Interactive Effects of HDL Cholesterol and hs-CRP in Relation to Cardiometabolic Risk Clustering Among Middle-Aged Adults

Background and Objectives: Cardiometabolic risk factors frequently cluster and substantially increase the risk of cardiovascular disease. While high-density lipoprotein cholesterol (HDL-C) and systemic inflammation, measured by high-sensitivity C-reactive protein (hs-CRP), are independently associated with cardiometabolic risk, whether systemic inflammation modifies the association between HDL-C and cardiometabolic risk clustering (CMRC) remains unclear. This study aimed to examine the independent associations of HDL-C and hs-CRP with CMRC and to evaluate the multiplicative product interaction between HDL-C and natural log-transformed hs-CRP in relation to CMRC among middle-aged adults. Materials and Methods: This cross-sectional study used data from 2283 adults aged 40–64 years who participated in the 2024 Korea National Health and Nutrition Examination Survey. CMRC was defined as the presence of ≥2 cardiometabolic risk factors. HDL-C and hs-CRP were analyzed as continuous variables. Complex sample logistic regression analyses were performed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs), including a multiplicative product interaction term calculated as HDL-C × ln hs-CRP. Results: The prevalence of CMRC was 46.4%. HDL-C was inversely associated with CMRC (OR = 0.946, 95% CI = 0.937–0.956, p < 0.001), whereas ln hs-CRP was positively associated with CMRC (OR = 1.224, 95% CI = 1.020–1.468, p = 0.030). The HDL-C × ln hs-CRP product interaction term was significantly associated with CMRC (OR = 1.005, 95% CI = 1.001–1.009, p = 0.008). This finding indicates that the association between HDL-C and CMRC may vary across levels of ln hs-CRP, but it does not indicate a direct association between HDL-C and ln hs-CRP. Conclusions: HDL-C and ln hs-CRP were independently associated with CMRC. The significant HDL-C × ln hs-CRP product interaction term suggests possible statistical effect modification of the HDL-C–CMRC association by systemic inflammatory status. These findings should be interpreted cautiously and do not establish a causal or mechanistic relationship.