Combined LDL-C, Lp(a) and hsCRP identify highest ASCVD risk across ethnicities, multiethnic HELIUS cohort of 15,676 (J Am Coll Cardiol 2026)

Background: Low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) (Lp[a]), and high-sensitivity C-reactive protein (hsCRP) capture different pathways driving atherosclerotic cardiovascular disease (ASCVD). However, it is unknown whether their combined assessment provides reliable risk stratification in different ethnic populations with markedly different distributions of these biomarkers as well as background risk of ASCVD.

Objectives: The goal was to evaluate independent and joint associations of LDL-C, Lp(a), and hsCRP with incident ASCVD and to formally assess additive and multiplicative interaction of these biomarkers in a multiethnic cohort, and to determine whether these associations are consistent across participants of African, European, and South Asian Surinamese descent.

Methods: Among 15,676 HELIUS (HEalthy Life In an Urban Setting) participants without prior myocardial infarction or ischemic stroke (mean age 44.4 ± 13.2 years; 56.0% women), incident ASCVD was identified through linkage to nationwide registries. Fine-Gray competing-risk models were used to assess associations across increasing biomarker quintiles and joint elevations. Additive interaction was assessed using the relative excess risk due to interaction, attributable proportion, and synergy index. Incremental predictive value of Lp(a) and hsCRP beyond a PREVENT-ASCVD (Predicting Risk of Cardiovascular Disease EVENTs-Atherosclerotic Cardiovascular Disease)-based clinical model was evaluated using time-dependent area under the curve and continuous net reclassification improvement.

Results: Over median 8.9-year follow-up (138,375 person-years), 378 ASCVD events occurred. Top vs bottom quintile adjusted subdistribution HRs were 1.39 (95% CI: 1.09-1.79) for LDL-C, 1.86 (95% CI: 1.54-2.25) for Lp(a), and 1.51 (95% CI: 1.34-1.71) for hsCRP. Formal interaction assessment showed no interaction on either the multiplicative or additive scale. Risk increased with the number of elevated biomarkers, reaching a 2.44-fold increase (95% CI: 1.46-4.09) among those with all 3 elevated. Consistent dose-response patterns were observed across ethnic groups (Pinteraction = 0.75), although absolute ASCVD risk was approximately 3-fold higher in South Asian Surinamese participants. Addition of Lp(a) and hsCRP to a clinical model modestly improved discrimination at 10 years (Δ area under the curve: 0.006; P = 0.030) and reclassification (continuous net reclassification improvement: 0.165; 95% CI: 0.050-0.289).

Conclusions: In a multiethnic primary prevention cohort, combined assessment of LDL-C, Lp(a), and hsCRP identified individuals at elevated long-term risk through independent pathways, with consistent relative risk gradients but divergent absolute risks across ethnicities.