Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-07-05 Epub Date: 2024-06-03 DOI:10.1161/CIRCRESAHA.123.323973
Thomas Gilliland, Jacqueline S Dron, Margaret Sunitha Selvaraj, Mark Trinder, Kaavya Paruchuri, Sarah M Urbut, Sara Haidermota, Rachel Bernardo, Md Mesbah Uddin, Michael C Honigberg, Gina M Peloso, Pradeep Natarajan
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Abstract

Background: Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort.

Methods: Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data.

Results: Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P=2×10-16), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P=2.6×10-12). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia.

Conclusions: Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.

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合并血脂紊乱的基因结构与临床结果
背景:脂蛋白异常血症通常涉及多种血脂特征的同时失调。我们的目的是评估基于普通人群的队列中合并血脂紊乱的表型和遗传特征:方法:在英国生物数据库(UK Biobank)参与者中,如果没有流行性冠状动脉疾病,我们使用血脂和载脂蛋白 B 浓度将其归入 6 种可重复且相互排斥的脂蛋白异常亚型中的一种。使用 Cox 比例危险模型估算了每个亚型的冠心病发病风险。对每个亚型进行了全表型分析和全基因组关联研究,然后进行了硅学因果基因优先排序和遗传率分析。此外,还利用全外显子组序列数据评估了孟德尔血脂紊乱病因基因中破坏性变异的发生率:结果:在 450 636 名英国生物库参与者中,有 63 人(0.01%)患有血脂紊乱:63人(0.01%)患有乳糜微粒血症;40 005人(8.9%)患有高胆固醇血症;94 785人(21.0%)患有合并高脂血症;13 998人(3.1%)患有残余高胆固醇血症;110 389人(24.5%)患有高甘油三酯血症;49人(0.01%)患有混合型高甘油三酯血症和高胆固醇血症。在11.1(10.4-11.8)年的中位数(四分位数间距)随访期间,不同亚型的冠心病发病风险各不相同,其中合并高脂血症的风险最大(危险比为1.92 [95% CI, 1.84-2.01];P=2×10-16),即使考虑到非高密度脂蛋白胆固醇(危险比为1.45 [95% CI, 1.30-1.60];P=2.6×10-12)。全基因组关联研究揭示了与脂蛋白血症亚型显著相关的 250 个位点,其中 72 个位点(28.8%)在之前的单一血脂性状全基因组关联研究中未被检测到。在脂蛋白血症患者中,孟德尔血脂变异携带者很少见(2.0%),但多基因遗传率很高,从残余高胆固醇血症的23%到合并高脂血症的54%不等:结论:对多种血脂异常的同时评估揭示了不同脂蛋白异常亚型的冠心病风险和遗传结构的细微差别。这些发现强调了超越单一血脂特征以更好地了解血脂和脂蛋白综合表型及其对疾病风险影响的重要性。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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