Whole-Genome Sequencing and Single-Cell Transcriptomics Identify Human Leukocyte Antigen Loci and a COG5 Variant in Aortic Dissection.

BACKGROUND

Aortic dissection (AD) is a lethal cardiovascular emergency with a complex and underexplored genetic basis.

METHODS

We performed whole-genome sequencing on 151 patients with sporadic Stanford type B AD and 965 healthy controls in a Chinese population as a discovery phase analysis to assess both common and rare variants. Cross-ancestry meta-analyses incorporating 4 external genome-wide association data sets were used to identify population-specific risk loci. To pinpoint functional candidates, we integrated epigenomic profiles and single-cell transcriptomes from human aortic tissues.

RESULTS

Whole-genome sequencing analysis identified 21 candidate common loci and 2 low-frequency variants associated with AD in this discovery cohort. Two candidate common variants in the human leukocyte antigen region (rs9260945 near HLA-A and rs9276409 within HLA-DQA2) showed strong associations and colocalized with regulatory elements in aortic and immune cells, indicating immune-mediated vascular pathology. A low-frequency missense variant in the COG5 gene (rs1203229795, effect allele frequency=0.019) emerged as an independent AD risk factor, likely affecting extracellular matrix glycosylation. Single-cell transcriptomic analysis of AD-associated variants in human aortic tissues demonstrated enhanced interactions among fibroblasts, vascular smooth muscle cells, and macrophages, supporting their roles in AD pathogenesis. Integrated gene-based and expression analyses further highlighted TPM4, a marker of vascular smooth muscle cell dedifferentiation, as a putative susceptibility gene in AD.

CONCLUSIONS

This multiomics investigation expands the genetic landscape of sporadic AD in Chinese individuals, revealing immune-related human leukocyte antigen loci and a functionally supported candidate COG5 variant. Our findings offer new insights into AD pathogenesis and identify candidate targets for future diagnostic and therapeutic strategies.