Causal association of small dense low-density lipoproteins with coronary heart disease risk:a multivariable Mendelian randomisation analysis
Pan Jin
Bai Tingting
Ding Lili
He Lin
Abstract：Objective To identify instrumental variables using Mendelian randomization(MR)analysis and evaluate the causal role of small dense low-density lipoprotein(sdLDL)in the etiology of coronary heart disease(CHD).Methods A genome-wide association study(GWAS)was conducted at the UK Biobank(UKBB)for circulating non-fasting lipid profiles of low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C),triglycerides(TG),and sdLDL to identify lipid-associated single nucleotide polymorphisms(SNPs).Univariate and multivariate MR analyses were performed using coronary heart disease data in CARDIoGRAMplusC4D.Results GWAS identified multiple independent SNPs associated with LDL-C(n=220),TG(n=440),HDL-C(n=534),sdLDL(n=440)at genome-wide significance(P＜5 × 10-8).In univariate MR-Inverse-variance weighted(IVW)analysis,sdLDL(β=0.897),HDL-C(β=-1.322),LDL-C(β=0.881)and TG(β=0.420)had significant effects on the risk of CHD(P＜0.001).In multivariate MR Analysis,only sdLDL(β=0.813;P＜0.001)maintained a robust effect,and the effect of LDL-C was reversed(β=0.057;P=0.251),TG(β=0.221;P＜0.001)and HDL-C(β=-0.048;P=0.011)had weakened estimates..The MR-Egger analysis and MR-Lasso analysis also showed similar results.According to Cochran's Q test,there was no heterogeneity between SNPs in MR-IVW(P=0.437)and MR-Egger regression analysis(P=0.395).Sensitivity analysis using the leave-one-out approach showed that no SNP had a significant impact on the results,thereby confirming the robustness of the findings.Conclusion sdLDL is one of the main characteristic molecules of the etiological relationship between lipids and CHD risk,and is crucial in explaining the causal relationship between lipids and CHD risk.
Keywords：Small dense low-density lipoproteinsCoronary heart diseaseMendelian randomizationGenome-wide association studiesCausal association
Publication Date：2025-05-20
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：5( 519-523 )