Discordance Analysis of VLDL-C and ApoB in UK Biobank and Framingham Study: A Prospective Observational Study

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 44; no. 10; pp. 2244 - 2251
• Main Authors: Bilgic, Selin, Pencina, Karol M, Pencina, Michael J, Cole, Justine, Dufresne, Line, Thanassoulis, George, Sniderman, Allan D
• Format: Journal Article
• Language: English
• Published: United States 01.10.2024
• Subjects: Adult; Aged; Apolipoprotein B-100 - blood; Apolipoproteins B - blood; Biological Specimen Banks; Biomarkers - blood; Cardiovascular Diseases - blood; Cardiovascular Diseases - diagnosis; Cardiovascular Diseases - epidemiology; Cholesterol, HDL - blood; Cholesterol, VLDL - blood; Female; Heart Disease Risk Factors; Humans; Incidence; Male; Middle Aged; Prospective Studies; Risk Assessment; Risk Factors; UK Biobank; United Kingdom - epidemiology; United Kingdom; Mendelian randomization analysis; atherosclerosis; cholesterol; triglycerides; chylomicron remnants
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.124.321165

Recent observational and Mendelian randomization analyses have reported significant effects of VLDL-C (very-low density lipoprotein cholesterol) on risk that is independent of ApoB (apolipoprotein B). We aim to determine the independent association of VLDL-C and ApoB with the risk of new onset cardiovascular events in the UK Biobank and Framingham Heart Study cohorts. We included 294 289 UK Biobank participants with a median age of 56 years, 42% men, and 2865 Framingham Heart Study participants (median age, 53 years; 47% men). The residual resulting from regressing VLDL-C on ApoB expresses the portion of VLDL-C not explained by ApoB, while the residual from regressing ApoB on VLDL-C expresses the portion of ApoB not explained by VLDL-C. Cox proportional hazards models for atherosclerotic cardiovascular disease incidence were created for residual VLDL-C and residual ApoB. Models were analyzed with and without high-density lipoprotein cholesterol (HDL-C). Furthermore, we investigated the independent effects of VLDL-C after accounting for ApoB and HDL-C and of HDL-C after accounting for ApoB and VLDL-C. In the UK Biobank, ApoB was highly correlated with VLDL-C (r=0.70; <0.001) but weakly negatively correlated with HDL-C (r=-0.11; <0.001). The ApoB residual and the VLDL-C residual were significantly associated with new-onset atherosclerotic cardiovascular disease (hazard ratio [HR], 1.08 and 1.05, respectively; <0.001). After adjusting for HDL-C, the ApoB residual remained similar in magnitude (HR, 1.10; <0.001), whereas the effect size of the VLDL-C residual was reduced (HR, 1.02; =0.029). The independent effect of HDL-C (after accounting for ApoB and VLDL-C) remained robust (HR, 0.86; <0.0001), while the independent effect of VLDL-C (after accounting for ApoB and HDL-C) was modest (HR, 1.02; =0.029). All results were consistent in the Framingham cohort. When adjusted for HDL-C, the association of VLDL-C with cardiovascular risk was no longer clinically meaningful. Our residual discordance analysis suggests that adjustment for HDL-C cannot be ignored.