LIPA, a risk locus for coronary artery disease: decoding the variant-to-function relationship.

Area of Science:

• Genomics
• Molecular Biology
• Cardiovascular Disease Research

Background:

• Genome-wide association studies identify LIPA as a coronary artery disease (CAD) risk locus.
• Previous research prioritized LIPA as a likely causal gene, but functional evidence was lacking.
• Understanding the variant-to-function relationship at the LIPA locus is crucial for mechanistic insights into CAD.

Purpose of the Study:

• To establish the variant-to-function relationship at the LIPA locus.
• To elucidate the causal variants, regulatory mechanisms, and target cell types involved.
• To determine the causal impact of LIPA on atherosclerosis.

Main Methods:

• Utilized post-genome-wide association study pipelines and molecular biology techniques (e.g., eQTL, Tri-HiC, CRISPRi).
• Investigated enhancer-promoter interactions and transcription factor binding (PU.1).
• Generated myeloid-specific Lipa overexpression mice (Ldlr-/-) to model atherosclerosis.

Main Results:

• Coronary artery disease risk alleles increase LIPA expression and enzyme activity in monocytes/macrophages via enhanced PU.1 binding to an intronic enhancer.
• Myeloid-specific Lipa overexpression in mice led to larger atherosclerotic lesions.
• Observed altered macrophage function, increased lesional macrophage accumulation, and changes in specific gene pathways.

Conclusions:

• Established a direct causal link between LIPA risk alleles and increased monocyte/macrophage LIPA.
• Demonstrated that increased LIPA exacerbates atherosclerosis.
• Bridged human functional genomic evidence with mechanistic understanding of CAD.