A transcriptome-wide analysis of whole blood RNA-seq from 6898 diverse individuals identified many genes associated with serum lipid levels (LDL, HDL, TRIG, TCHO), with Mendelian randomization and colocalization suggesting candidate causal genes and regulatory mechanisms as potential therapeutic targets for lipid dysregulation.
Key Findings
Results
Meta-analysis of four discovery datasets identified many genes whose blood expression was significantly associated with serum lipid levels.
Discovery used whole blood RNA-sequencing and mixed-effects linear regression, meta-analyzed across four datasets (n = 4398 participants).
Significant associations were found for 27 genes with LDL, 974 with HDL, 1229 with TRIG, and 276 with TCHO.
The total study population was 6898 individuals (17% Black or African American, 15% Hispanic Latino/a, 68% White).
Results
Two replication datasets confirmed a subset of the discovery gene-lipid associations, with the largest number of replicated genes for triglycerides.
Replication used two datasets (n = 2500 participants).
Confirmed associations: 3 genes for LDL, 55 for HDL, 380 for TRIG, and 31 for TCHO.
Results
Genes associated with LDL, HDL, and TCHO were enriched for lipid metabolic processes, including LDLR, NPC2, and SQLE for LDL and TCHO.
Enrichment analysis was performed on the associated genes.
LDLR, NPC2, and SQLE were highlighted for LDL and TCHO.
Results
Triglyceride-associated genes were enriched for immune and allergic response, cancer, and molecular signaling pathways rather than primarily lipid metabolic pathways.
This contrasted with the lipid-metabolism enrichment seen for LDL, HDL, and TCHO genes.
The title links the findings to immune-cell regulation.
Results
Bidirectional two-sample Mendelian randomization identified expression of 8 genes as possibly causal for lipid levels.
Notably, EEPD1 expression, linked with cellular cholesterol homeostasis, was inversely associated with TRIG levels.
Analyses were bidirectional two-sample MR combined with colocalization.
Results
Colocalization identified novel shared genetic variants between lipid levels and gene expression for DDAH2 (with LDL) and FCGRT (with TRIG).
DDAH2 is associated with cardiovascular disease.
FCGRT is linked with maintaining triglyceride homeostasis.
The variants were described as novel.
Results
Phenome-wide enrichment analyses found that TRIG-associated genes were enriched for secondary malignancy of bone.
The authors interpret this as suggesting broader systemic health implications of modified lipid levels.
What This Means
This study looked at which genes are more or less active in the blood of people with different cholesterol and triglyceride levels. Using blood samples from 6898 people of diverse backgrounds, the researchers found hundreds of genes linked to HDL ("good") cholesterol and triglycerides, and fewer for LDL ("bad") and total cholesterol. A second group of 2500 people confirmed a portion of these links, especially for triglycerides.
Genes tied to LDL, HDL, and total cholesterol were mostly involved in how the body handles fats, including well-known genes like LDLR. Triglyceride-linked genes, however, were more tied to immune and allergic responses, cancer, and cell signaling. Using genetic methods that help separate cause from correlation, the researchers pointed to 8 genes whose activity may actually influence lipid levels, such as EEPD1 for triglycerides, and identified new shared genetic signals for DDAH2 (LDL) and FCGRT (triglycerides).
This research suggests new candidate genes and biological pathways that could be explored as targets for treating abnormal blood lipids. These are hypotheses generated by statistical analysis and would need laboratory and clinical follow-up before any practical use.
Lundin J, Graff M, Haessler J, Zhang X, Cai Y, Fuller H, et al.. (2026). Transcriptomic signatures of lipids in blood provide hypotheses of functional mechanisms linked to lipid metabolism and immune-cell regulation.. Human molecular genetics. https://doi.org/10.1093/hmg/ddag113