Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: A meta-analysis

Research output: Contribution to journalArticle


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 thismeta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other geneswas associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.


  • Luca A. Lotta
  • Stephen J. Sharp
  • Stephen Burgess
  • John R B Perry
  • Isobel D. Stewart
  • Sara M. Willems
  • Jian'an Luan
  • Eva Ardanaz
  • Larraitz Arriola
  • Beverley Balkau
  • Heiner Boeing
  • Panos Deloukas
  • Nita G. Forouhi
  • Sara Grioni
  • Rudolf Kaaks
  • Timothy J. Key
  • Carmen Navarro
  • Kim Overvad
  • Domenico Palli
  • Salvatore Panico
  • Jose Ramón Quirós
  • Elio Riboli
  • Olov Rolandsson
  • Carlotta Sacerdote
  • Elena Salamanca-Fernandez
  • Nadia Slimani
  • Annemieke M W Spijkerman
  • Anne Tjonneland
  • Rosario Tumino
  • Daphne L. Van Der A
  • Yvonne T. Van Der Schouw
  • Mark I. McCarthy
  • Inês Barroso
  • Stephen O'Rahilly
  • David B. Savage
  • Naveed Sattar
  • Claudia Langenberg
  • Robert A. Scott
  • Nicholas J. Wareham
External organisations
  • University of Cambridge
  • Health Research Institute of Navarra (IDISNA)
  • CIBER Epidemiology and Public Health (CIBERESP)
  • Centre for Research in Epidemiology and Population Health (CESP)
  • Umeå University
  • University Medical Center Utrecht
  • University of Glasgow
  • University of Paris-Sud
  • German Institute of Human Nutrition
  • University of Milan
  • German Cancer Research Centre
  • University of Oxford
  • University of Murcia
  • Murcia Regional Health Council
  • Aarhus University
  • Aalborg University Hospital
  • Cancer Research and Prevention Institute (ISPO)
  • Public Health Directorate
  • Imperial College London
  • Citta' della Salute e della Scienza Hospital-University of Turin
  • Human Genetics Foundation (HuGeF)
  • Instituto de Investigación Biosanitaria de Granada (Granada.ibs)
  • International Agency for Research on Cancer, World Health Organization
  • National Institute for Public Health and the Environment (RIVM)
  • Azienda Sanitaria Provinciale di Ragusa
  • Wellcome Trust Sanger Institute
  • University of Naples Federico II
  • Danish Cancer Society Research Center
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
  • Cardiac and Cardiovascular Systems
Original languageEnglish
Pages (from-to)1383-1391
Number of pages9
JournalJAMA: The Journal of the American Medical Association
Issue number13
Publication statusPublished - 2016 Oct 4
Publication categoryResearch