Transcriptomic signatures of lipids in blood provide hypotheses of functional mechanisms linked to lipid metabolism and immune-cell regulation
Year: 2026
Type: article
Study design: Observational Study
Abstract: Blood lipids are well-established risk factors for cardiovascular and other chronic diseases, yet the underlying functional mechanisms remain unclear. We conducted a large-scale, genome-wide transcriptome analysis of serum lipid levels using whole blood RNA-sequencing data from 6898 individuals of diverse races and ethnicities (17% Black or African American, 15% Hispanic Latino/a, 68% White). We utilized mixed-effects linear regression and meta-analyzed four discovery datasets (n = 4398 participants), identifying significant associations for 27 genes with low-density lipoproteins (LDL), 974 with high-density lipoproteins (HDL), 1229 with triglycerides (TRIG), and 276 with total cholesterol (TCHO). Two replication datasets (n = 2500 participants) confirmed 3, 55, 380, and 31 genes, respectively. Enrichment analysis revealed lipid metabolic processes for LDL, HDL, and TCHO associated genes, including LDLR, NPC2, and SQLE for LDL and TCHO, while TRIG associated genes highlighted immune and allergic response, cancer, and molecular signaling gene enrichment pathways. To infer causality, we performed bidirectional two-sample Mendelian randomization (MR) and colocalization analyses. MR identified the expression of 8 genes as possibly causal for lipid levels; notable EEPD1 expression, linked with cellular cholesterol homeostasis, was inversely linked with TRIG levels. We also identified novel variants shared with LDL levels and gene expression of DDAH2, associated with cardiovascular disease, and TRIG level and expression of FCGRT, linked with maintaining triglyceride homeostasis. Phenome-wide enrichment analyses reported TRIG associated genes were enriched in secondary malignancy of bone suggesting broader systemic health implications of modified lipid levels. These findings highlight novel associations and genetic regulatory mechanisms as potential therapeutic targets for lipid dysregulation.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddag113
Authors: Jessica I Lundin, Mariaelisa Graff, Jeff Haessler, Xinruo Zhang, Yanwei Cai, Harriett Fuller, Nancy Heard-Costa, Tianxiao Huan, Roby Joehanes, Joshua M Landman, Gina Marie Peloso, Yuxuan Wang, Zhe Wang, Jennifer E Below, Daniel Levy, Kari E North, Alex P Reiner, Ryan Zukowski, Ulrike Peters, Charles Kooperberg
Institutions: Fred Hutch Cancer Center, University of North Carolina at Chapel Hill, Boston University, Framingham Heart Study, National Institutes of Health, National Heart, Lung, and Blood Institute, Vanderbilt University, Vanderbilt University Medical Center, University of Alabama at Birmingham, Icahn School of Medicine at Mount Sinai, University of Washington
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: U.S. Department of Health and Human Services, Fred Hutchinson Cancer Research Center, School of Medicine, Boston University, Evans Medical Foundation, New York Genome Center, National Institutes of Health, Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Center for Advancing Translational Sciences, NHLBI Division of Intramural Research
Awards: G1052645489, G1129490614, G1131636781, G122915289, Using genetic variation to study biology of blood lipids & coronary heart disease, G1490530680, Center for Clinical and Translational Sciences (CCTS), G1757295093, G1830252914, G1851406594, G205646552, G205733141, G2096685756, G232264632, G2544448910, G2574430291, G2615153583, G264675175, G2777343687, G278200998, G2786316047, G2833631237, G3078883119, G3161388866, G3190602077, G3194560040, Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care, G3769459334, G3819938352, G3827278403, G3904784472, G4030405119, G4040422891, Rare variants and NHLBI traits in deeply phenotyped cohorts, PAGE III: Population Architecture using Genomics and Epidemiology, G447592127, G4499735890, G4514711904, G472208673, G4826951158, G4949958486, G4976486911, G5163278296, G53375319, G5519421502, G554960330, G5631728042, G5717342023, G5805320778, Framingham: Inflammation, Genes & Cardiovascular Disease, G631129105, G6374953548, G6615318374, G6668578234, G6894818919, G7159829730, G7270333588, G738282736, G7821233859, G7851177580, G7865763634, G7945866738, G8323569422, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, G8566225511, G8683204365, G9000135092, Whole genome sequences in ethnically diverse individuals to comprehensively characterize the genetic mechanisms of dyslipidemias, IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVAL, Genotypic and phenotypic approaches to subtype individuals with coronary heart disease
OpenAlex ID: W7224420806