Evaluating genetically-predicted causal effects of lipoprotein(a) in human diseases: a phenome-wide Mendelian randomization study

Jingchunzi Shi, Suyash S. Shringarpure, David Hinds, 23andMe Research Team, Adam Auton, Michael V. Holmes
{"title":"Evaluating genetically-predicted causal effects of lipoprotein(a) in human diseases: a phenome-wide Mendelian randomization study","authors":"Jingchunzi Shi, Suyash S. Shringarpure, David Hinds, 23andMe Research Team, Adam Auton, Michael V. Holmes","doi":"10.1101/2024.07.24.24310950","DOIUrl":null,"url":null,"abstract":"Background: Lipoprotein(a) (Lp[a]) is a circulating plasma lipoprotein that is emerging as an important independent risk factor for vascular disease. Lp(a) levels are 75-90% heritable, predominantly determined by copy number variation and single nucleotide polymorphisms (SNPs) at the LPA gene. Methods: Using ~370K individuals with serum measurements of Lp(a) in the UK Biobank European cohort, we constructed a genetic risk score (GRS) consisting of 29 SNPs in the vicinity of LPA which explained 68.18% of variation in Lp(a). Using the LPA GRS to instrument Lp(a), we conducted phenome-wide Mendelian randomization analysis (MR-PheWAS) across a spectrum of 489 medically-relevant phenotypes in ~7.3M individuals from the 23andMe, Inc. database, and compared effects to those derived from a GRS for low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Through multivariable MR, we sought to assess the direct causal effect of Lp(a) on cardiovascular disease risks while keeping LDL-C or apoB constant. Results: MR-PheWAS confirmed previously reported Lp(a) causal effects on coronary artery disease (CAD: OR = 1.199, 95% CI = [1.193, 1.205], p-value < 2.23e-308, for every 59.632 nmol/L higher Lp(a) instrumented by the LPA GRS), and revealed additional genetically-predicted effects largely confined to cardiovascular endpoints, including a novel effect for restrictive cardiomyopathy (OR = 1.101, 95% CI = [1.068, 1.134], p-value = 3e-10). We scaled the LPA, LDL-C and apoB GRS such that they each had the same OR for MACE (major adverse cardiovascular events). Using the scaling rubric, similar magnitudes of effect were seen for the three lipid traits for most vascular diseases, with the exception of peripheral artery disease, aortic stenosis and dilated cardiomyopathy, where Lp(a) had larger genetically-predicted effect sizes compared to LDL-C and apoB. Multivariable MR identified Lp(a) to retain a causal effect on MACE while accounting for LDL-C or apoB. To achieve the 25% relative risk reduction in major vascular events, as seen with a 1 mmol/L reduction in LDL-C from statin trials, we anticipate that Lp(a) ought to be reduced by ~ 90 mg/dL (200 nmol/L), highlighting the importance of not only using therapies that have a profound impact on Lp(a) lowering, but also selecting individuals that have high Lp(a) concentrations at baseline. Conclusion: Lp(a) has genetically-predicted causal effects on a broad range of cardiovascular diseases beyond CAD, with minimal effects seen for non-vascular disease.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv - Cardiovascular Medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.07.24.24310950","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Lipoprotein(a) (Lp[a]) is a circulating plasma lipoprotein that is emerging as an important independent risk factor for vascular disease. Lp(a) levels are 75-90% heritable, predominantly determined by copy number variation and single nucleotide polymorphisms (SNPs) at the LPA gene. Methods: Using ~370K individuals with serum measurements of Lp(a) in the UK Biobank European cohort, we constructed a genetic risk score (GRS) consisting of 29 SNPs in the vicinity of LPA which explained 68.18% of variation in Lp(a). Using the LPA GRS to instrument Lp(a), we conducted phenome-wide Mendelian randomization analysis (MR-PheWAS) across a spectrum of 489 medically-relevant phenotypes in ~7.3M individuals from the 23andMe, Inc. database, and compared effects to those derived from a GRS for low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Through multivariable MR, we sought to assess the direct causal effect of Lp(a) on cardiovascular disease risks while keeping LDL-C or apoB constant. Results: MR-PheWAS confirmed previously reported Lp(a) causal effects on coronary artery disease (CAD: OR = 1.199, 95% CI = [1.193, 1.205], p-value < 2.23e-308, for every 59.632 nmol/L higher Lp(a) instrumented by the LPA GRS), and revealed additional genetically-predicted effects largely confined to cardiovascular endpoints, including a novel effect for restrictive cardiomyopathy (OR = 1.101, 95% CI = [1.068, 1.134], p-value = 3e-10). We scaled the LPA, LDL-C and apoB GRS such that they each had the same OR for MACE (major adverse cardiovascular events). Using the scaling rubric, similar magnitudes of effect were seen for the three lipid traits for most vascular diseases, with the exception of peripheral artery disease, aortic stenosis and dilated cardiomyopathy, where Lp(a) had larger genetically-predicted effect sizes compared to LDL-C and apoB. Multivariable MR identified Lp(a) to retain a causal effect on MACE while accounting for LDL-C or apoB. To achieve the 25% relative risk reduction in major vascular events, as seen with a 1 mmol/L reduction in LDL-C from statin trials, we anticipate that Lp(a) ought to be reduced by ~ 90 mg/dL (200 nmol/L), highlighting the importance of not only using therapies that have a profound impact on Lp(a) lowering, but also selecting individuals that have high Lp(a) concentrations at baseline. Conclusion: Lp(a) has genetically-predicted causal effects on a broad range of cardiovascular diseases beyond CAD, with minimal effects seen for non-vascular disease.
评估脂蛋白(a)在人类疾病中的基因预测因果效应:全表观孟德尔随机研究
背景:脂蛋白(a)(Lp[a])是一种循环血浆脂蛋白,正逐渐成为血管疾病的重要独立风险因素。脂蛋白(a)水平的 75-90% 可遗传,主要由 LPA 基因的拷贝数变异和单核苷酸多态性(SNPs)决定。研究方法利用英国生物库欧洲队列中约 37 万血清 Lp(a) 测量值的个体,我们构建了由 LPA 附近 29 个 SNPs 组成的遗传风险评分(GRS),这些 SNPs 解释了 68.18% 的 Lp(a) 变异。利用 LPA GRS 来检测脂蛋白(a),我们对 23andMe 公司数据库中约 730 万个体的 489 种医学相关表型进行了全表型孟德尔随机分析(MR-PheWAS),并将其效果与低密度脂蛋白胆固醇(LDL-C)和载脂蛋白 B(apoB)的 GRS 得出的效果进行了比较。在保持低密度脂蛋白胆固醇或载脂蛋白 B 不变的情况下,通过多变量 MR,我们试图评估脂蛋白(a)对心血管疾病风险的直接因果效应。结果:MR-PheWAS证实了之前报道的脂蛋白(a)对冠状动脉疾病(CAD)的因果效应:OR = 1.199,95% CI = [1.193,1.205],p-value < 2.23e-308,LPA GRS 中 Lp(a) 每升高 59.632 nmol/L),并揭示了主要局限于心血管终点的其他基因预测效应,包括对限制性心肌病的新效应(OR = 1.101,95% CI = [1.068,1.134],p-value = 3e-10)。我们对低密度脂蛋白胆固醇、低密度脂蛋白胆固醇和载脂蛋白B GRS进行了缩放,使它们在MACE(主要不良心血管事件)方面的OR值相同。使用缩放比例后,三种血脂特质对大多数血管疾病的影响大小相似,但外周动脉疾病、主动脉狭窄和扩张型心肌病除外,与 LDL-C 和 apoB 相比,Lp(a) 的遗传预测效应大小更大。多变量磁共振研究发现,在考虑低密度脂蛋白胆固醇或载脂蛋白B的情况下,脂蛋白(a)对MACE仍具有因果效应。为了达到他汀类药物试验中低密度脂蛋白胆固醇降低 1 毫摩尔/升所带来的主要血管事件相对风险降低 25% 的目标,我们预计脂蛋白(a)应降低约 90 毫克/分升(200 毫摩尔/升),这突出了不仅使用对降低脂蛋白(a)有深远影响的疗法,而且选择基线脂蛋白(a)浓度高的个体的重要性。结论根据基因预测,脂蛋白(a)对心血管疾病(CAD)之外的多种心血管疾病都有因果影响,而对非血管疾病的影响则微乎其微。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信