Cross-population heterogeneity in the association between estimated sdLDL-C and gallstone disease: a dual-source two-sample cross-sectional study

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Background While conventional lipid parameters are linked to gallstone disease, the specific role of small dense low-density lipoprotein cholesterol (sdLDL-C)—a highly atherogenic subfraction—remains unexplored. We aimed to evaluate the independent association between estimated sdLDL-C and gallstone risk, and to map potential cross-population dose-response relationships. Methods This dual-source cross-sectional study integrated a strictly defined Chinese clinical sample ( n = 730, comprising 334 symptomatic surgical cases and 396 healthy controls from routine health check-ups) and the US NHANES database ( n = 6,799). To facilitate large-scale, cost-effective screening, serum sdLDL-C was estimated using the internationally validated Sampson equation, strictly excluding subjects with extreme hypertriglyceridemia (TG ≥ 800 mg/dL). Multivariate logistic regression and two-piecewise models were utilized to evaluate independent associations and potential non-linear patterns. Sensitivity analyses rigorously excluded patients with major metabolic comorbidities (hypertension, diabetes, and clinical dyslipidemia). Results In the multivariable-adjusted models, when analyzed as a continuous variable, elevated estimated sdLDL-C was significantly and positively associated with gallstone risk in both the Chinese sample (OR = 1.12, 95% CI: 1.08–1.15) and the NHANES cohort (OR = 1.03, 95% CI: 1.01–1.04). Sensitivity analysis excluding individuals with diabetes and hypertension confirmed the stability of this positive association (OR = 1.11, 95% CI: 1.07–1.15). Dose-response analysis revealed a non-linear threshold effect in the Chinese sample, with an inflection point at 34.51 mg/dL (sdLDL-C ≥ 34.51 mg/dL: OR = 1.27, 95% CI: 1.20–1.34, p < 0.001), whereas a steady linear association was observed in the NHANES population. Stratified analyses indicated that this positive association was particularly prominent in females and diabetic individuals. Conclusion Estimated sdLDL-C exhibits an independent and positive association with gallstone disease, suggesting it might be more than merely a secondary manifestation of late-stage metabolic syndrome. The identification of a specific non-linear threshold in the Chinese population, juxtaposed with a linear pattern in the US, suggests the potential value of exploring sdLDL-C for risk stratification in biliary diseases, though these cross-sectional findings require prospective validation.

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