Background: Ultraviolet B exposure may influence vascular homeostasis and extracellular matrix remodeling. Thoracic aortic aneurysm (TAA) is characterized by progressive aortic wall degeneration; however, its relationship with sunburn susceptibility remains unclear.Objective:This study was aimed at investigating whether genetically predicted sunburn susceptibility might be associated with TAA risk, and to explore potential genomic and transcriptomic mechanisms. Methods: We performed two-sample Mendelian randomization on sunburn susceptibility and TAA GWAS data from 350,232 and 19,646 individuals of European ancestry. PheWAS and pigmentation-locus sensitivity analyses were conducted to assess instrument architecture. Genetic loci were annotated using FUMA SNP2GENE and GTEx eQTL mapping, and molecular evidence was explored using ssGSEA, differential-expression analysis, functional enrichment, PPI analysis, and exploratory candidate-gene prioritization. Results: Genetically predicted sunburn susceptibility was inversely associated with TAA (inverse-variance weighted OR = 0.403, 95% CI = 0.216-0.752, P = 0.004). However, this association was attenuated after exclusion of 11 pigmentation-related SNPs. Transcriptomic analyses implicated UV-response signatures, matrix and vascular remodeling, immune trafficking, ERK signaling, cell junctions, and vesicle-related processes. Integrated analyses identified HYAL1 and PREPL as priority candidates for further exploration. Conclusion: The association between sunburn susceptibility and TAA appeared to be largely driven by the pigmentation and tanning-response genetic architecture. Exploratory evidence linked phototype-related variation to matrix turnover, intracellular trafficking, and vascular remodeling.
