Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, 6020, Austria.
Department of Internal Medicine, Lausanne University Hospital, Lausanne, 1015, Switzerland.
Sci Rep. 2017 Aug 18;7(1):8734. doi: 10.1038/s41598-017-07213-9.
Apolipoprotein A-IV (apoA-IV) has been observed to be associated with lipids, kidney function, adiposity- and diabetes-related parameters. To assess the causal relationship of apoA-IV with these phenotypes, we conducted bidirectional Mendelian randomization (MR) analyses using publicly available summary-level datasets from GWAS consortia on apoA-IV concentrations (n = 13,813), kidney function (estimated glomerular filtration rate (eGFR), n = 133,413), lipid traits (HDL cholesterol, LDL cholesterol, triglycerides, n = 188,577), adiposity-related traits (body-mass-index (n = 322,206), waist-hip-ratio (n = 210,088)) and fasting glucose (n = 133,010). Main analyses consisted in inverse-variance weighted and multivariable MR, whereas MR-Egger regression and weighted median estimation were used as sensitivity analyses. We found that eGFR is likely to be causal on apoA-IV concentrations (53 SNPs; causal effect estimate per 1-SD increase in eGFR = -0.39; 95% CI = [-0.54, -0.24]; p-value = 2.4e-07). Triglyceride concentrations were also causally associated with apoA-IV concentrations (40 SNPs; causal effect estimate per 1-SD increase in triglycerides = -0.06; 95% CI = [-0.08, -0.04]; p-value = 4.8e-07), independently of HDL-C and LDL-C concentrations (causal effect estimate from multivariable MR = -0.06; 95% CI = [-0.10, -0.02]; p-value = 0.0014). Evaluating the inverse direction of causality revealed a possible causal association of apoA-IV on HDL-cholesterol (2 SNPs; causal effect estimate per one percent increase in apoA-IV = -0.40; 95% CI = [-0.60, -0.21]; p-value = 5.5e-05).
载脂蛋白 A-IV（apoA-IV）与脂质、肾功能、肥胖和糖尿病相关参数有关。为了评估 apoA-IV 与这些表型的因果关系，我们使用来自 apoA-IV 浓度（n=13813）、肾功能（估计肾小球滤过率（eGFR），n=133413）、脂质特征（HDL 胆固醇、LDL 胆固醇、甘油三酯，n=188577）、肥胖相关特征（体重指数（n=322206）、腰臀比（n=210088）和空腹血糖（n=133010）的 GWAS 联盟的公开汇总数据集进行了双向孟德尔随机化（MR）分析。主要分析包括反向方差加权和多变量 MR，而 MR-Egger 回归和加权中位数估计则作为敏感性分析。我们发现，eGFR 可能对 apoA-IV 浓度有因果关系（53 个 SNP；每增加 1-SD 的 eGFR，apoA-IV 浓度的因果效应估计值为-0.39；95%CI=-0.54，-0.24；p 值=2.4e-07）。甘油三酯浓度也与 apoA-IV 浓度有因果关系（40 个 SNP；每增加 1-SD 的甘油三酯，apoA-IV 浓度的因果效应估计值为-0.06；95%CI=-0.08，-0.04；p 值=4.8e-07），独立于 HDL-C 和 LDL-C 浓度（多变量 MR 的因果效应估计值为-0.06；95%CI=-0.10，-0.02；p 值=0.0014）。评估因果关系的逆方向表明，apoA-IV 与 HDL 胆固醇之间可能存在因果关系（2 个 SNP；apoA-IV 每增加 1%，HDL 胆固醇的因果效应估计值为-0.40；95%CI=-0.60，-0.21；p 值=5.5e-05）。
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