Accelerated aging is a determinant of arterial thrombosis risk in individuals with low genetic and cardiovascular risk factor burden

Background The relative contribution of genetics and exposomal cardiovascular risk factors (CVRFs) to arterial thrombosis incidence varies across the lifespan. Individuals with low genetic and CVRF burden also experience arterial thrombosis. Aims To evaluate how genetic and exposomal risk contribute to arterial thrombosis risk over the lifespan, and to assess whether accelerated biological aging explains residual events in the subgroup of low genetic and exposomal risk. Methods Data from the longitudinal, population-based Gutenberg Health Study (GHS; 1,001 events) and the UK Biobank (UKB; 44,108 events) were used for attained-age time-varying Cox regression with restricted cubic splines. A polygenic risk score (PRS) for arterial thrombotic events was constructed from SNPs previously identified in genome-wide association studies, via LASSO-regularized Cox regression in UKB. In GHS, the CVRF burden was defined repeatedly over a 10-year follow-up. The low-PRS-low-CVRF subgroup was defined as individuals in the lower 50% of the PRS distribution with ≤1 CVRF. Two measures of accelerated aging (PhenoAgeAccel and C-reactive protein–based inflammaging) were calculated as baseline chronological age-adjusted residuals. Results In UKB, the PRS hazard ratio per SD (HR) declined from 1.85 at 53 years of age to 1.10 by age 80. In GHS, the HR was 1.22 [95% CI 1.07–1.39] at age 55 and reached 1.10 [95% CI 1.01–1.20] by age 75. Concurrently, the median [interquartile range] CVRF burden increased from 1 [0–2] at age 55 to 2 [1–2] at age 75. The CVRF burden HR declined from 2.36 [95% CI 2.16–2.58] at age 55 to 1.09 [95% CI 1.02–1.17] by age 75 (p<0.001). The low-PRS-low-CVRF subgroup represented 27.3% of participants (n = 3,312) and accounted for 17.3% of all arterial events (n = 173). In this subgroup, PhenoAgeAccel (HR = 1.21; 95% CI 1.08–1.36; p = 0.0012) and inflammaging (HR = 1.18; 95% CI 1.01–1.37; p = 0.033) were robust predictors of residual risk. By age 75, low-PRS-low-CVRF individuals ≥90th percentile of PhenoAgeAccel had a predicted cumulative incidence of 21.7% (95% CI 16.8–26.3) versus 14.7% (95% CI 10.9–18.3) in the ≤10th percentile. Conclusions Genetics and the exposome have attenuating effect sizes in old age. Accelerated biological aging and inflammaging are predictors of arterial thrombosis in those at low genetic and exposomal risk. These results support incorporating biological age into risk assessment and prevention strategies.