Association Between Low-Density Lipoprotein Cholesterol–Lowering Genetic Variants and Risk of Type 2 Diabetes
Year: 2016
Type: review
Abstract: 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 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.
Source: JAMA
Authors: 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
Institutions: University of Cambridge, MRC Epidemiology Unit, Instituto de Salud Pública de Navarra, Navarre Institute of Health Research, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Basque Government, Inserm, Centre de recherche en Epidémiologie et Santé des Populations, German Institute of Human Nutrition, Wellcome Sanger Institute, Lund University, Skåne University Hospital, German Cancer Research Center, University of Oxford, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, Aarhus University, Aalborg University Hospital, Federico II University Hospital, University of Naples Federico II, Gobierno del Principado de Asturias, Imperial College London, Umeå University, Italian institute for Genomic Medicine, University of Turin, Instituto de Investigación Biosanitaria de Granada, Andalusian School of Public Health, Centre international de recherche sur le cancer, National Institute for Public Health and the Environment, Danish Cancer Society, University Medical Center Utrecht, Centre for Human Genetics, Oxford Centre for Diabetes, Endocrinology and Metabolism, Wellcome/MRC Institute of Metabolic Science, University of Glasgow
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: World Health Organization, Aarhus Universitet, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, Imperial College London, University of Oxford, University of Glasgow, Aalborg Universitet, Lunds Universitet, Universidad de Murcia, Umeå Universitet, Aalborg Universitetshospital, Università degli Studi di Torino, Medical Research Council, School of Public Health, Imperial College London
Awards: NIHR Senior Investigator Award, Characterising causal alleles for common disease., Understanding the biophysical basis of energy storage in adipocyte lipid droplets and the metabolic consequences of the failure of this process., G2826529823, NIHR Senior Investigator Award, G3812975344, G385201875, G4211044638, G4612446324, NIHR Senior Investigator Award, G5517677352, G6723261869, G6957823285, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application (renewal). (Joint funding with MRC), RENEWAL: Systematic approaches to the evaluation of emerging coronary risk markers. Large-scale epidemiological analyses of existing data and stored biological samples, NIHR Senior Investigator Award, G8820554905
OpenAlex ID: W2529053508