MTHFR基因A1298C(rs1801131)位点多态性与阿尔茨海默病患者脑脊液生物标志物、认知水平及脑结构变化的关系

MTHFR gene A1298C(rs1801131)polymorphism and its correlations with cerebrospinal fluid biomarkers,cognitive level,and brain structure changes in patients with Alzheimer’s disease

目的探讨亚甲基四氢叶酸还原酶(MTHFR)基因A1298C(rs1801131)位点多态性与阿尔茨海默病(Alzheimer’s disease,AD)患者脑脊液β-淀粉样蛋白1-42亚型(Aβ_(1-42))水平、认知水平及脑结构变化的关系。方法选取AD神经影像学倡议计划(ADNI)数据库中符合纳入标准的1271例研究对象,采用多元线性回归模型分析MTHFR基因A1298C(rs1801131)位点多态性与AD患者脑脊液Aβ_(1-42)水平、认知水平及脑结构变化的关系。采用中介分析模型分析脑脊液Aβ_(1-42)水平在MTHFR基因A1298C(rs1801131)位点多态性与认知水平关联中的中介作用。结果多元线性回归模型分析显示,A1298C-C等位基因与AD患者脑脊液Aβ_(1-42)水平、海马体积及认知水平呈负相关(β=-0.121~-0.084,t=-3.308~-1.953,P<0.05),与认知状态、脑室体积呈正相关(β=0.108、0.126,t=3.749、3.653,P<0.05)。中介分析模型显示,脑脊液Aβ_(1-42)水平在A1298C-C等位基因与记忆功能(ADNI_MEM)评分的关系中介导比率为26.0%,脑脊液Aβ_(1-42)水平在A1298C-C等位基因与简易精神状态检查表评分的关系中介导比率为19.9%。结论MTHFR基因A1298C(rs1801131)位点多态性影响AD患者脑脊液生物标志物、认知水平及海马体积和脑室体积,A1298C-C等位基因可能通过降低脑脊液Aβ_(1-42)水平促进AD的发生发展。MTHFR基因靶向修饰可能成为未来高AD遗传风险人群的重要干预靶点。

Objective To investigate the relationship of A1298C(rs1801131)polymorphism in the MTHFR gene encoding methylenetetrahydrofolate reductase with the cerebrospinal fluidβ-amyloid 1-42 subtype(Aβ_(1-42))level,cognitive level,and brain structure changes in patients with Alzheimer’s disease(AD).Methods A total of 1271 subjects who met the inclusion criteria in the Alzheimer’s Disease Neuroimaging Initiative(ADNI)database were selected.A multivariable linear regression model was used to analyze the relationship of MTHFR gene A1298C(rs1801131)polymorphism with cerebrospinal fluid Aβ_(1-42)level,cognitive level,and brain structure changes in AD patients.A mediation model was used to analyze the role of cerebrospinal fluid Aβ_(1-42)level in mediating the relationship between MTHFR gene A1298C(rs1801131)polymorphism and cognitive level.Results Multivariable linear regression model analysis showed that A1298C-C allele was negatively correlated with the level of Aβ_(1-42)in cerebrospinal fluid,hippocampal volume,and cognitive level(β=-0.121--0.084,t=-3.308--1.953,P<0.05),and positively correlated with cognitive status and ventricular volume(β=0.108,0.126,t=3.749,3.653,P<0.05).The mediation model showed that the level of Aβ_(1-42)in cerebrospinal fluid mediated 26.0%of the relationship between A1298C-C allele and memory function(ADNI_Memory score),and 19.9%of the relationship between A1298C-C allele and Mini-Mental State Examination score.Conclusion MTHFR gene A1298C(rs1801131)polymorphism affects cerebrospinal fluid biomarkers,cognitive level,hippocampal volume,and ventricular volume in AD patients.A1298C-C allele may promote the development and progression of AD by reducing the level of Aβ_(1-42)in cerebrospinal fluid.Targeted modification of the MTHFR gene may represent an important intervention stra-tegy for populations with a high genetic risk of AD in the future.