Huang Yun, Stinson Sara Elizabeth, Thodberg Malte, Holm Louise Aas, Thielemann Roman, Sulek Karolina, Lund Morten Asp Vonsild, Fonvig Cilius Esmann, Kim Min, Trost Kajetan, Juel Helene Bæk, Nielsen Trine, Rossing Peter, Thiele Maja, Krag Aleksander, Legido-Quigley Cristina, Holm Jens-Christian, Hansen Torben
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Denmark.
EBioMedicine. 2025 Feb;112:105537. doi: 10.1016/j.ebiom.2024.105537. Epub 2025 Jan 2.
Lipid species are emerging as biomarkers for cardiometabolic risk in both adults and children. The genetic regulation of lipid species and their impact on cardiometabolic risk during early life remain unexplored.
Using mass spectrometry-based lipidomics, we measured 227 plasma lipid species in 1149 children and adolescents (44.8% boys) with a median age of 11.2 years. We performed genome-wide association analyses to identify genetic variants influencing lipid species. Colocalisation and Mendelian randomisation (MR) analyses were performed to infer causality between lipid species and cardiometabolic outcomes.
We identified 37 genome-wide significant loci for 52 lipid species, nine of which are previously unreported. Colocalisation analyses revealed that seven lipid loci shared genetic variants associated with adult cardiometabolic outcomes. One-sample MR analysis identified positive causal associations between ceramides and liver enzymes, sphingomyelins and hemoglobin A1c (HbA1c), and phosphatidylethanolamines and high-sensitivity C-reactive protein in children and adolescents. Two-sample MR using adult-based summary statistics showed consistent direction of associations and indicated additional causal links, specifically between ceramides and elevated HbA1c levels, and phosphatidylinositols with elevated liver enzymes.
These findings highlight the potential long-term implications of plasma lipid genetic determinants on cardiometabolic risk.
Novo Nordisk Foundation, The Innovation Fund Denmark, The Danish Heart Foundation, EU Horizon, and LundbeckFonden.
脂质种类正在成为成人和儿童心脏代谢风险的生物标志物。脂质种类的遗传调控及其在生命早期对心脏代谢风险的影响仍未得到探索。
我们采用基于质谱的脂质组学技术，对1149名儿童和青少年（44.8%为男孩）的227种血浆脂质种类进行了测量，这些儿童和青少年的中位年龄为11.2岁。我们进行了全基因组关联分析，以确定影响脂质种类的基因变异。进行了共定位和孟德尔随机化（MR）分析，以推断脂质种类与心脏代谢结局之间的因果关系。
我们确定了52种脂质种类的37个全基因组显著位点，其中9个位点此前未被报道。共定位分析显示，7个脂质位点共享与成人心脏代谢结局相关的基因变异。单样本MR分析确定了儿童和青少年中神经酰胺与肝酶、鞘磷脂与糖化血红蛋白（HbA1c）、磷脂酰乙醇胺与高敏C反应蛋白之间存在正向因果关联。使用基于成人的汇总统计数据进行的两样本MR分析显示了一致的关联方向，并表明了其他因果联系，特别是神经酰胺与HbA1c水平升高之间，以及磷脂酰肌醇与肝酶升高之间的因果联系。
这些发现突出了血浆脂质遗传决定因素对心脏代谢风险的潜在长期影响。
诺和诺德基金会、丹麦创新基金、丹麦心脏基金会、欧盟地平线计划和伦贝克基金会。
