at positions 46 and 299 : c.374G>T : E46D in exon 2 and c.1132G>A : C299Y in exon 6. There were three other variants in the coding region that did not replace amino acids, 977C>T : R247R in exon 5. 1346C>T : D370D in exon 7. and c.3018G>T : P927P in exon 18. Allelic frequencies of the E46D variant were 52% and 53% in AD patients and normal subjects, respectively. There was one C299Y allele in AD patients and two in normal subjects, respectively.