Elevated Remnant and LDL Cholesterol and the Risk of Peripheral Artery Disease: A Mendelian Randomization Study

Abstract

Background: Elevated remnant cholesterol and low-density lipoprotein (LDL) cholesterol both increase the risk of coronary artery disease (CAD), but it is not known if the same is true for peripheral artery disease (PAD).

Objectives: This study tested the hypothesis that elevated remnant cholesterol and LDL cholesterol, each independent of the other, have causal effects on risk of PAD.

Methods: The authors constructed genetic scores from variants near genes known to directly affect levels of remnant cholesterol and LDL cholesterol, identified through a genome-wide association study of individuals in the UK Biobank. Univariable (remnant cholesterol and LDL cholesterol genetic scores separately) and multivariable (remnant cholesterol and LDL cholesterol genetic scores combined) Mendelian randomization were used to estimate the causal effects of higher remnant cholesterol and LDL cholesterol levels on ORs for PAD (n = 38,414 cases and 758,308 controls) and CAD (n = 221,445 cases and 770,615 controls).

Results: Increments in remnant and LDL genetic scores corresponding to 1 mmol/L (39 mg/dL) higher remnant and LDL cholesterol, respectively, were associated with univariable ORs for PAD of 2.72 (95% CI: 2.10-3.52) and 1.37 (95% CI: 1.25-1.51); corresponding multivariable ORs were 2.16 (95% CI: 1.49-3.12) and 1.14 (95% CI: 1.00-1.30). For CAD, corresponding univariable ORs were 2.92 (95% CI: 2.34-3.64) and 1.67 (95% CI: 1.56-1.79), whereas multivariable ORs were 1.86 (95% CI: 1.39-2.47) and 1.44 (95% CI: 1.29-1.60). Scaled to 1 SD increments in remnant cholesterol and LDL cholesterol, corresponding univariable ORs were 1.37 (95% CI: 1.27-1.49) and 1.29 (95% CI: 1.20-1.39) for PAD, and 1.40 (95% CI: 1.31-1.51) and 1.51 (95% CI: 1.43-1.59) for CAD; corresponding multivariable ORs were 1.28 (95% CI: 1.14-1.43) and 1.11 (95% CI: 1.00-1.23) for PAD, and 1.22 (95% CI: 1.11-1.33) and 1.34 (95% CI: 1.23-1.46) for CAD.

Conclusions: Elevated remnant cholesterol had a causal effect on risk of PAD even after accounting for elevated LDL cholesterol, whereas most of the causal effect of elevated LDL cholesterol on risk of PAD was dependent on simultaneously elevated remnant cholesterol. These results indicate that remnant cholesterol may be the major cholesterol fraction responsible for increased risk of PAD. Future studies should investigate the biological mechanisms behind these findings to find improved therapies for prevention and treatment of PAD.

Keywords: critical limb ischemia; lipoprotein lipase; lower-extremity arterial disease; triglyceride-rich lipoprotein; very-low-density lipoprotein.