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LDL Cholesterol Uptake Assay Using Live Cell Imaging Analysis with Cell Health Monitoring
Published on: November 17, 2018
Impact of LDL Cholesterol on Microvascular Versus Macrovascular Disease: A Mendelian Randomization Study
Frida Emanuelsson1, Børge G Nordestgaard2, Anne Tybjærg-Hansen3
1Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Electronic address: https://twitter.com/Frida_Emanuel.
Insights
High LDL-C is not linked to retinopathy or neuropathy risk. However, elevated LDL-C is causally associated with increased risks of peripheral arterial disease (PAD) and chronic kidney disease (CKD).
Area of Science:
- Cardiovascular Genetics
- Metabolic Disease Research
- Vascular Health
Background:
- Low-density lipoprotein cholesterol (LDL-C) is a known risk factor for coronary artery disease.
- The causal relationship between LDL-C and other vascular diseases remains under investigation.
Purpose of the Study:
- To investigate the causal link between high LDL-C and the risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD).
- To assess the role of LDL-C in the pathogenesis of these conditions in the general population.
Main Methods:
- Utilized one-sample and two-sample Mendelian randomization (MR) analyses on large datasets, including Danish individuals, the Global Lipid Genetics Consortium (GLGC), and the UK Biobank.
- Conducted a meta-analysis of randomized statin trials to corroborate findings.
Main Results:
- High LDL-C showed no causal association with retinopathy or neuropathy risk.
- Observational and genetic analyses revealed a stepwise increase in CKD and PAD risk with higher LDL-C levels.
- Higher LDL-C was associated with increased risk of PAD (HR 1.41) and CKD (HR 1.05) when comparing highest to lowest LDL-C percentiles.
- Genetic analyses indicated a causal risk ratio of 2.09 for PAD and 3.83 for CKD per 1 mmol/L higher LDL-C.
Conclusions:
- High LDL-C is not causally linked to retinopathy and neuropathy.
- Evidence supports a causal role for high LDL-C in the pathogenesis of peripheral arterial disease (PAD) and chronic kidney disease (CKD).
Background:
Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown.
Objectives:
The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population.
Methods:
One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed.
Results:
Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy.
Conclusions:
High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases.
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