Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.
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Lotta Luca A, Sharp Stephen J, Burgess Stephen, Perry John R B, Stewart Isobel D, Willems Sara M, Luan Jian'an, Ardanaz Eva, Arriola Larraitz, Balkau Beverley, Boeing Heiner, Deloukas Panos, Forouhi Nita G, Franks Paul W, Grioni Sara, Kaaks Rudolf, Key Timothy J, Navarro Carmen, Nilsson Peter M, Overvad Kim, Palli Domenico, Panico Salvatore, Quirós Jose-Ramón, Riboli Elio, Rolandsson Olov, Sacerdote Carlotta, Salamanca Elena C, Slimani Nadia, Spijkerman Annemieke Mw, Tjonneland Anne, Tumino Rosario, van der A Daphne L, van der Schouw Yvonne T, McCarthy Mark I, Barroso Inês, O'Rahilly Stephen, Savage David B, Sattar Naveed, Langenberg Claudia, Scott Robert A, Wareham Nicholas J
Аннотация
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 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.