Metabolic syndrome, genetic susceptibility, and risk of cardiovascular disease: a prospective study in the UK Biobank

Background How metabolic syndrome (MetS) and genetic susceptibility jointly relate to cardiovascular disease (CVD) remains uncertain. We examined associations of MetS with incident CVD and evaluated their variation by polygenic risk score (PRS). Methods This prospective cohort study included 385,036 participants in the UK Biobank without CVD at recruitment. Cox regression models were used to estimate adjusted hazard ratios (HRs) for overall CVD, coronary heart disease (CHD), stroke, atrial fibrillation (AF), heart failure (HF), cardiovascular mortality, and all-cause mortality. We further evaluated the impact of specific MetS components and their cumulative burden on the risk for multiple CVD outcomes. Stratified analyses were conducted by sex and body mass index (BMI). Genetic predisposition was assessed by the PRS. Results During a median follow-up of 13.6 years, 61,129 incident CVD events, 5,585 CVD deaths, and 30,513 all-cause deaths were recorded. MetS was associated with incident CVD (HR 1.39, 95% CI 1.35–1.42), CHD (1.64, 1.59–1.69), stroke (1.38, 1.31–1.45), AF (1.14, 1.10–1.19), and HF (1.41, 1.33–1.49). It was also associated with CVD mortality (1.54, 1.42–1.67) and all-cause mortality (1.25, 1.21–1.30). Higher MetS component burden was associated with higher hazards of these outcomes. MetS associations with CVD were stronger in women (FDR-adjusted interaction P < 0.001), but did not differ significantly by BMI category ( P = 0.233). Exploratory HR-based RERI estimates were positive for CVD and CHD. Continuous PRSs were associated with CVD and CHD, but not HF. Conclusion MetS was associated with higher hazards of incident cardiovascular outcomes and mortality. Associations with incident CVD were stronger in women, whereas evidence of modification by BMI was limited. Genetic interaction findings were exploratory and require independent validation.