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  • Lotta, Luca A.University of Cambridge,National Institute for Public Health and the Environment (RIVM) (author)

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

  • Article/chapterEnglish2016

Publisher, publication year, extent ...

  • American Medical Association (AMA),2016
  • 9 s.

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:df76abf0-cd9b-420e-a934-3768d23e0f88
  • https://lup.lub.lu.se/record/df76abf0-cd9b-420e-a934-3768d23e0f88URI
  • https://doi.org/10.1001/jama.2016.14568DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-127947URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Sharp, Stephen J.University of Cambridge (author)
  • Burgess, StephenUniversity of Cambridge (author)
  • Perry, John R BUniversity of Cambridge,University of Paris-Saclay (author)
  • Stewart, Isobel D.University of Cambridge (author)
  • Willems, Sara M.University of Cambridge (author)
  • Luan, Jian'anUniversity of Cambridge (author)
  • Ardanaz, EvaCIBER Epidemiology and Public Health (CIBERESP),Health Research Institute of Navarra (IDISNA)(Swepub:lu)extLU-05 (author)
  • Arriola, LarraitzCentre for Research in Epidemiology and Population Health (CESP) (author)
  • Balkau, BeverleyUniversity of Paris-Saclay,University of Cambridge (author)
  • Boeing, HeinerGerman Institute of Human Nutrition (author)
  • Deloukas, PanosWellcome Trust Sanger Institute (author)
  • Forouhi, Nita G.University of Cambridge (author)
  • Franks, Paul W.Umeå universitet,Umeå University,Lund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Medicin,Skane University Hospital, Malmö, Sweden(Swepub:umu)pafr0003 (author)
  • Grioni, SaraUniversity of Milan (author)
  • Kaaks, RudolfGerman Cancer Research Centre (author)
  • Key, Timothy J.University of Oxford (author)
  • Navarro, CarmenMurcia Regional Health Council,University of Murcia (author)
  • Nilsson, Peter M.Lund University,Lunds universitet,Internmedicin - epidemiologi,Forskargrupper vid Lunds universitet,Internal Medicine - Epidemiology,Lund University Research Groups(Swepub:lu)medf-pni (author)
  • Overvad, KimAalborg University Hospital,Aarhus University (author)
  • Palli, DomenicoCancer Research and Prevention Institute (ISPO) (author)
  • Panico, SalvatoreUniversity of Naples Federico II (author)
  • Quirós, Jose RamónPublic Health Directorate (author)
  • Riboli, ElioImperial College London (author)
  • Rolandsson, OlovUmeå universitet,Umeå University,Allmänmedicin(Swepub:umu)olro0005 (author)
  • Sacerdote, CarlottaCitta' della Salute e della Scienza Hospital-University of Turin,Human Genetics Foundation (HuGeF) (author)
  • Salamanca-Fernandez, ElenaAndalusian School Of Public Health (EASP),CIBER Epidemiology and Public Health (CIBERESP) (author)
  • Slimani, NadiaInternational Agency for Research on Cancer, World Health Organization (author)
  • Spijkerman, Annemieke M WNational Institute for Public Health and the Environment (RIVM) (author)
  • Tjonneland, AnneDanish Cancer Society (author)
  • Tumino, RosarioCivic and M.P Arezzo Hospital (author)
  • Van Der A, Daphne L.National Institute for Public Health and the Environment (RIVM) (author)
  • Van Der Schouw, Yvonne T.University Medical Center Utrecht (author)
  • McCarthy, Mark I.University of Oxford (author)
  • Barroso, InêsWellcome Trust Sanger Institute (author)
  • O'Rahilly, StephenUniversity of Cambridge (author)
  • Savage, David B.University of Cambridge (author)
  • Sattar, NaveedUniversity of Glasgow (author)
  • Langenberg, ClaudiaUniversity of Cambridge (author)
  • Scott, Robert A.University of Cambridge (author)
  • Wareham, Nicholas J.University of Cambridge (author)
  • University of CambridgeNational Institute for Public Health and the Environment (RIVM) (creator_code:org_t)

Related titles

  • In:JAMA: The Journal of the American Medical Association: American Medical Association (AMA)316:13, s. 1383-13910098-74841538-3598

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