Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
J Alzheimers Dis. 2022;89(3):1063-1073. doi: 10.3233/JAD-220649.
The relationship between serum uric acid (UA) and Alzheimer's disease (AD) risk still remained ambiguous despite extensive attempts.
Via the two-sample Mendelian randomization (MR) design, we aimed to examine the bidirectional causal relationships of serum UA, gout, and the risk of AD.
Genetic variants of UA, gout, and AD were extracted from published genome-wide association summary statistics. The inverse-variance weighted (IVW, the primary method), and several sensitivity methods (MR-Egger, weighted median, and weighted mode) were used to calculate the effect estimates. Egger regression, MR-PRESSO and leave-one-SNP-out analysis were performed to identify potential violations.
Genetic proxies for serum UA concentration [odds ratio (ORIVW) = 1.09, 95% confidence interval (CI) = 1.01-1.19, p = 0.031] were related with an increased risk of AD using 25 single nucleotide polymorphisms (SNPs). This causal effect was confirmed by sensitivity analyses including MR-Egger (1.22, 1.06-1.42, p = 0.014), weighted median (1.18, 1.05-1.33, p = 0.006), and weighted mode (1.20, 1.07-1.35, p = 0.005) methods. No evidence of notable directional pleiotropy and heterogeneity were identified (p > 0.05). Three SNPs (rs2078267, rs2231142, and rs11722228) significantly drove the observed causal effects. Supportive causal effect of genetically determined gout on AD risk was demonstrated using two SNPs (ORIVW = 1.05, 95% CI = 1.00-1.11, p = 0.057). No reverse causal effects of AD on serum UA levels and gout risk were found.
The findings revealed a causal relationship between elevated serum UA level and AD risk. However, further research is still warranted to investigate whether serum UA could be a reliable biomarker and therapeutic target for AD.
尽管进行了广泛的尝试，但血清尿酸 (UA) 与阿尔茨海默病 (AD) 风险之间的关系仍然不明确。
通过两样本 Mendelian 随机化 (MR) 设计，我们旨在检验血清 UA、痛风与 AD 风险之间的双向因果关系。
从已发表的全基因组关联汇总统计数据中提取 UA、痛风和 AD 的遗传变异。使用逆方差加权（IVW，主要方法）和几种敏感性方法（MR-Egger、加权中位数和加权众数）计算效应估计值。进行 Egger 回归、MR-PRESSO 和单 SNP 剔除分析以识别潜在的违反情况。
使用 25 个单核苷酸多态性 (SNP)，血清 UA 浓度的遗传标志物[比值比 (ORIVW) = 1.09，95%置信区间 (CI) = 1.01-1.19，p = 0.031]与 AD 风险增加相关。这种因果关系通过包括 MR-Egger（1.22，1.06-1.42，p = 0.014）、加权中位数（1.18，1.05-1.33，p = 0.006）和加权众数（1.20，1.07-1.35，p = 0.005）方法的敏感性分析得到了证实。未发现明显的方向性异质性和异质性（p > 0.05）。三个 SNP（rs2078267、rs2231142 和 rs11722228）显著驱动了观察到的因果效应。使用两个 SNP（ORIVW = 1.05，95%CI = 1.00-1.11，p = 0.057）证明了遗传决定的痛风对 AD 风险的因果作用。未发现 AD 对血清 UA 水平和痛风风险的反向因果关系。
研究结果表明，血清 UA 水平升高与 AD 风险之间存在因果关系。然而，仍需要进一步研究以确定血清 UA 是否可以作为 AD 的可靠生物标志物和治疗靶点。
