Lotta, Luca ASharp, Stephen JBurgess, StephenPerry, John R BStewart, Isobel DWillems, Sara MLuan, Jian'anArdanaz, EvaArriola, LarraitzBalkau, BeverleyBoeing, HeinerDeloukas, PanosForouhi, Nita GFranks, Paul WGrioni, SaraKaaks, RudolfKey, Timothy JNavarro, CarmenNilsson, Peter MOvervad, KimPalli, DomenicoPanico, SalvatoreQuirós, Jose-RamónRiboli, ElioRolandsson, OlovSacerdote, CarlottaSalamanca, Elena CSlimani, NadiaSpijkerman, Annemieke MwTjonneland, AnneTumino, Rosariovan der A, Daphne Lvan der Schouw, Yvonne TMcCarthy, Mark IBarroso, InêsO'Rahilly, StephenSavage, David BSattar, NaveedLangenberg, ClaudiaScott, Robert AWareham, Nicholas J2023-01-252023-01-252016http://hdl.handle.net/10668/10502Low-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. 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. 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. Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. Odds ratios (ORs) for type 2 diabetes and coronary artery disease. 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  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.enATP Binding Cassette Transporter, Subfamily G, Member 5AdultAgedCholesterol, LDLCohort StudiesCoronary Artery DiseaseDiabetes Mellitus, Type 2Drug Therapy, CombinationEzetimibeGenetic Association StudiesGenetic VariationHumansHydroxymethylglutaryl CoA ReductasesHydroxymethylglutaryl-CoA Reductase InhibitorsLipoproteinsMembrane ProteinsMembrane Transport ProteinsMiddle AgedOdds RatioPolymorphism, GeneticProprotein Convertase 9Receptors, LDLRiskSimvastatinresearch article27701660open access10.1001/jama.2016.145681538-3598PMC5386134http://spiral.imperial.ac.uk/bitstream/10044/1/41515/2/161004%20Lotta%20JAMA.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386134/pdf