孟德尔随机化研究表明高密度脂蛋白胆固醇相关机制与年龄相关性黄斑变性的病因有关。

Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration.

作者信息

Burgess Stephen, Davey Smith George

机构信息

MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom; Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

出版信息

Ophthalmology. 2017 Aug;124(8):1165-1174. doi: 10.1016/j.ophtha.2017.03.042. Epub 2017 Apr 26.

DOI:10.1016/j.ophtha.2017.03.042

PMID:28456421

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5526457/

Abstract

PURPOSE

Undertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk.

DESIGN

Two-sample Mendelian randomization investigation using published data.

PARTICIPANTS

A total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium.

METHODS

We consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD. We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy. We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk. We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison.

MAIN OUTCOME MEASURES

Diagnosis of AMD.

RESULTS

We find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol. No causal effect of LDL-cholesterol or triglycerides was found. Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD.

CONCLUSIONS

Some genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk.

摘要

目的

对血脂成分的基因预测指标与年龄相关性黄斑变性（AMD）风险之间的关联进行系统研究。

设计

使用已发表数据进行两样本孟德尔随机化研究。

参与者

来自国际年龄相关性黄斑变性基因组学联盟的总共33526名个体（16144例病例，17832名对照），主要为欧洲血统。

方法

我们考虑了185个先前已证明在全基因组显著性水平上与低密度脂蛋白（LDL）胆固醇、高密度脂蛋白（HDL）胆固醇或甘油三酯中至少一种相关的变体，并测试它们与AMD的关联。我们特别关注作为脂质治疗特定药物替代指标的基因区域中的变体。然后，我们进行两样本孟德尔随机化研究，以评估LDL胆固醇、HDL胆固醇和甘油三酯对AMD风险的因果作用。我们还对冠状动脉疾病（CAD）（作为阳性对照）和阿尔茨海默病（阴性对照）进行了平行研究以作比较。

主要观察指标

AMD的诊断。

结果

我们发现有证据表明HDL胆固醇是AMD的因果风险因素，HDL胆固醇每增加1个标准差，比值比（OR）估计值为1.22（95%置信区间[CI]，1.03 - 1.44）。未发现LDL胆固醇或甘油三酯的因果效应。与循环HDL胆固醇升高相关的CETP基因区域中的变体也与AMD风险增加相关，尽管增加循环HDL胆固醇的LIPC基因区域中的变体与AMD风险的关联方向相反。平行分析表明，与阿尔茨海默病相比，脂质对AMD的作用更大，但比CAD的作用小。