载脂蛋白 A-I 浓度与冠状动脉疾病风险：一项孟德尔随机化研究。
Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study.
机构信息
Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland.
Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK; Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
出版信息
Atherosclerosis. 2020 Apr;299:56-63. doi: 10.1016/j.atherosclerosis.2020.02.002. Epub 2020 Feb 14.
BACKGROUND AND AIMS
Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD). Although circulating apoA-I concentrations inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking. The aim was to assess the causal role of apoA-I using human genetics.
METHODS
We identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations (p < 5 × 10) in 20,370 Finnish participants, and meta-analyzed our data with a previous GWAS of apoA-I. We obtained genetic estimates of CAD from UK Biobank and CARDIoGRAMplusC4D (totaling 122,733 CAD cases) and conducted a two-sample Mendelian randomization analysis. We compared our genetic findings to observational associations of apoA-I with risk of CAD in 918 incident CAD cases among 11,535 individuals from population-based prospective cohorts.
RESULTS
ApoA-I was associated with a lower risk of CAD in observational analyses (HR 0.81; 95%CI: 0.75, 0.88; per 1-SD higher apoA-I), with the association showing a dose-response relationship. Rs12225230 associated with apoA-I concentrations (per-C allele beta 0.076 SD; SE: 0.013; p = 1.5 × 10) but not with confounders. In Mendelian randomization analyses, apoA-I was not related to risk of CAD (OR 1.13; 95%CI: 0.98,1.30 per 1-SD higher apoA-I), which was different from the observational association. Similar findings were observed using an independent ABCA1 variant in sensitivity analysis.
CONCLUSIONS
Genetic evidence fails to support a cardioprotective role for apoA-I. This is in line with the cumulative evidence showing that HDL-related phenotypes are unlikely to have a protective role in CAD.
背景和目的
载脂蛋白 A-I（apoA-I）输注代表了预防冠状动脉疾病（CAD）的一种潜在新的治疗方法。尽管循环 apoA-I 浓度与 CAD 风险呈负相关，但缺乏这种关系代表因果关系的证据。本研究旨在使用人类遗传学来评估 apoA-I 的因果作用。
方法
我们在 20370 名芬兰参与者中鉴定出 APOA1 基因座中的一个变体（rs12225230），该变体与循环 apoA-I 浓度相关（p<5×10），并对我们的数据进行了荟萃分析与以前的 apoA-I 的 GWAS 进行了 meta 分析。我们从英国生物库（UK Biobank）和 CARDIOGRAMplusC4D（总计 122733 例 CAD 病例）获得了 CAD 的遗传估计值，并进行了两样本 Mendelian 随机分析。我们将我们的遗传发现与 apoA-I 与 918 例新发生的 CAD 病例在 11535 名来自基于人群的前瞻性队列的个体中的 CAD 风险的观察关联进行了比较。
结果
在观察性分析中，apoA-I 与 CAD 风险呈负相关（HR 0.81；95%CI：0.75，0.88；每 1-SD 更高的 apoA-I），且该关联呈剂量反应关系。rs12225230 与 apoA-I 浓度相关（每-C 等位基因 beta 0.076 SD；SE：0.013；p=1.5×10），但与混杂因素无关。在 Mendelian 随机分析中，apoA-I 与 CAD 风险无关（OR 1.13；95%CI：0.98，1.30 每 1-SD 更高的 apoA-I），这与观察性关联不同。在敏感性分析中使用独立的 ABCA1 变体也观察到了类似的发现。
结论
遗传证据不支持 apoA-I 的心脏保护作用。这与累积证据一致，表明 HDL 相关表型不太可能在 CAD 中具有保护作用。
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