The Population-Attributable Role of Systemic Inflammation in Obesity-Related Dyslipidemia: A Cross-Sectional Mediation Study of U.S. Adults with a History of Smoking

Background: Obesity drives a substantial population burden of atherogenic dyslipidemia, contributing to cardiovascular morbidity and mortality. Systemic inflammation is a modifiable pathway linking adiposity to dyslipidemia; however, its population-attributable contribution has not been quantified in high-risk populations. Objective: To estimate the proportion of obesity-related hypertriglyceridemia statistically attributable to systemic inflammation in a national sample of U.S. adults with smoking history and evaluate implications for population health strategies. Methods: Cross-sectional analysis of 863 adults from the Midlife in the United States (MIDUS) Refresher Biomarker Project. We estimated mediation via C-reactive protein (CRP) using a product-of-coefficients approach, adjusting for age, sex, smoking intensity, statin use, and alcohol consumption. Multiple imputation addressed missingness. Robustness was assessed through phantom variable sensitivity testing. Results: In this sample of ever-smokers (mean age 52.7 years, 52.1% female), obesity prevalence (BMI ≥30 kg/m²) was 38.2%, 28.6% had elevated CRP (>3.0 mg/L), and 24.3% had hypertriglyceridemia (>150 mg/dL). CRP mediated 24.7% (95% Monte Carlo CI: 11.9% to 41.3%) of the BMI-triglyceride association. This corresponds to an estimated inflammation-mediated triglyceride increase of 2.7% (95% CI: 1.0% to 4.5%) per 5 kg/m² BMI increment. Sensitivity testing across 27 plausible confounding scenarios showed consistent mediation. Conclusions: Systemic inflammation accounts for approximately one-quarter of obesity-related dyslipidemia burden in this national sample of adults with smoking history. These findings quantify a substantial modifiable pathway and support integrated public health strategies that address both adiposity and inflammation, particularly in high-risk populations. CRP may have utility in identifying high-risk individuals for targeted intervention.