Author + information
- Received March 22, 2019
- Revision received June 24, 2019
- Accepted July 2, 2019
- Published online September 9, 2019.
- Frida Emanuelsson, MDa,b,c@Frida_Emanuel,
- Børge G. Nordestgaard, MD, DMScb,c,d,e,
- Anne Tybjærg-Hansen, MD, DMSca,b,c,e and
- Marianne Benn, MD, DMSca,b,c,∗ (, )@Rigshospitalet@uni_copenhagen
- aDepartment of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- bFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- cThe Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- dDepartment of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- eThe Copenhagen City Heart Study, Frederiksberg and Bispebjerg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark
- ↵∗Address for correspondence:
Dr. Marianne Benn, Department of Clinical Biochemistry, Rigshospitalet Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
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.
- chronic kidney disease
- Mendelian randomization
- peripheral arterial disease
This work was supported by the Danish Council for Independent Research (#4183-00171B) (to Dr. Emanuelsson). Dr. Nordestgaard has served as a consultant for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutics; and has received lecture honoraria from Amgen, Kowa, and Amarin. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received March 22, 2019.
- Revision received June 24, 2019.
- Accepted July 2, 2019.
- 2019 American College of Cardiology Foundation
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