ArticleEuropean heart journal2025
LIPA, a risk locus for coronary artery disease: decoding the variant-to-function relationship.
Article in European heart journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
3 citing papers in PubMed.
- Enhancer Dynamics for Gene Regulation in the Cardiovascular System.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Integrative genetic and expression profiling prioritizesFrontiers in immunology · 2026Article
- Identification of key biomarkers for myocardial infarction by multi-omics analysis and machine learning.Frontiers in immunology · 2026Article
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Authors and funding
23 authors.
Funding
Abstract
BACKGROUND AND
aimsTranslating human genomic discoveries into mechanistic insights requires linking genetic variations to candidate genes and their causal functional phenotypes. Genome-wide association studies have consistently identified LIPA (lipase A, lysosomal acid type) as a risk locus for coronary artery disease, with previous analyses prioritising LIPA as a likely causal gene. However, functional studies elucidating causal variants, regulatory mechanisms, target cell types, and their causal impact on atherosclerosis have been lacking. This study aims to address this gap by establishing the variant-to-function relationship at the LIPA locus.
methodsPost-genome-wide association study pipelines and molecular biology techniques, including expression quantitative trait loci analysis, Tri-HiC, luciferase assay, CRISPRi, allele-specific binding, motif analysis, and electrophoretic mobility shift assay, were used to link functional variants to target genes and define the direction of their regulatory effects in causal cell types. To determine how increased myeloid LIPA impacts atherosclerosis, myeloid-specific Lipa overexpression mice on an Ldlr-/- background were generated.
resultsCoronary artery disease-risk alleles in the LIPA locus increase LIPA expression and enzyme activity specifically in monocytes/macrophages by enhancing PU.1 binding to an intronic enhancer region that interacts with the LIPA promoter. Myeloid-specific Lipa overexpression in Ldlr-/- mice fed a western diet resulted in larger atherosclerotic lesions, accompanied by altered macrophage function, characterized by increased accumulation of lesional macrophages derived from circulating monocytes, reduced neutral lipid content, and up-regulation of integrin and extracellular matrix pathway genes.
conclusionsThe work establishes a direct causal link between LIPA-risk alleles and increased monocyte/macrophage LIPA that exacerbates atherosclerosis, bridging human functional genomic evidence to the mechanistic understanding of coronary artery disease.
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