Potential association of genetic variants with thoracic aortic aneurysm and dissection: Evidence from a Japanese...

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition for which early risk stratification and preventive strategies present critical challenges. Although genetic contributions are well established in high-risk populations, the clinical relevance of rare variants in the general population remains poorly understood. We aimed to explore the association between low-frequency homozygous minor allele genotypes in TAAD-related genes and TAAD-related mortality using a Japanese community-based cohort.

We selected 14 single-nucleotide polymorphisms from genes with definitive or strong clinical validity for TAAD, based on the criterion that the frequency of individuals homozygous for the minor allele was less than 5%. Participants with any low-frequency homozygous minor allele genotypes were classified as carriers, while those without such genotypes were classified as non-carriers. The primary outcome was TAAD-related mortality, and we examined whether carrier status was associated with the risk of TAAD-related death.

Among 24,478 participants, we analyzed 5,722 individuals (1,499 carriers and 4,223 non-carriers) who had genome-wide genotyping data. TAAD-related deaths were observed in 12 individuals (8 carriers and 4 non-carriers). Carriers exhibited lower survival rates compared to non-carriers. Univariate Cox model analysis showed carrier status was associated with increased TAAD-related mortality. These variants had not been previously classified as pathogenic.

Low-frequency homozygous minor allele genotypes in established TAAD-related genes were associated with TAAD-related mortality in a general Japanese population. These findings should be interpreted as hypothesis-generating and are limited to mortality as the endpoint, providing population-based epidemiological evidence on the potential clinical relevance of currently unclassified variants.