Association Between Low-Density Lipoprotein Cholesterol–Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis
Open accessAbstract
Importance: Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. Objective: To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. Design, Setting, and Participants: The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. Exposures: Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. Main Outcomes and Measures: Odds ratios (ORs) for type 2 diabetes and coronary artery disease. Results: Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. Conclusions and Relevance: In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.
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Mendelian randomisation studies of variants mimicking statins, ezetimibe, or PCSK9 inhibitors suggest that lifelong LDL cholesterol lowering, by any mechanism, is linked to higher diabetes risk.
“mendelian randomisation studies 8,[19][20][21] of genetic polymorphisms that mimic the effects of statins, ezetimibe, or PCSK9 inhibitors suggest that lifelong reductions in LDL cholesterol, irrespective of the mechanism, are associated with an increased risk of diabetes.”
Mendelian randomisation analyses show that genetically determined PCSK9 loss of function is associated with higher incident diabetes, while clinical trials of PCSK9 inhibitors show no such effect.
“Mendelian randomisation analyses 8,20,21 have shown that genetically determined loss of function of PCSK9 is associated with an increased risk of incident diabetes, but clinical trials of PCSK9 inhibitors have shown no such effect.9”
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References 48 · Cited by 394
- Authors
- Lotta, L. A., Sharp, S. J., Burgess, S., Perry, J. R. B., Stewart, I. D., Willems, S. M., Luan, J., Ardanaz, E., Arriola, L., Balkau, B., Boeing, H., Deloukas, P., Forouhi, N. G., Franks, P. W., Grioni, S., Kaaks, R., Key, T. J., Navarro, C., Nilsson, P. M., Overvad, K., Palli, D., Panico, S., Quirós, J.-R., Riboli, E., Rolandsson, O., Sacerdote, C., Salamanca-Fernandez, E., Slimani, N., Spijkerman, A. M. W., Tjonneland, A., Tumino, R., van der A, D. L., van der Schouw, Y. T., McCarthy, M. I., Barroso, I., O’Rahilly, S., Savage, D. B., Sattar, N., Langenberg, C., Scott, R. A., & Wareham, N. J.
- Affiliations
- University of Cambridge (GB)
- Navarre Public Health Institute, Pamplona, Spain4Navarra Institute for Health Research, Pamplona, Spain5CIBER Epidemiología y Salud Pública, Madrid, Spain
- Basque Government (ES)
- Inserm (FR)
- German Institute of Human Nutrition (DE)
- Wellcome Sanger Institute (GB)
- Lund University (SE)
- Epidemiology and Prevention Unit, Milan, Italy
- German Cancer Research Center (DE)
- University of Oxford (GB)
- Instituto Murciano de Investigación Biosanitaria (ES)
- Aarhus University (DK)
- Cancer Research and Prevention Institute, Florence, Italy
- Federico II University Hospital (IT)
- Gobierno del Principado de Asturias (ES)
- School of Public Health, Imperial College London, London, United Kingdom
- Umeå University (SE)
- Italian institute for Genomic Medicine (IT)
- CIBER Epidemiología y Salud Pública, Madrid, Spain27Andalusian School of Public Health, Granada, Spain28Instituto de Investigación Biosanitaria de Granada, Granada, Spain
- Centre international de recherche sur le cancer (FR)
- National Institute for Public Health and the Environment (NL)
- Danish Cancer Society Research Center, Copenhagen, Denmark
- Azienda Sanitaria Provinciale di Ragusa, Ragusa, Italy
- National Institute for Public Health and the Environment, Bilthoven, the Netherlands
- University Medical Center Utrecht, Utrecht, the Netherlands
- Centre for Human Genetics (GB)
- University of Glasgow (GB)
- Corresponding author
- Wareham, Nicholas J.
- ORCID
- Lotta, Luca A.
- Sharp, Stephen J.
- Burgess, Stephen
- Perry, John R. B.
- Luan, Jian’an
- Arriola, Larraitz
- Balkau, Beverley
- Boeing, Heiner
- Deloukas, Panos
- Forouhi, Nita G.
- Franks, Paul W.
- Grioni, Sara
- Kaaks, Rudolf
- Key, Timothy J.
- Navarro, Carmen
- Nilsson, Peter M.
- Overvad, Kim
- Palli, Domenico
- Panico, Salvatore
- Rolandsson, Olov
- Sacerdote, Carlotta
- Slimani, Nadia
- Tumino, Rosario
- McCarthy, Mark I.
- Barroso, Inês
- O’Rahilly, Stephen
- Savage, David B.
- Sattar, Naveed
- Langenberg, Claudia
- Scott, Robert A.
- Wareham, Nicholas J.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2016-10-04
- Volume
- 316
- Issue
- 13
- Pages
- 1383
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC5386134
- OpenAlex
- W2529053508
- Cited by
- 394
- References
- 48
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 47 · 2023: 33 · 2022: 39 · 2021: 38 · 2020: 34 · 2019: 46 · 2018: 54 · 2017: 55 · 2016: 7
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
- Rivm Repository (Netherlands National Institute for Public Health and the Environment) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- World Health Organization
- Aarhus Universitet
- Wellcome Trust (098381, 107064/Z/15/Z, WT 098051, 090532)
- Cancer Research UK (16491)
- National Institute for Health and Care Research (NF-SI-0512-10165, NF-SI-0513-10109, NF-SI-0507-10380, NF-SI-0512-10135, CL-2011-18-004)
- British Heart Foundation (RG/13/13/30194, RG/08/014/24067)
- Imperial College London
- University of Oxford
- University of Glasgow
- Aalborg Universitet
- Lunds Universitet
- Universidad de Murcia
- Umeå Universitet
- Aalborg Universitetshospital
- Università degli Studi di Torino
- Medical Research Council (MC_UU_12015/5, MC_PC_13046, MC_PC_13048, MR/L003120/1, MC_UU_12015/2, MC_UU_12015/1)
- School of Public Health, Imperial College London
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 2 diabetes, NPC1L1, HMGCR, PCSK9, ABCG5/G8, LDL receptor, coronary artery disease, lipid-lowering therapy, statins, ezetimibe, genetic risk prediction, LDL cholesterol lowering, genetic association meta-analysis, lipid metabolism genes, ABCA1, ABCG1
- MeSH terms
- Ezetimibe, ATP Binding Cassette Transporter, Subfamily G, Member 5, Proprotein Convertase 9, Adult, Aged, Coronary Artery Disease, Diabetes Mellitus, Type 2, Drug Therapy, Combination, Humans, Hydroxymethylglutaryl CoA Reductases, Lipoproteins, Cholesterol, LDL, Membrane Proteins, Middle Aged, Polymorphism, Genetic, Receptors, LDL, Risk, Genetic Variation, Cohort Studies, Odds Ratio, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Membrane Transport Proteins, Genetic Association Studies
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