Associations of metabolic changes and polygenic risk scores with cardiovascular outcomes and all-cause mortality across BMI categories: a prospective cohort study

Abstract

Background: Associations between metabolic status and metabolic changes with the risk of cardiovascular outcomes have been reported. However, the role of genetic susceptibility underlying these associations remains unexplored. We aimed to examine how metabolic status, metabolic transitions, and genetic susceptibility collectively impact cardiovascular outcomes and all-cause mortality across diverse body mass index (BMI) categories.

Methods: In our analysis of the UK Biobank, we included a total of 481,576 participants (mean age: 56.55; male: 45.9%) at baseline. Metabolically healthy (MH) status was defined by the presence of < 3 abnormal components (waist circumstance, blood pressure, blood glucose, triglycerides, and high-density lipoprotein cholesterol). Normal weight, overweight, and obesity were defined as 18.5 ≤ BMI < 25 kg/m², 25 ≤ BMI < 30 kg/m², and BMI ≥ 30 kg/m², respectively. 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, 31,883 (7.3%) all-cause deaths, 8133 (1.8%) cardiovascular disease (CVD) deaths, and 67,260 (14.8%) CVD cases were documented. Among those with a high PRS, individuals classified as metabolically healthy overweight had the lowest risk of all-cause mortality (hazard ratios [HR] 0.70; 95% confidence interval [CI] 0.65, 0.76) and CVD mortality (HR 0.57; 95% CI 0.50, 0.64) compared to those who were metabolically unhealthy obesity, with the beneficial associations appearing to be greater in the moderate and low PRS groups. Individuals who were metabolically healthy normal weight had the lowest risk of CVD morbidity (HR 0.54; 95% CI 0.51, 0.57). Furthermore, the inverse associations of metabolic status and PRS with cardiovascular outcomes and all-cause mortality across BMI categories were more pronounced among individuals younger than 65 years (P_interaction < 0.05). Additionally, the combined protective effects of metabolic transitions and PRS on these outcomes among BMI categories were observed.

Conclusions: MH status and a low PRS are associated with a lower risk of adverse cardiovascular outcomes and all-cause mortality across all BMI categories. This protective effect is particularly pronounced in individuals younger than 65 years. Further research is required to confirm these findings in diverse populations and to investigate the underlying mechanisms involved.

Keywords: All-cause mortality; Cardiovascular disease; Metabolic change; Metabolic health; Metabolic syndrome; Polygenic risk scores.

Fig. 1

Flow diagram: Selection of participants. Note MH status was defined as < 3 abnormal components; WC, waist circumstance; HDL-C, high density lipoprotein-cholesterol; TG, triglycerides; BMI, body mass index; MH, metabolically healthy; MHN, metabolically healthy normal weight; MHOW, metabolically healthy overweight; MHO, metabolically healthy obesity; MUN, metabolically unhealthy normal weight; MUOW, metabolically unhealthy overweight; MUO, metabolically unhealthy obesity; AF, atrial fibrillation; HF, heart failure; MI, myocardial infarction; CAD, coronary disease; CVD, cardiovascular disease

Fig. 2

Combined effects of metabolic status, metabolic transitions, and PRSs on the risk of cardiovascular outcomes and all-cause mortality. Note MH status was defined as < 3 abnormal components; MH, metabolically healthy; MU, metabolically unhealthy; PRS, polygenic risk score; the PRSs presented are specifically used based on corresponding outcomes; Model 1: adjusted for age, sex, race, Townsend Deprivation Index, annual household income, educational attainment, 22 assessment centers, and the first 5 principal components of ancestry; Model 2: further adjusted for family history of diabetes, family history of high blood pressure, and lifestyle factors including sleep duration, healthy diet, physical activity, smoking status, and alcohol intake frequency based on Model 1; ^alikelihood tests were applied to test the significance of the interaction term by comparing the model with and without the interaction term; *P < 0.05

Fig. 3

The cumulative incidence of all-cause death, CVD events, and CVD death according to metabolically related status (metabolic status, BMI-metabolic status, and their transitions) and PRSs. Note MH was defined as < 3 abnormal components; PRS, polygenic risk score; BMI, body mass index; CVD, cardiovascular disease; MH, metabolically healthy; MU, metabolically unhealthy; MHN, metabolically healthy normal weight; MHOW, metabolically healthy overweight; MHO, metabolically healthy obesity; MUN, metabolically unhealthy normal weight; MUOW, metabolically unhealthy overweight; MUO, metabolically unhealthy obesity

Fig. 4

Combined effects of BMI-metabolic status, transitions in BMI-metabolic status, and PRSs on the risk of cardiovascular outcomes and all-cause mortality. Note Metabolically healthy status was defined as < 3 abnormal components; BMI, body mass index; MHN, metabolically healthy normal weight; MHOW, metabolically healthy overweight; MHO, metabolically healthy obesity; MUN, metabolically unhealthy normal weight; MUOW, metabolically unhealthy overweight; MUO, metabolically unhealthy obesity; PRS, polygenic risk score; the PRSs presented are specifically used based on corresponding outcomes; Model 1: adjusted for age, sex, race, Townsend Deprivation Index, annual household income, education attainment, 22 assessment centers, and the first 5 principal components of ancestry; Model 2: further adjusted for family history of diabetes, family history of high blood pressure, and lifestyle factors including sleep duration, healthy diet, physical activity, smoking status, and alcohol intake frequency based on Model 1; ^alikelihood tests were applied to test the significance of interaction term by comparing the model with and without the interaction term; *P < 0.05