High Low-Density Lipoprotein Cholesterol Levels and Risk of Peripheral Vascular Diseases: A Mendelian Randomisation Study Including 116,419 Individuals From The General Population

| Diabetes
Frida Emanuelsson,1 Børge G. Nordestgaard,2,3 Anne Tybjærg-Hansen,1 *Marianne Benn1

Dr Emanuelsson was funded by the Danish Council of Independent Research. The other authors have declared no conflicts of interest.


The authors thank staff and participants of the Copenhagen General Population Study and the Copenhagen City Heart Study; the participants of the Global Lipid Genetics Consortium, the UK Biobank, and the CARDIoGRAMC4D consortia for their generous participation; and the consortia for making data publicly available.

EMJ Diabet. ;6[1]:41-42. Abstract Review No. AR4.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.


High low-density lipoprotein (LDL) cholesterol levels are causally involved in the pathogenesis of atherosclerosis and are related to an increased risk of cardiovascular disease.1 It is unknown whether high LDL cholesterol levels are causally related to an increased risk of microvascular diseases, such as retinopathy and neuropathy, and peripheral vascular diseases also involving larger arteries, such as chronic kidney disease (CKD) and peripheral arterial disease (PAD). We hypothesised that high LDL cholesterol levels are causally related to the risk of retinopathy, neuropathy, CKD, and PAD in the general population.


We included 116,419 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study and used Mendelian randomisation to examine causality between high LDL cholesterol levels and peripheral vascular endpoints. We selected and genotyped 11 variants in the LDLR, APOB, HMGCR, NPC1L1, and PCSK9 genes and calculated a weighted genetic risk score. Peripheral vascular endpoints were based on International Statistical Classification of Diseases and Related Health Problems codes collected from all hospital admissions and outpatient clinic visits in the national Danish Patient Registry and the national Danish Registry of Causes of Death. To test whether the findings could be replicated in another general population cohort, we performed a two-sample Mendelian randomisation analysis using genetic variants associated with high LDL cholesterol levels in the Global Lipid Genetic Consortium, and peripheral vascular endpoints from the UK Biobank.


Observationally, we found no association between high LDL cholesterol levels and risk of retinopathy (p=0.12) or neuropathy (p=0.005). We found a stepwise increase in the hazard rate of CKD and PAD with higher LDL cholesterol levels, with a hazard ratio of 1.06 (95% confidence interval [CI]: 0.99–1.14) for CKD and 1.37 (95% CI: 1.20–1.57) for PAD in individuals with LDL cholesterol levels above the 95th percentile versus those below the 50th percentile. In the genetic, causal analyses, the risk ratio of disease for a 1 mmol/L higher LDL cholesterol level was 1.06 (95% CI: 0.24–4.58) for retinopathy, 1.05 (95% CI: 0.25–1.72) for neuropathy, 3.10 (95% CI: 1.79–5.39) for CKD, and 1.96 (95% CI: 1.26–3.06) for PAD. Summary level data from the UK Biobank using the weighted median of instrumental variable estimates Mendelian randomisation gave a risk ratio of 0.65 (95% CI: 0.25–1.70) for retinopathy, 0.86 (95% CI: 0.51–1.46) for neuropathy, 0.88 (95% CI: 0.66–1.18) for CKD, and 1.57 (95% CI: 0.91–2.71) for PAD.


Our study suggests that LDL cholesterol has no causal effect on peripheral microvascular diseases, such as retinopathy and neuropathy; however, it may have a causal effect on peripheral arterial diseases involving larger arteries such as PAD and CKD. The findings were replicated in the UK Biobank cohort with similar results for retinopathy, neuropathy, and PAD, but with inconsistent results for CKD.2 The inconsistent findings for CKD may be due to several reasons, including the low participation rate and shorter follow-up time in the UK Biobank may cause a healthy participant bias, which could explain the inconsistency.3 Previous studies have found that fenofibrates reduce the risk of retinopathy progression.4 Our findings suggest that this is through mechanisms other than the lowering of LDL cholesterol.

Ference BA et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-72. Emanuelsson F et al. High LDL cholesterol and risk of peripheral vascular diseases - A Mendelian randomization study including 116,419 individuals from the gerneral population. Abstract 19762. EASD Annual Meeting, 1-5 October, 2018. Munafò MR et al. Collider scope: When selection bias can substantially influence observed associations. Int J Epidemiol. 2018;47(1):226-35. Keech AC et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): A randomised controlled trial. Lancet. 2007;370(9600):1687-97.