Genetic Variation in Targets of Antidiabetic Drugs and Alzheimer Disease Risk: A Mendelian Randomization Study.
Genetic Variation in Targets of Antidiabetic Drugs and Alzheimer Disease Risk: A Mendelian Randomization Study.
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DOI：
10.1212/wnl.0000000000200771
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发表时间：
2022-08-16
期刊：
影响因子：
9.9
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中科院分区：
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以前的研究已经强调抗糖尿病药物作为阿尔茨海默病（AD）的再利用候选者，但疾病修饰作用仍不清楚。采用2样本孟德尔随机化研究设计，以检查4种降糖药物靶点的遗传变异与AD风险之间的关联。使用英国生物银行326，885名参与者的数据分析了血糖的遗传汇总统计量，而AD的汇总统计量来自先前的全基因组关联研究，包括24，087例临床诊断的AD病例和55，058例对照。对2型糖尿病（T2 DM）、胰岛素分泌、胰岛素抵抗和肥胖相关性状进行阳性对照分析，以验证工具变量的选择。在阳性对照分析中，磺脲类药物靶点的遗传变异与胰岛素分泌增加、T2 DM风险降低以及体重指数、腰围和臀围增加相关，与药物机制作用和既往试验证据一致。在初步分析中，磺脲类药物靶点的遗传变异与AD风险降低相关（血糖每降低1 mmol/L，比值比[OR] = 0.38，95% CI 0.19-0.72，p = 0.0034）。在使用遗传变异rs757110的敏感性分析中，磺脲类药物的这些结果基本不变，该变异已被验证可调节磺脲类药物的靶蛋白（血糖每降低1 mmol/L，OR = 0.35，95% CI 0.15-0.82，p = 0.016）。还观察到胰高血糖素样肽1（GLP-1）类似物靶点的遗传变异与AD风险降低之间存在相关性（OR = 0.32/1 mmol/L血糖降低，95% CI 0.13-0.79，p = 0.014）。然而，应谨慎解释该结果，因为GLP-1类似物的阳性对照分析不符合既往临床试验中显示的减肥作用。关于其他药物类别的结果是不确定的。磺酰脲类药物靶点的遗传变异与AD的低风险相关，未来的研究有必要阐明磺酰脲类药物与AD之间的潜在机制途径。
Previous studies have highlighted antidiabetic drugs as repurposing candidates for Alzheimer disease (AD), but the disease-modifying effects are still unclear. A 2-sample mendelian randomization study design was applied to examine the association between genetic variation in the targets of 4 antidiabetic drug classes and AD risk. Genetic summary statistics for blood glucose were analyzed using UK Biobank data of 326,885 participants, whereas summary statistics for AD were retrieved from previous genome-wide association studies comprising 24,087 clinically diagnosed AD cases and 55,058 controls. Positive control analysis on type 2 diabetes mellitus (T2DM), insulin secretion, insulin resistance, and obesity-related traits was conducted to validate the selection of instrumental variables. In the positive control analysis, genetic variation in sulfonylurea targets was associated with higher insulin secretion, a lower risk of T2DM, and an increment in body mass index, waist circumference, and hip circumference, consistent with drug mechanistic actions and previous trial evidence. In the primary analysis, genetic variation in sulfonylurea targets was associated with a lower risk of AD (odds ratio [OR] = 0.38 per 1 mmol/L decrement in blood glucose, 95% CI 0.19–0.72, p = 0.0034). These results for sulfonylureas were largely unchanged in the sensitivity analysis using a genetic variant, rs757110, that has been validated to modulate the target proteins of sulfonylureas (OR = 0.35 per 1 mmol/L decrement in blood glucose, 95% CI 0.15–0.82, p = 0.016). An association between genetic variations in the glucagon-like peptide 1 (GLP-1) analogue target and a lower risk of AD was also observed (OR = 0.32 per 1 mmol/L decrement in blood glucose, 95% CI 0.13–0.79, p = 0.014). However, this result should be interpreted with caution because the positive control analyses for GLP-1 analogues did not comply with a weight-loss effect as shown in previous clinical trials. Results regarding other drug classes were inconclusive. Genetic variation in sulfonylurea targets was associated with a lower risk of AD, and future studies are warranted to clarify the underlying mechanistic pathways between sulfonylureas and AD.