Background Numerous observational studies have demonstrated circulating lipoprotein(a) [Lp(a)] to be inversely related to occurrence of type 2 diabetes [T2D]. However, this is not consistently supported by Mendelian randomization [MR] studies. In vitro studies have shown insulin to downregulate Lp(a) expression, which might be another mechanism behind the correlation observed between Lp(a) and T2D. Purpose In this MR study, we investigated the influence of genetically predicted levels of insulin on genetically predicted Lp(a) levels to elucidate the potential causal links between Lp(a) and diabetes. Methods Independent genetic variants associated with insulin levels were acquired from a meta-analysis of genome-wide association studies (GWAS, N=151,013). Summary data for Lp(a) were acquired from a GWAS study in the UK Biobank (N=361,194). Inverse-variance-weighted (IVM) method was used to perform a two sample MR study. Sensitivity analysis was conducted via MR Egger, weighted median (WME), as well as leave-one-out analysis. Results Genetically predicted insulin levels were negatively associated with Lp(a) levels according to IVM estimate (p=0.003). In sensitivity analysis, WME supported this result (p=0.0002), while MR-Egger was not statistically significant (p=0.11). Leave-one-out analysis did not show the results to depend on any single variant. Conclusion This MR study provides robust evidence supporting the association between plasma insulin levels and decreased Lp(a) concentration. These findings suggest that hyperinsulinemia triggered by insulin resistance can be in part responsible for the observed negative correlation between low Lp(a) and T2D risk. Figure 1. Genetic associations between insulin levels and Lp(a). Each genetic variant included in the analysis is represented as a point + 95% CI. Localization on the horizontal axis represents the correlation of the variant with exposure (plasma fasting insulin, inverse variance normal transformed values). Localization on the vertical axis represents the correlation of the variant with outcome (Lp(a), natural log transformed values). Lines represent estimates of different MR methods.Figure 1.

中文翻译：

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胰岛素和 Lp（a） 水平的因果关系：一项孟德尔随机化研究


背景 许多观察性研究表明，循环脂蛋白 （a） [Lp（a）] 与 2 型糖尿病 [T2D] 的发生呈负相关。然而，孟德尔随机化 [MR] 研究并未始终支持这一点。体外研究表明胰岛素下调 Lp（a） 表达，这可能是观察到 Lp（a） 和 T2D 之间相关性的另一种机制。目的 在这项 MR 研究中，我们调查了遗传预测的胰岛素水平对遗传预测的 Lp（a） 水平的影响，以阐明 Lp（a） 与糖尿病之间的潜在因果关系。方法 从全基因组关联研究的荟萃分析中获得与胰岛素水平相关的独立遗传变异 （GWAS，N=151,013）。Lp（a） 的汇总数据来自英国生物样本库的 GWAS 研究 （N=361,194）。使用逆方差加权 （IVM） 方法进行双样本 MR 研究。敏感性分析通过 MR Egger 、加权中位数 （WME） 以及留一法分析进行。结果 根据 IVM 估计，遗传预测的胰岛素水平与 Lp（a） 水平呈负相关 （p=0.003）。在敏感性分析中，WME 支持这一结果 （p=0.0002），而 MR-Egger 没有统计学意义 （p=0.11）。留一法分析未显示结果取决于任何单个变体。结论 这项 MR 研究提供了强有力的证据，支持血浆胰岛素水平与 Lp（a） 浓度降低之间的关联。这些发现表明，胰岛素抵抗引发的高胰岛素血症可能是观察到的低 Lp（a） 和 T2D 风险之间负相关的部分原因。图 1.胰岛素水平与 Lp（a） 之间的遗传关联。 分析中包含的每个遗传变异都表示为一个点 + 95% CI。横轴上的定位表示变体与暴露（血浆空腹胰岛素、逆方差、正常转换值）的相关性。纵轴上的定位表示变体与结果（Lp（a），自然对数转换值）的相关性。线条表示不同 MR 方法的估计值。图 1.