Distinct Somatic Mutational Landscapes in Paired Blood and Arterial Tissues in Coronary Artery Disease

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) is associated with ageing and atherosclerotic coronary artery disease (CAD), but evidence has largely come from peripheral blood. Whether somatic mutational profiles differ between arterial tissue and blood, and whether hematopoietic clones are represented in arterial tissue, remain poorly understood. MethodsWe performed deep whole-exome sequencing on 302 blood granulocytes and 263 arterial tissues from patients undergoing coronary artery bypass graft surgery, including 221 matched blood-tissue pairs, with mean sequencing depths of 130.5X and 120.8X, respectively. Somatic variants were identified using Mutect2. Associations with age and CAD complexity, assessed using SYNTAX score, were evaluated using multivariable regression. Primary analyses focused on variants with variant allele fractions of 10-25%. ResultsCHIP was detected in 24/302 (7.9%) blood granulocytes, predominantly involving DNMT3A, TET2, and ASXL1. In contrast, somatic mutations in CHIP-associated genes in arterial tissues showed a distinct profile dominated by CALR, SETDB1, and PDSS2. Somatic mutation carrier status increased with age in blood ({beta} = 0.07, p = 0.02) and arterial tissues ({beta} = 0.06, p = 0.04). Blood CHIP was associated with lower SYNTAX score ({beta} = -1.05, p = 2.66 x 10-3), partly driven by DNMT3A carriers ({beta} = -1.06, p = 0.04), whereas arterial CALR mutations were associated with higher SYNTAX score ({beta} = 1.14, p = 0.03). Among 221 matched pairs, only four identical variants, involving CHEK2, DNMT3A, GNB1, and SRSF1, were detected in both compartments. Genome-wide analyses showed compartment specificity, with bile acid metabolism enriched among arterial tissue-specific mutations (PAdj = 0.038). ConclusionBlood and arterial tissues in CAD harbour distinct somatic mutational landscapes with limited cross-compartment sharing. These findings suggest that cardiovascular somatic mutations may reflect both hematopoietic and arterial tissue-associated processes and motivate cell-resolved and spatial studies to define their origins and roles in cardiovascular ageing.