基于降脂药物靶点的遗传中介物与欧洲血统个体血清微量营养素之间的关联：一项孟德尔随机研究。

Associations between Genetically Proxied Inhibition of Lipid-Lowering Drug Targets and Serum Micronutrients among Individuals of European Descent: A Mendelian Randomization Study.

机构信息

College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.

Shang Cheng County People's Hospital, Xinyang, Henan, China.

出版信息

J Nutr. 2022 May 5;152(5):1283-1290. doi: 10.1093/jn/nxac012.

DOI:10.1093/jn/nxac012

PMID:35349717

Abstract

BACKGROUND

Limited and inconclusive data exist concerning the associations between lipid-lowering drugs and serum micronutrient concentrations.

METHODS

We conducted Mendelian randomization (MR) analyses to explore the associations between lipid-lowering drug targets and serum micronutrients. Single-nucleotide polymorphisms in genes encoding molecular targets of LDL cholesterol-lowering therapies were selected as instrumental variables for 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR; target of statins), proprotein convertase subtilisin/kexin type 9 (PCSK9; target of PCSK9 inhibitors), and Niemann-Pick C1-Like 1 (NPC1L1; target of ezetimibe). Exposure data were extracted from a published genome-wide association study (GWAS) of lipids in 188,577 European individuals, with outcome data obtained from the Integrative Epidemiology Unit (IEU) GWAS database (https://gwas.mrcieu.ac.uk). Overall, age and sex information were not calculable from the summary-level GWAS data. MR analyses were performed using the inverse-variance weighted method and MR sensitivity analysis methods.

RESULTS

We found genetically proxied inhibition of HMGCR to lower iron (effect, -0.16; 95% CI: -0.27, -0.06; P value = 0.003), zinc (effect, -0.83; 95% CI: -1.36, -0.31; P value = 0.002), magnesium (effect, -0.17; 95% CI: -0.27, -0.06; P value = 0.003), potassium (effect, -0.17; 95% CI: -0.27, -0.06; P value = 0.002), genetically proxied inhibition of NPC1L1 to increase calcium (effect, 0.28; 95% CI: 0.10, 0.46; P value = 0.003), retinol (effect, 0.25; 95% CI: 0.07, 0.44; P value = 0.01), and genetically proxied inhibition of PCSK9 to increase vitamin D (effect, 0.10; 95% CI: 0.07, 0.12; P value = 1.8 × 10-19). These associations were robust in MR sensitivity analyses. However, the associations between genetically proxied inhibition of HMGCR and NPC1L1 and the micronutrients were not consistent in multiple comparisons.

CONCLUSIONS

Our results provide evidence that statin use may lower serum concentrations of iron, zinc, magnesium, and potassium, PCSK9 inhibitors may increase serum vitamin D, and ezetimibe may increase serum calcium and retinol concentrations.

摘要

背景

关于降脂药物与血清微量营养素浓度之间的关联，目前的数据有限且结论不一致。

方法

我们进行了孟德尔随机化（MR）分析，以探讨降脂药物靶点与血清微量营养素之间的关联。选择编码 LDL 胆固醇降低治疗分子靶点的基因中的单核苷酸多态性作为 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGCR；他汀类药物的靶点）、前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9；PCSK9 抑制剂的靶点）和尼曼-匹克 C1 样 1（NPC1L1；依折麦布的靶点）的工具变量。暴露数据取自欧洲 188577 人血脂的已发表全基因组关联研究（GWAS），结局数据取自整合流行病学单位（IEU）GWAS 数据库（https://gwas.mrcieu.ac.uk）。总体而言，从汇总水平 GWAS 数据中无法计算年龄和性别信息。MR 分析采用逆方差加权法和 MR 敏感性分析方法进行。

结果

我们发现 HMGCR 基因抑制作用可降低铁（效果，-0.16；95%CI：-0.27，-0.06；P 值=0.003）、锌（效果，-0.83；95%CI：-1.36，-0.31；P 值=0.002）、镁（效果，-0.17；95%CI：-0.27，-0.06；P 值=0.003）、钾（效果，-0.17；95%CI：-0.27，-0.06；P 值=0.002），NPC1L1 基因抑制作用可增加钙（效果，0.28；95%CI：0.10，0.46；P 值=0.003）、视黄醇（效果，0.25；95%CI：0.07，0.44；P 值=0.01），PCSK9 基因抑制作用可增加维生素 D（效果，0.10；95%CI：0.07，0.12；P 值=1.8×10-19）。这些关联在 MR 敏感性分析中是稳健的。然而，在多重比较中，HMGCR 和 NPC1L1 基因抑制作用与微量营养素之间的关联并不一致。