TY - JOUR
T1 - Genetic factors shaping the plasma lipidome and the relations to cardiometabolic risk in children and adolescents
AU - Huang, Yun
AU - Stinson, Sara Elizabeth
AU - Thodberg, Malte
AU - Holm, Louise Aas
AU - Thielemann, Roman
AU - Sulek, Karolina
AU - Lund, Morten Asp Vonsild
AU - Fonvig, Cilius Esmann
AU - Kim, Min
AU - Trost, Kajetan
AU - Juel, Helene Bæk
AU - Nielsen, Trine
AU - Rossing, Peter
AU - Thiele, Maja
AU - Krag, Aleksander
AU - Legido-Quigley, Cristina
AU - Holm, Jens-Christian
AU - Hansen, Torben
N1 - Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.
PY - 2025/2
Y1 - 2025/2
N2 - BACKGROUND: 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.METHODS: 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.FINDINGS: 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.INTERPRETATION: These findings highlight the potential long-term implications of plasma lipid genetic determinants on cardiometabolic risk.FUNDING: Novo Nordisk Foundation, The Innovation Fund Denmark, The Danish Heart Foundation, EU Horizon, and LundbeckFonden.
AB - BACKGROUND: 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.METHODS: 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.FINDINGS: 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.INTERPRETATION: These findings highlight the potential long-term implications of plasma lipid genetic determinants on cardiometabolic risk.FUNDING: Novo Nordisk Foundation, The Innovation Fund Denmark, The Danish Heart Foundation, EU Horizon, and LundbeckFonden.
KW - Adolescent
KW - Biomarkers
KW - Cardiometabolic Risk Factors
KW - Cardiovascular Diseases/genetics
KW - Child
KW - Female
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Lipid Metabolism/genetics
KW - Lipidomics/methods
KW - Lipids/blood
KW - Male
KW - Mendelian Randomization Analysis
KW - Polymorphism, Single Nucleotide
KW - Risk Factors
KW - Cardiometabolic risk
KW - Lipidomics
KW - Genome-wide association study
KW - Children
KW - Mendelian randomisation
U2 - 10.1016/j.ebiom.2024.105537
DO - 10.1016/j.ebiom.2024.105537
M3 - Article
C2 - 39753034
SN - 2352-3964
VL - 112
JO - EBioMedicine
JF - EBioMedicine
M1 - 105537
ER -