Background

Associations between metabolic status and changes in metabolic status and the risk of adverse cardiovascular outcomes have been reported. However, the role of genetic susceptibility has not been considered. We aimed to examine the combined effects of metabolic status, metabolic transitions, and genetic susceptibility on cardiovascular outcomes and all-cause mortality across all BMI categories.

Method

In the dataset from the UK Biobank, we retrieved a total of 420 383 participants at baseline and 13 183 participants at the second resurvey. Metabolically healthy (MH) status was determined by < 3 abnormal components (waist circumstance, blood pressure, blood glucose, triglycerides, and high-density lipoprotein cholesterol). Genetic predisposition was estimated using the polygenic risk score (PRS). Cox regressions were performed to evaluate the associations of metabolic status, metabolic transitions, and PRS with cardiovascular outcomes and all-cause mortality across BMI categories.

Results

During a median follow-up of 14.38 years, all-cause mortality occurred in 28,347 of 384,860 participants, cardiovascular mortality in 7220 of 399,359 participants, and cardiovascular morbidity in 59,229 of 399,359 participants. Compared to individuals with metabolically unhealthy obesity and a high PRS, participants with a metabolically healthy normal weight and low PRS demonstrated the lowest risk of cardiovascular outcomes, including morbidity from CVD (hazard ratios [HR]: 0.31; 95% confidence interval [CI]: 0.30, 0.33), CAD, MI, stroke, and HF, along with mortality from MI and AF; participants with a metabolically healthy overweight and low PRS had the lowest risk of all-cause mortality (HR: 0.57; 95% CI: 0.52, 0.61) and specific mortality from CVD, CAD, and HF. These protective associations were more pronounced in females and younger individuals (< 65 years) (P additive interaction < 0.05). Additionally, participants with stable MH status and a low PRS exhibited a reduced risk for adverse cardiovascular outcomes across all BMI categories.

Conclusion

Maintaining MH status and a low PRS were associated with a reduced risk of cardiovascular outcomes and all-cause mortality across BMI categories, particularly in females and individuals younger than 65 years. Improving the MH status across all BMI categories should be recommended, especially for individuals with a high CVD PRS, as well as for males and those older than 65 years.

Keywords: metabolic changes; polygenic risk scores; cardiovascular outcomes; all-cause mortalit; BMI categories

Prof. Youxin Wang (1979-), dean of the School of Public Health, North China University of Science and Technology, director of the Hebei Key Laboratory of Organ Fibrosis, and Chief Scientist of the National Key Research and Development Program.

He is an adjunct professor at Edith Cowan University in Australia, the Fellowship of the Royal Society of Medicine, the Membership of the International Society of Global Health, the Membership of the American Public Health Association, and the Vice President of the Occupational Health Professional Committee of the China Association for Occupational Safety and Health.

Prof. Wang mainly engaged in molecular epidemiological research, leading one National Key R&D Program and 5 projects funded by the National Natural Science Foundation of China. In the past 5 years, As the first author or corresponding author, he has published more than 40 research papers and has served as editorial boards for BMC Public Health, Biomedical and Environmental Sciences, and reviewer for the British Medical Journal, Nature Communication, etc.