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

Abstract

BackgroundThoracic 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. MethodsWe 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. ResultsAmong 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). ConclusionsRare 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. Research PerspectiveO_ST_ABSWhat New Question Does This Study Raise?C_ST_ABSWhether previously unclassified rare homozygous variants in definitive or strong TAAD-related genes contribute to disease-related mortality in the general population. What Question Should be Addressed Next?Future studies should determine whether these unclassified variants have true pathogenic roles or represent linkage with causal alleles, through functional validation and replication in other cohorts. What Are the Broader Clinical Implications?These findings may provide a foundation for novel clinical evaluation in general population, ultimately contributing to risk stratification and preventive interventions that could shift management strategies for TAAD.