Miyashita Akinori, Obinata Ai, Hara Norikazu, Mitsumori Risa, Kaneda Daita, Hashizume Yoshio, Sano Terunori, Takao Masaki, Gabdulkhaev Ramil, Tada Mari, Kakita Akiyoshi, Arakawa Akira, Morishima Maho, Murayama Shigeo, Saito Yuko, Hatsuta Hiroyuki, Matsubara Tomoyasu, Akagi Akio, Riku Yuichi, Miyahara Hiroaki, Sone Jun, Yoshida Mari, Yamaguchi Haruyasu, Tsukie Tamao, Hasegawa Mai, Kasuga Kensaku, Kikuchi Masataka, Akatsu Hiroyasu, Kuwano Ryozo, Iwatsubo Takeshi, Niida Shumpei, Ozaki Kouichi, Ikeuchi Takeshi
Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan.
J Alzheimers Dis. 2025 Jul;106(1):363-377. doi: 10.1177/13872877251340710. Epub 2025 May 21.
BackgroundLittle is known about the rare missense variants (RMVs) of in East Asians, including the Japanese, and their association with Alzheimer's disease (AD) and lipid metabolism.ObjectiveTo identify RMVs in the Japanese population and investigate their association with AD and lipid metabolism, including low-density lipoprotein cholesterol levels.Methods RMVs were explored in the Niigata (NIG; 2589 subjects) and Tohoku (ToMMo; 3307 subjects) cohorts. A case-control study included 6261 AD cases and 16,331 controls, all of whom were aged 65 or older. Sanger sequencing, whole-exome sequencing, or a combination of both was performed on the NIG subjects. We used the genotype data from the ToMMo cohort. RMV frequencies in the Japanese population were compared with various ethnic populations. Associations between RMV genotypes, AD, and lipoproteins were examined.ResultsFourteen RMVs were identified (minor allele frequency 0.02-0.73%), with 10 unique to East Asians. Five previously reported RMVs, such as the Christchurch RMV, were absent in Japanese individuals. Two RMVs (rs140808909 and rs190853081), which exhibit complete linkage disequilibrium, were found to have protective effects against AD: = 4.28E-02, OR (95% CI) = 0.70 (0.54-0.92). No significant differences in cholesterol levels were observed between RMV carriers and non-carriers.ConclusionsThe two RMVs identified in Japanese individuals may have exhibited potential protective effects against AD. Further large-scale studies are needed to confirm these findings and to explore their roles in AD and lipid metabolism.
背景
在包括日本人在内的东亚人群中，关于[具体基因]的罕见错义变体（RMVs）及其与阿尔茨海默病（AD）和脂质代谢的关联知之甚少。
目的
在日本人群中鉴定[具体基因]的RMVs，并研究它们与AD和脂质代谢（包括低密度脂蛋白胆固醇水平）的关联。
方法
在新潟（NIG；2589名受试者）和东北（ToMMo；3307名受试者）队列中探索[具体基因]的RMVs。一项病例对照研究包括6261例AD病例和16331例对照，所有参与者年龄均在65岁及以上。对NIG受试者进行了桑格测序、全外显子测序或两者结合的测序。我们使用了ToMMo队列的基因型数据。将日本人群中[具体基因]的RMV频率与不同种族人群进行比较。检查了[具体基因]的RMV基因型、AD和脂蛋白之间的关联。
结果
鉴定出14个RMVs（次要等位基因频率为0.02 - 0.73%），其中10个是东亚人特有的。在日本个体中未发现5个先前报道的RMVs，如克赖斯特彻奇RMV。发现两个呈现完全连锁不平衡的RMVs（rs140808909和rs190853081）对AD具有保护作用：P = 4.28E - 02，OR（95%CI）= 0.70（0.54 - 0.92）。RMV携带者和非携带者之间的胆固醇水平未观察到显著差异。
结论
在日本个体中鉴定出的两个[具体基因]的RMVs可能对AD具有潜在的保护作用。需要进一步的大规模研究来证实这些发现，并探索它们在AD和脂质代谢中的作用。
