Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management.
Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management.
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DOI：
10.1016/j.ebiom.2022.104038
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发表时间：
2022-06
期刊：
影响因子：
11.1
通讯作者：
Edwards, Todd L.
中科院分区：
文献类型：
--
作者：
Khankari, Nikhil K.;Keaton, Jacob M.;Walker, Venexia M.;Lee, Kyung Min;Shuey, Megan M.;Clarke, Shoa L.;Heberer, Kent R.;Miller, Donald R.;Reaven, Peter D.;Lynch, Julie A.;Vujkovic, Marijana;Edwards, Todd L.
关键词：
保持健康的生活方式以降低2型糖尿病（T2 D）风险具有挑战性，需要额外的T2 D预防策略。我们在两样本孟德尔随机化（MR）设计中使用组织特异性预测基因表达汇总统计量评估了几种血脂控制药物作为T2 D预防的潜在治疗选择。在我们的多阶段分析中利用了大规模欧洲全基因组脂质和T2 D的汇总统计数据，以估计由组织特异性预测基因表达驱动的脂质水平或T2 D风险的变化。我们将组织特异性预测基因表达汇总统计纳入三种血脂控制药物的治疗效果[即，他汀类药物、二十碳五烯酸乙酯（IPE）和前蛋白转化酶枯草杆菌蛋白酶/kexin 9型抑制剂（PCSK-9 i）]对T2 D易感性的影响。通过增加FADS 1表达，预计IPE可降低甘油三酯，并与T2 D风险降低53%相关。预测他汀类药物和PCSK-9 i（分别由HMGCR和PCSK 9表达降低所代表）可降低LDL-C水平，但与T2 D易感性无关。通过IPE降低甘油三酯可能会降低欧洲血统人群发生T2 D的风险。然而，需要使用动物模型的实验验证来证实我们的结果，并激励IPE作为T2 D预防的假定治疗的随机对照试验（RCT）。本分析仅使用汇总统计量。资金信息详见鸣谢。
Maintaining a healthy lifestyle to reduce type 2 diabetes (T2D) risk is challenging and additional strategies for T2D prevention are needed. We evaluated several lipid control medications as potential therapeutic options for T2D prevention using tissue-specific predicted gene expression summary statistics in a two-sample Mendelian randomisation (MR) design. Large-scale European genome-wide summary statistics for lipids and T2D were leveraged in our multi-stage analysis to estimate changes in either lipid levels or T2D risk driven by tissue-specific predicted gene expression. We incorporated tissue-specific predicted gene expression summary statistics to proxy therapeutic effects of three lipid control medications [i.e., statins, icosapent ethyl (IPE), and proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK-9i)] on T2D susceptibility using two-sample Mendelian randomisation (MR). IPE, as proxied via increased FADS1 expression, was predicted to lower triglycerides and was associated with a 53% reduced risk of T2D. Statins and PCSK-9i, as proxied by reduced HMGCR and PCSK9 expression, respectively, were predicted to lower LDL-C levels but were not associated with T2D susceptibility. Triglyceride lowering via IPE may reduce the risk of developing T2D in populations of European ancestry. However, experimental validation using animal models is needed to substantiate our results and to motivate randomized control trials (RCTs) for IPE as putative treatment for T2D prevention. Only summary statistics were used in this analysis. Funding information is detailed under Acknowledgments.
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