Functional noncoding SNPs in human endothelial cells fine-map vascular trait associations.

Area of Science:

• Genomics
• Molecular Biology
• Cardiovascular Genetics

Background:

• Noncoding genetic variations pose challenges in understanding disease mechanisms.
• Endothelial cells (ECs) play a crucial role in vascular health and disease.
• Previous molecular quantitative trait locus (molQTL) analyses identified potential functional noncoding single nucleotide polymorphisms (SNPs).

Purpose of the Study:

• To identify functional noncoding SNPs affecting enhancer activity in human endothelial cells.
• To investigate the context-specific effects of these SNPs, particularly under inflammatory conditions.
• To elucidate the mechanisms by which noncoding SNPs contribute to vascular disease risk.

Main Methods:

• Utilized molQTL data to nominate candidate functional noncoding SNPs.
• Employed a highly multiplexed STARR-seq assay to test enhancer perturbation by 34,344 variants in ECs.
• Analyzed SNP effects under pro-inflammatory stimulation (IL1B) and fine-mapped vascular disease loci.

Main Results:

• Validated 5711 functional noncoding SNPs with enriched attributes including transcription factor binding motif disruption (ETS, AP-1), location in active chromatin, and molQTL associations.
• Observed significant context-specific SNP effects (>50%) under IL1B stimulation, indicating gene-by-environment interactions.
• Fine-mapped two vascular disease loci, suggesting mechanisms for SNP effects on POU4F1 and LDAH in pulse pressure/large artery stroke and abdominal aortic aneurysm risk.

Conclusions:

• Identified key attributes of functional noncoding SNPs in ECs, emphasizing their context-dependent nature.
• Provided novel mechanistic insights into how noncoding genetic variations influence vascular disease susceptibility.
• Highlighted the importance of studying noncoding variation in endothelial cells for understanding complex trait genetics.