Kuwano Ryozo, Miyashita Akinori, Arai Hiroyuki, Asada Takashi, Imagawa Masaki, Shoji Mikio, Higuchi Susumu, Urakami Katsuya, Kakita Akiyoshi, Takahashi Hitoshi, Tsukie Tamao, Toyabe Shinichi, Akazawa Kohei, Kanazawa Ichiro, Ihara Yasuo
Genome Science Branch, Center for Bioresource-Based Researches, Brain Research Institute, Niigata University, Niigata, Japan.
Hum Mol Genet. 2006 Jul 1;15(13):2170-82. doi: 10.1093/hmg/ddl142. Epub 2006 Jun 1.
The apolipoprotein E (APOE) gene has been consistently shown to be a major genetic risk factor; however, all cases of Alzheimer's disease (AD) cannot be attributed to the epsilon4 variant of APOE, because about half of AD patients have the APOE-epsilon33 genotype. To identify an additional genetic risk factor(s), we performed large-scale single nucleotide polymorphism (SNP)-based association analysis of 1526 late-onset AD patients and 1666 control subjects in a Japanese population. We prepared two independent sets consisting of exploratory and validation samples, respectively, with only the APOE-epsilon33 genotype, and first carried out genotyping for the exploratory set with 1206 SNPs in the region between 60 and 107 Mb on chromosome 10q that is implicated by linkage studies as containing an AD susceptibility locus. Thirty-five SNPs that showed significant values (P<0.01) were followed-up to detect any association with the validation samples. Finally, six SNPs exhibited replicated significant associations (P=0.000035-0.00048) on meta-analysis of both sets. These SNPs were clustered in a locus spanning 220 kb at genomic position 101 Mb, and three of the six SNPs were located in the dynamin-binding protein (DNMBP) gene. Quantitative real-time RT-PCR analysis demonstrated that neuropathologically confirmed AD brains exhibit a significant reduction of DNMBP mRNA compared with age-matched ones (P<0.0169). Thus, we confirmed the association of DNMBP with AD individuals with the APOE-epsilon3*3 genotype or lacking the epsilon4 allele, and DNMBP may be one of the susceptibility genes for AD.
载脂蛋白E（APOE）基因一直被证明是主要的遗传风险因素；然而，并非所有阿尔茨海默病（AD）病例都可归因于APOE的ε4变体，因为约一半的AD患者具有APOE-ε33基因型。为了确定其他遗传风险因素，我们对日本人群中的1526例晚发性AD患者和1666例对照者进行了基于单核苷酸多态性（SNP）的大规模关联分析。我们分别制备了由探索性样本和验证性样本组成的两个独立样本集，且均仅具有APOE-ε33基因型，并首先对探索性样本集进行基因分型，该样本集包含位于10号染色体10q上60至107 Mb区域的1206个SNP，连锁研究表明该区域含有一个AD易感基因座。对显示出显著值（P<0.01）的35个SNP进行后续分析，以检测其与验证性样本的任何关联。最后，对两个样本集进行荟萃分析时，有6个SNP表现出重复的显著关联（P=0.000035 - 0.00048）。这些SNP聚集在基因组位置101 Mb处一个跨度为220 kb的基因座中，6个SNP中的3个位于发动蛋白结合蛋白（DNMBP）基因中。定量实时RT-PCR分析表明，与年龄匹配的大脑相比，经神经病理学证实的AD大脑中DNMBP mRNA显著减少（P<0.0169）。因此，我们证实了DNMBP与具有APOE-ε3*3基因型或缺乏ε4等位基因的AD个体相关，并且DNMBP可能是AD的易感基因之一。
