• Luca A Lotta, Stephen J Sharp, Stephen Burgess, PerryJohn R BJRBMRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom., 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 C Salamanca, Nadia Slimani, Annemieke Mw 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, and Nicholas J Wareham.
• MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
• JAMA. 2016 Oct 4; 316 (13): 138313911383-1391.

ImportanceLow-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.ObjectiveTo 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 ParticipantsThe 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.ExposuresLow-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR.Main Outcomes And MeasuresOdds ratios (ORs) for type 2 diabetes and coronary artery disease.ResultsLow-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 RelevanceIn 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.

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