Integrated Assessment of Abdominal Adiposity and Muscle Strength for Atherosclerotic Cardiovascular Disease Risk in UK Biobank: A Comprehensive Analysis From Population Cohort to Multi‐Omics Molecular Exploration

Background Waist circumference (WC) and grip strength (GS) are independently associated with atherosclerotic cardiovascular disease (ASCVD) risk. However, their joint impact remains insufficiently explored. This study aimed to investigate the association between WC, GS and ASCVD risk and to explore the underlying mediating factors. Methods This prospective cohort study included 271 061 UK Biobank participants. WC was categorised using World Health Organization sex‐specific thresholds and GS was categorised into age‐ and sex‐specific tertiles. Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Additive interaction was assessed using the relative excess risk due to interaction (RERI), attributable proportion (AP) and synergy index (SI). Multiple sensitivity and exploratory mediation analyses were performed. Results During a median follow‐up of 14.8 years, 27 189 participants developed ASCVD. High WC and low GS were associated with higher ASCVD risk than their respective reference groups, with HRs of 1.35 (95% CI 1.31–1.39) and 1.14 (95% CI 1.11–1.17), respectively. Participants with both high WC and low GS had the highest risk (HR 1.53, 95% CI 1.46–1.61), with evidence of additive interaction (RERI 0.11, 95% CI 0.03–0.19, AP 7.04%, 95% CI 1.67%–12.41%, SI 1.26, 95% CI 1.01–1.50). Results were consistent across sensitivity analyses. Exploratory mediation analyses identified shared metabolite and protein mediators and implicated inflammatory, immune, metabolic and vascular remodelling pathways. Conclusions Higher WC and lower GS were independently and jointly associated with incident ASCVD. Their combination identified the highest‐risk group and showed modest additive interaction. Exploratory multi‐omics analyses identified shared inflammatory and metabolic mediators that may partly underlie these associations, highlighting the value of integrating simple physical measures with molecular signatures for improved ASCVD risk characterisation.