Li Xiaoling, Zhu Xiaoquan, Zhang Wandong, Yang Fan, Hui Juan, Tan Jiping, Xie Haiqun, Peng Dantao, Ma Lihua, Cui Lianqi, Zhang Shouzi, Lv Zeping, Sun Liang, Yuan Huiping, Zhou Qi, Wang Luning, Qi Shige, Wang Zhihui, Hu Caiyou, Yang Ze
Graduate School of Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100001, P.R.China.
The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, 100730, P.R.China.
Aging (Albany NY). 2018 Sep 16;10(9):2316-2337. doi: 10.18632/aging.101548.
Latent genetic variations of cholesterol metabolism-related genes in late-onset Alzheimer's disease, especially, as well as in mild cognitive impairment pathogenesis are still to be studied extensively. Thus, we performed the targeted-sequencing of 12 nuclear receptor genes plus which were involved in cholesterol content modulation to screen susceptible genetic variants and focused on a new risk variant rs9340803 at 6q25.1 for both late-onset Alzheimer's disease (OR=3.30[1.844.22], <0.001) and mild cognitive impairment (OR=3.08[1.753.89], <0.001). This low-frequency variant was validated in three independent cohorts totaling 854 late-onset Alzheimer's disease cases, 1059 mild cognitive impairment cases and 1254 controls from nine provinces of China mainland. Preliminary functional study on it revealed decreased expression in vitro. Besides, we detected higher serum Aβ1-40 concentration in participants carrying this variant (=0.038) and lower plasma total cholesterol level in this variant carriers with late-onset Alzheimer's disease (=0.009). In summary, we identified a susceptible variant which might contribute to developing mild cognitive impairment at earlier stage and Alzheimer's Disease later. Our study would provide new insight into the disease causation of late-onset Alzheimer's disease and could be exploited therapeutically.
晚发性阿尔茨海默病以及轻度认知障碍发病机制中胆固醇代谢相关基因的潜在遗传变异仍有待深入研究。因此，我们对12个参与胆固醇含量调节的核受体基因进行了靶向测序，以筛选易感基因变异，并聚焦于6q25.1处的一个新的风险变异rs9340803，其与晚发性阿尔茨海默病（比值比=3.30[1.844.22]，P<0.001）和轻度认知障碍（比值比=3.08[1.753.89]，P<0.001）均相关。这个低频变异在来自中国大陆九个省份的三个独立队列中得到了验证，该队列共有854例晚发性阿尔茨海默病患者、1059例轻度认知障碍患者和1254名对照。对其进行的初步功能研究显示，该变异在体外表达降低。此外，我们检测到携带此变异的参与者血清Aβ1-40浓度较高（P=0.038），且晚发性阿尔茨海默病患者中该变异携带者的血浆总胆固醇水平较低（P=0.009）。总之，我们鉴定出一个易感变异，它可能在早期导致轻度认知障碍，后期导致阿尔茨海默病。我们的研究将为晚发性阿尔茨海默病的病因提供新的见解，并可用于治疗开发。
