Journal Article

Insulin resistance-related indices, genetic risk, and the risk of cardiovascular disease in individuals with preclinical or clinical obesity: a large prospective cohort study in the UK biobank

Zhang, Jing, Hu, Jinling, Sun, Chaonan, Shang, Cong, Huang, Yueqing

2025

Overview

Background Insulin resistance (IR)-related indices are validated prognostic markers in metabolic disorders, but have not been applied to preclinical or clinical obesity. This study aimed to investigate the relationship between IR-related indices and cardiovascular disease (CVD) incidence, considering genetic factors and biomarkers. Methods This prospective study analyzed 112,866 UK Biobank participants with preclinical or clinical obesity. IR-related indices were evaluated: triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), and TyG-waist-to-height ratio (TyG-WHtR). Genetic risk was estimated using the polygenic risk score. Outcomes, including total CVD, coronary artery disease (CAD), and stroke, were ascertained through medical records linkage. Cox proportional hazard models were used to evaluate the associations and modification effects of genetic risk. Incremental predictive value was assessed by net reclassification index (NRI) and integrated discrimination improvement index (IDI). Mediation analyses explored the role of inflammatory, hepatic, and renal biomarkers. Results Over a median follow-up period of 13.45 years, 21,601 total CVD, 11,942 CAD, and 3347 stroke cases were documented. Compared with the lowest quartile of IR-related indices, participants in the highest quartile presented increased CVD risk. For total CVD, hazard ratios (HRs) (95% confidence intervals, CIs) for the fourth versus the first quartiles were 1.33 (1.28–1.39) for TyG-BMI, 1.41 (1.34–1.48) for TyG-WC, and 1.25 (1.20–1.31) for TyG-WHtR. All IR-related indices demonstrated significant associations with CAD. Borderline significant associations were observed for stroke. Distinct dose-response association patterns with total CVD were observed: TyG-BMI and TyG-WHtR exhibited nonlinear relationships, while TyG-WC demonstrated a linear association. The CVD risk was highest in individuals with high genetic risk and high IR indices, with an additive interaction between TyG-WC and genetic risk being observed. Significantly higher NRI and IDI were observed for TyG-WC, TyG-BMI, and TyG-WHtR in predicting CVD, with TyG-WC achieving the highest performance. Mediation analyses indicated that inflammation, liver, and renal biomarkers might partially mediate the relationship. Conclusion Elevated IR-related indices, particularly TyG-WC, were associated with increased total CVD and CAD risks in preclinical or clinical obesity. Additive effects of TyG-WC and genetic risk on CVD were revealed, with mediating biomarkers suggesting potential targeted interventions for CVD risk reduction. Graphical abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adult / Aged / Angiology / Anthropometry / Biobanks / Biological Specimen Banks / Biomarkers / Biomarkers - blood / Blood Glucose - metabolism / Body Mass Index / Cardiology / Cardiovascular disease / Cardiovascular diseases / Cardiovascular Diseases - diagnosis / Cardiovascular Diseases - epidemiology / Cardiovascular Diseases - genetics / Chronic illnesses / Cohort analysis / Coronary artery disease / Diabetes / Disease prevention / Endocrinology / Female / Genetic factors / Genetic Predisposition to Disease / Genetic risk / Glucose / Health risk assessment / Heart Disease Risk Factors / Heart diseases / Humans / Incidence / Insulin resistance / Insulin Resistance - genetics / Joint / Male / Medical records / Medicine / Medicine & Public Health / Metabolic disorders / Metabolism / Middle Aged / Obesity / Obesity - blood / Obesity - diagnosis / Obesity - epidemiology / Obesity - genetics / Obesity, Metabolically Benign - blood / Obesity, Metabolically Benign - diagnosis / Obesity, Metabolically Benign - epidemiology / Obesity, Metabolically Benign - genetics / Pain / Phenotype / Physiology / Preclinical or clinical obesity / Prognosis / Prospective Studies / Risk Assessment / Risk Factors / Time Factors / Triglyceride glucose / Triglycerides - blood / UK Biobank / United Kingdom - epidemiology / Waist Circumference