Metabolomic phenotyping of obesity for profiling cardiovascular and ocular diseases

Abstract

Background: We aimed to evaluate the impacts of metabolomic body mass index (metBMI) phenotypes on the risks of cardiovascular and ocular diseases outcomes.

Methods: This study included cohorts in UK and Guangzhou, China. By leveraging the serum metabolome and BMI data from UK Biobank, this study developed and validated a metBMI prediction model using a ridge regression model among 89,830 participants based on 249 metabolites. Five obesity phenotypes were obtained by metBMI and actual BMI (actBMI): normal weight (NW, metBMI of 18.5-24.9 kg/m²), overweight (OW, metBMI of 25-29.9 kg/m²), obesity (OB, metBMI ≥ 30 kg/m²), overestimated (OE, metBMI-actBMI > 5 kg/m²), and underestimated (UE, metBMI-actBMI < - 5 kg/m²). Additional participants from the Guangzhou Diabetes Eye Study (GDES) were included for validating the hypothesis. Outcomes included all-cause and cardiovascular (CVD)-cause mortality, as well as incident CVD (coronary heart disease, heart failure, myocardial infarction [MI], and stroke) and age-related eye diseases (age-related macular degeneration [AMD], cataracts, glaucoma, and diabetic retinopathy [DR]).

Results: In the UKB, although OE group had lower actBMI than NW group, the OE group had a significantly higher risk of all-cause mortality than those in NW prediction group (HR, 1.68; 95% CI 1.16-2.43). Similarly, the OE group had a 1.7-3.6-fold higher risk than their NW counterparts for cardiovascular mortality, heart failure, myocardial infarction, and coronary heart disease (all P < 0.05). In addition, risk of age-related macular denegation (HR, 1.96; 95% CI 1.02-3.77) was significantly higher in OE group. In the contrast, UE and OB groups showed similar risks of mortality and of cardiovascular and age-related eye diseases (all P > 0.05), though the UE group had significantly higher actBMI than OB group. In the GDES cohort, we further confirmed the potential of metabolic BMI (metBMI) fingerprints for risk stratification of cardiovascular diseases using a different metabolomic approach.

Conclusions: Gaps of metBMI and actBMI identified novel metabolic subtypes, which exhibit distinctive cardiovascular and ocular risk profiles. The groups carrying obesity-related metabolites were at higher risk of mortality and morbidity than those with normal health metabolites. Metabolomics allowed for leveraging the future of diagnosis and management of 'healthily obese' and 'unhealthily lean' individuals.

Keywords: Age-related eye disease; Comorbidity; Metabolome; Mortality; NMR; Obesity; Systemic diseases.

Fig. 1

Overall workflow of the study. Five categories were obtained by difference of the metabolome-defined BMI (metBMI) and actual BMI (actBMI). BMI: body mass index; metBMI: metabolic body mass index; CVD: cardiovascular disease; NW: normal weight of metabolic BMI; OW: overweight of metabolic BMI; OB: obesity of metabolic BMI; OE: metabolome-defined BMI over than actual BMI; UE: metabolome-defined BMI under than actual BMI; AMD: age-related macular degeneration

Fig. 2

Flowchart for selecting participants in the whole study. BMI: body mass index; metBMI: metabolic body mass index; CVD: cardiovascular disease; NW: normal weight of metabolic BMI; OW: overweight of metabolic BMI; OB: obesity of metabolic BMI; OE: metabolome-defined BMI over than actual BMI; UE: metabolome-defined BMI under than actual BMI; AMD: age-related macular degeneration

Fig. 3

Distribution of metabolomic BMI, actual BMI, and metabolites used to predict BMI in the applicative set. A subgrouping for all individuals in application dataset, the correlation r² value is 0.381; B distribution of actBMI across groups; C refers to the top 30 metabolites with high correlation ratio selected by ridge regression model. NW: normal weight of metabolic BMI; OW: overweight of metabolic BMI; OB: obesity of metabolic BMI; OE: metabolome-defined BMI over than actual BMI; UE: metabolome-defined BMI under than actual BMI

Fig. 4

Survival plots showing the risks of cardiovascular and ocular diseases outcomes comparing OE versus NW groups. OE: metabolome-defined BMI over than actual BMI; NW: normal weight of metabolic BMI; CVD: cardiovascular disease; AMD: age-related macular degeneration. The log-rank tests for NW and OE group show: P-values are < 0.001 for all the incident events, except for incident AMD (P = 0.002) and glaucoma (P = 0.003)