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

Benjamin Nilsson Wadström¹, Maria Carolina Borges², Anders Berg Wulff³

¹Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Department of Clinical Biochemistry, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark; The Copenhagen General Population Study, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Journal of the American College of Cardiology

|March 26, 2025

Insights

Elevated remnant cholesterol, not just LDL cholesterol, causally increases peripheral artery disease (PAD) risk. Remnant cholesterol appears to be the primary driver, suggesting new therapeutic targets for PAD prevention and treatment.

Area of Science:

Cardiovascular Genetics
Lipid Metabolism
Epidemiology

Background:

Both elevated remnant cholesterol and low-density lipoprotein (LDL) cholesterol are established risk factors for coronary artery disease (CAD).
The independent causal relationship between remnant cholesterol, LDL cholesterol, and peripheral artery disease (PAD) risk remains unclear.

Purpose of the Study:

To investigate the independent causal effects of remnant cholesterol and LDL cholesterol on the risk of developing PAD.
To determine if remnant cholesterol or LDL cholesterol is the predominant lipid-related risk factor for PAD.

Main Methods:

Utilized Mendelian randomization analysis with genetic scores derived from UK Biobank data.
Assessed causal effects of remnant and LDL cholesterol on PAD and CAD risk using univariable and multivariable models.
Included large case-control cohorts for PAD (n=38,414 cases) and CAD (n=221,445 cases).

Main Results:

Higher remnant cholesterol showed a significant causal effect on PAD risk, independent of LDL cholesterol.
The causal effect of LDL cholesterol on PAD risk was largely mediated by elevated remnant cholesterol.
Both lipid fractions demonstrated causal effects on CAD risk, with remnant cholesterol also showing a significant independent contribution.

Conclusions:

Remnant cholesterol is a significant, independent causal factor for PAD risk.
Remnant cholesterol, rather than LDL cholesterol, may be the primary lipid-associated risk factor for PAD.
Further research into the biological mechanisms underlying these findings is warranted for developing novel PAD therapies.

Read full analysis

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

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