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

  • 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
  • Paul W. Franks
  • Sara Grioni
  • Rudolf Kaaks
  • Timothy J. Key
  • Carmen Navarro
  • Peter M. Nilsson
  • 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
Publishing year: 2016-10-04
Language: English
Pages: 1383-1391
Publication/Series: JAMA: the journal of the American Medical Association
Volume: 316
Issue: 13
Document type: Journal article
Publisher: American Medical Association

Abstract english

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.


  • Endocrinology and Diabetes
  • Cardiac and Cardiovascular Systems


  • Genetic and Molecular Epidemiology
  • Internal Medicine
  • ISSN: 0098-7484
Paul Franks
E-mail: paul [dot] franks [at] med [dot] lu [dot] se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49



Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00