The etiological effect of a new low-frequency ESR1 variant on Mild Cognitive Impairment and Alzheimer's Disease: a population-based study.
The etiological effect of a new low-frequency ESR1 variant on Mild Cognitive Impairment and Alzheimer's Disease: a population-based study.
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新的低频 ESR1 变异对轻度认知障碍和阿尔茨海默氏病的病因学影响_一项基于人群的研究
DOI：
10.18632/aging.101548
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发表时间：
2018-09-16
期刊：
影响因子：
--
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Li X;Zhu X;Zhang W;Yang F;Hui J;Tan J;Xie H;Peng D;Ma L;Cui L;Zhang S;Lv Z;Sun L;Yuan H;Zhou Q;Wang L;Qi S;Wang Z;Hu C;Yang Z
胆固醇代谢相关基因在晚发性阿尔茨海默病，特别是在轻度认知障碍发病机制中的潜在遗传变异仍有待广泛研究。因此，我们对12个参与胆固醇含量调节的核受体基因和载脂蛋白E进行了靶向测序，以筛选易感遗传变异，并将重点放在位于6q25.1的新的风险变异ESR1rs9340803上，以同时发现晚发性阿尔茨海默病(OR=3.3[1.84~4.22]，p<；0.001)和轻度认知障碍(OR=3.08[1.75~3.89]，p<；0.001)。这个低频变异在三个独立的队列中得到了验证，共854例晚发性阿尔茨海默病病例，1059例轻度认知障碍病例和1254例对照，来自中国大陆九省。初步的功能研究表明，在体外ESR1的表达降低。此外，我们检测到携带这种变异的参与者的血清Aβ1-40浓度较高(p=0.038)，而这种变异的阿尔茨海默病携带者的血浆总胆固醇水平较低(p=0.009)。综上所述，我们发现了一种易感变异，这种变异可能会在早期导致轻度认知障碍，并在以后导致阿尔茨海默病。我们的研究将为迟发性阿尔茨海默病的病因提供新的见解，并可用于治疗。
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 APOE which were involved in cholesterol content modulation to screen susceptible genetic variants and focused on a new risk variant ESR1 rs9340803 at 6q25.1 for both late-onset Alzheimer’s disease (OR=3.30[1.84~4.22], p<0.001) and mild cognitive impairment (OR=3.08[1.75~3.89], p<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 ESR1 expression in vitro. Besides, we detected higher serum Aβ1-40 concentration in participants carrying this variant (p=0.038) and lower plasma total cholesterol level in this variant carriers with late-onset Alzheimer’s disease (p=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.
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DOI：
10.1016/j.jalz.2011.03.005
发表时间：
2011-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
McKhann GM;Knopman DS;Chertkow H;Hyman BT;Jack CR Jr;Kawas CH;Klunk WE;Koroshetz WJ;Manly JJ;Mayeux R;Mohs RC;Morris JC;Rossor MN;Scheltens P;Carrillo MC;Thies B;Weintraub S;Phelps CH
通讯作者：
Phelps CH
影响因子：
5.3
作者：
Kölsch H;Lütjohann D;Jessen F;Popp J;Hentschel F;Kelemen P;Friedrichs S;Maier TA;Heun R
通讯作者：
Heun R
影响因子：
4
作者：
Rolstad, Sindre;Berg, Anne Ingeborg;Wallin, Anders
通讯作者：
Wallin, Anders
影响因子：
10.6
作者：
Karch CM;Goate AM
通讯作者：
Goate AM
影响因子：
9.8
作者：
Raj, Towfique;Shulman, Joshua M.;De Jager, Philip L.
通讯作者：
De Jager, Philip L.