Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study.
Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study.
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DOI：
10.1136/bmj.j1648
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发表时间：
2017-04-24
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影响因子：
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通讯作者：
Tybjærg-Hansen A
中科院分区：
文献类型：
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作者：
Benn M;Nordestgaard BG;Frikke-Schmidt R;Tybjærg-Hansen A
目的验证低密度脂蛋白（LDL）胆固醇代谢和生物合成基因（PCSK 9和3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR））的遗传变异与阿尔茨海默病（AD）、血管性痴呆（VD）、任何痴呆（AD）和帕金森病（PD）的高风险相关的假设。 设计孟德尔随机化研究。 设置哥本哈根一般人口研究和哥本哈根城市心脏研究。 参与者111 194人从丹麦一般人口。 主要结果测量阿尔茨海默病、血管性痴呆、所有痴呆和帕金森病的风险。 结果在观察性分析中，低密度脂蛋白胆固醇水平<1.8 mmol/L与≥4.0 mmol/L受试者中帕金森病的多因素校正风险比为1.70（95%置信区间为1.03至2.79），而阿尔茨海默病、血管性痴呆或任何痴呆的相应风险比与1.0无差异。PCSK 9和HMGCR变体组合与LDL胆固醇水平降低9.3%相关。在校正了年龄、性别和出生年份的遗传、因果分析中，LDL胆固醇水平终身降低1 mmol/L的风险比为0.57（0.27至1.17）对于阿尔茨海默病，0.81（0.34至1.89），对于任何痴呆为0.66（0.34至1.26），对于帕金森病为1.02（0.26至4.00）。国际阿尔茨海默病基因组学项目使用Egger Mendelian随机化分析的汇总水平数据显示，26种PCSK 9和HMGCR变体的阿尔茨海默病风险比为0.24（0.02至2.79），380种LDL胆固醇水平降低变体的风险比为0.64（0.52至0.79）。 结论PCSK 9和HMGCR变异体导致的低LDL胆固醇水平对阿尔茨海默病、血管性痴呆、任何痴呆或帕金森病的高风险没有因果关系;然而，低LDL胆固醇水平可能对降低阿尔茨海默病的风险有因果关系。
Objective To test the hypothesis that low density lipoprotein (LDL) cholesterol due to genetic variation in the genes responsible for LDL cholesterol metabolism and biosynthesis(PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), respectively) is associated with a high risk of Alzheimer’s disease, vascular dementia, any dementia, and Parkinson’s disease in the general population. Design Mendelian randomisation study. Setting Copenhagen General Population Study and Copenhagen City Heart Study. Participants 111 194 individuals from the Danish general population. Main outcome measures Risk of Alzheimer’s disease, vascular dementia, all dementia, and Parkinson’s disease. Results In observational analyses, the multifactorially adjusted hazard ratio for Parkinson’s disease in participants with an LDL cholesterol level <1.8 mmol/L versus ≥4.0 mmol/L was 1.70 (95% confidence interval 1.03 to 2.79), whereas the corresponding hazard ratios for Alzheimer’s disease, vascular dementia, or any dementia did not differ from 1.0. PCSK9 and HMGCR variants combined were associated with a 9.3% lower LDL cholesterol level. In genetic, causal analyses adjusted for age, sex, and year of birth, the risk ratios for a lifelong 1 mmol/L lower LDL cholesterol level were 0.57 (0.27 to 1.17) for Alzheimer’s disease, 0.81 (0.34 to 1.89) for vascular dementia, 0.66 (0.34 to 1.26) for any dementia, and 1.02 (0.26 to 4.00) for Parkinson’s disease. Summary level data from the International Genomics of Alzheimer’s Project using Egger Mendelian randomisation analysis gave a risk ratio for Alzheimer’s disease of 0.24 (0.02 to 2.79) for 26 PCSK9 and HMGCR variants, and of 0.64 (0.52 to 0.79) for 380 variants of LDL cholesterol level lowering. Conclusion Low LDL cholesterol levels due to PCSK9 and HMGCR variants had no causal effect on high risk of Alzheimer’s disease, vascular dementia, any dementia, or Parkinson’s disease; however, low LDL cholesterol levels may have a causal effect in reducing the risk of Alzheimer’s disease.