Novel Genetic Variants of Thoracic Aortic Aneurysm and Dissection: Evidence from a Japanese Community-Based Cohort

Background: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition for which early risk stratification and preventive strategies represent critical challenges in modern medicine. Although genetic contributions have been well-established in high-risk populations, the clinical relevance of rare variants in the general population remains poorly understood. This study aimed to investigate their clinical significance using a community-based cohort. Methods: We conducted a population-based survival analysis using the Yamagata Cohort, a prospective study in Japan. 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 < 5%. Participants were categorized as carriers if they harbored homozygous rare variants, and as non-carriers otherwise. The primary outcome was TAAD-related mortality. Results: Among 24,478 participants, we analyzed 5,722 individuals with genome-wide genotyping data. The carrier group included 1,499 individuals, and the non-carrier group comprised 4,223 individuals. TAAD-related deaths occurred in 12 individuals (8 carriers vs 4 non-carriers). The carrier group showed significantly lower survival rates than the non-carrier group (P=0.0010). In the multivariable Cox model, carrier status was independently associated with increased TAAD-related mortality (hazard ratio, 2.27; 95% confidence interval, 1.24?4.14; P=0.0056). Conclusions: Rare homozygous variants in specific TAAD-related genes were significantly associated with TAAD-related mortality in this general Japanese population, despite the absence of prior pathogenic classification. These findings provide novel insights for pre-symptomatic risk stratification and a foundation for developing future preventive strategies in TAAD.