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Rigshospitalet - a part of Copenhagen University Hospital
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Impact of LDL cholesterol on microvascular versus macrovascular disease: A Mendelian Randomization Study

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  1. Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome

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  2. Natural History of Subclinical Atrial Fibrillation Detected by Implanted Loop Recorders

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  3. Effects of Interatrial Shunt on Pulmonary Vascular Function in Heart Failure With Preserved Ejection Fraction

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  4. Reply: Enterococcus faecalis Infective Endocarditis

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  5. Direct Current Cardioversion of Atrial Fibrillation in Patients With Left Atrial Appendage Occlusion Devices

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  1. Impact of Glucose Level on Micro- and Macrovascular Disease in the General Population: A Mendelian Randomization Study

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  2. Coffee intake protects against symptomatic gallstone disease in the general population: a Mendelian randomization study

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  3. High Risk of Fatty Liver Disease Amplifies the Alanine Transaminase-Lowering Effect of a HSD17B13 Variant

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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 m 2 (95% CI: 1.88 to 2.02 ml/min/1.73 m 2) observationally, 5.92 ml/min/1.73 m 2 (95% CI: 4.97 to 6.86 ml/min/1.73 m 2) genetically, and 2.69 ml/min/1.73 m 2 (95% CI: 1.48 to 3.94 ml/min/1.73 m 2) 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.

Original languageEnglish
JournalJournal of the American College of Cardiology
Volume74
Issue number11
Pages (from-to)1465-1476
Number of pages12
ISSN0735-1097
DOIs
Publication statusPublished - 17 Sep 2019

    Research areas

  • chronic kidney disease, LDL-C, Mendelian randomization, meta-analysis, neuropathy, peripheral arterial disease, retinopathy

ID: 58287943