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Original Investigation
October 4, 2016

Association Between Low-Density Lipoprotein Cholesterol–Lowering Genetic Variants and Risk of Type 2 DiabetesA Meta-analysis

Author Affiliations
  • 1MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
  • 2Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 3Navarre Public Health Institute, Pamplona, Spain
  • 4Navarra Institute for Health Research, Pamplona, Spain
  • 5CIBER Epidemiología y Salud Pública, Madrid, Spain
  • 6Public Health Division of Gipuzkoa, San Sebastian, Spain
  • 7Instituto BIO-Donostia, Basque Government, San Sebastian, Spain
  • 8Inserm, CESP, U1018, Villejuif, France
  • 9Université of Paris-Sud, UMRS 1018, Villejuif, France
  • 10German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany
  • 11Wellcome Trust Sanger Institute, Cambridge, United Kingdom
  • 12Department of Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden
  • 13Umeå University, Umeå, Sweden
  • 14Epidemiology and Prevention Unit, Milan, Italy
  • 15German Cancer Research Centre, Heidelberg, Germany
  • 16University of Oxford, Oxford, United Kingdom
  • 17Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
  • 18Unit of Preventive Medicine and Public Health, School of Medicine, University of Murcia, Murcia, Spain
  • 19Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark
  • 20Aalborg University Hospital, Aalborg, Denmark
  • 21Cancer Research and Prevention Institute, Florence, Italy
  • 22Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
  • 23Public Health Directorate, Asturias, Spain
  • 24School of Public Health, Imperial College London, London, United Kingdom
  • 25Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention, Turin, Italy
  • 26Human Genetics Foundation, Turin, Italy
  • 27Andalusian School of Public Health, Granada, Spain
  • 28Instituto de Investigación Biosanitaria de Granada, Granada, Spain
  • 29International Agency for Research on Cancer, Lyon, France
  • 30National Institute for Public Health and the Environment, Bilthoven, the Netherlands
  • 31Danish Cancer Society Research Center, Copenhagen, Denmark
  • 32Azienda Sanitaria Provinciale di Ragusa, Ragusa, Italy
  • 33University Medical Center Utrecht, Utrecht, the Netherlands
  • 34Oxford Centre for Diabetes, Endocrinology and Metabolism, and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
  • 35Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
  • 36Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland
JAMA. 2016;316(13):1383-1391. doi:10.1001/jama.2016.14568

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.