Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis
Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, Luan J, Ardanaz E, Arriola L, Balkau B, Boeing H, Deloukas P, Forouhi NG, Franks PW, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quirós JR, Riboli E, Rolandsson O, Sacerdote C, Salamanca EC, Slimani N, Spijkerman AM, Tjonneland A, Tumino R, van der A DL, van der Schouw YT, McCarthy MI, Barroso I, O'Rahilly S, Savage DB, Sattar N, Langenberg C, Scott RA, Wareham NJ
JAMA · 330 citas
Cómo se estudió
- Diseño
- Metaanálisis (indexado por PubMed)
- Estudiado en
- Personas
- Resultado principal
- Eventos clínicos como enfermedad o muerte
Quién lo pagó
- Financiación
- Financiación independiente
- Gobierno
- World Health Organization
- Universidad u hospital
- Aarhus Universitet
- Organización sin fines de lucro
- Wellcome Trust
- Organización sin fines de lucro
- Cancer Research UK
- Gobierno
- National Institute for Health and Care Research
- Organización sin fines de lucro
- British Heart Foundation
- Universidad u hospital
- Imperial College London
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- University of Oxford
- Universidad u hospital
- University of Glasgow
- Universidad u hospital
- Aalborg Universitet
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- Lunds Universitet
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- Universidad de Murcia
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- Umeå Universitet
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- Aalborg Universitetshospital
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- Università degli Studi di Torino
- Gobierno
- Medical Research Council
- Universidad u hospital
- School of Public Health, Imperial College London
- Gobierno
- National Institute for Health Research (NIHR)
- Subvenciones
- National Institute for Health and Care Research (NF-SI-0512-10165); Wellcome Trust (098381); Wellcome Trust (107064/Z/15/Z); Medical Research Council (MC_UU_12015/5); National Institute for Health and Care Research (NF-SI-0513-10109); Medical Research Council (MC_PC_13046); Medical Research Council (MC_PC_13048); Medical Research Council (MR/L003120/1); Wellcome Trust (WT 098051); National Institute for Health and Care Research (NF-SI-0507-10380); Medical Research Council (MC_UU_12015/2); Cancer Research UK (16491); Medical Research Council (MC_UU_12015/1); Wellcome Trust (090532); British Heart Foundation (RG/13/13/30194); British Heart Foundation (RG/08/014/24067); National Institute for Health and Care Research (NF-SI-0512-10135); National Institute for Health and Care Research (CL-2011-18-004)
Según 18 financiadores declarados.
Publicación
- Publicado
- 2016-10-04 · JAMA · vol. 316 · número 13 · pág. 1383
- Editorial
- American Medical Association
- Citado
- 393 citas · más que el 100% de estudios similares · 53.8× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 49 trabajos
- Acceso
- Lectura gratuita
- Áreas de investigación
- Lipoproteins and Cardiovascular Health · Genetic Associations and Epidemiology · Diabetes, Cardiovascular Risks, and Lipoproteins
- Palabras clave
- type 2 diabetes, NPC1L1, HMGCR, PCSK9, ABCG5/G8, LDL receptor, coronary artery disease, lipid-lowering therapy, statins, ezetimibe, genetic risk prediction, LDL cholesterol lowering, genetic association meta-analysis, lipid metabolism genes, ABCA1, ABCG1
- MeSH
- humans, diabetes mellitus, type 2, simvastatin, hydroxymethylglutaryl coa reductases, lipoproteins, membrane transport proteins, membrane proteins, receptors, ldl, hydroxymethylglutaryl-coa reductase inhibitors, drug therapy, combination, odds ratio, risk, cohort studies, polymorphism, genetic, adult, aged, middle aged, cholesterol, ldl, coronary artery disease, genetic variation, genetic association studies, ezetimibe, proprotein convertase 9, atp binding cassette transporter, subfamily g, member 5
41 autores
- Luca Andrea Lotta🇬🇧University of Cambridge; MRC Epidemiology Unit
- Stephen J. Sharp🇬🇧University of Cambridge; MRC Epidemiology Unit
- Stephen Burgess🇬🇧University of Cambridge
- John R. B. Perry🇬🇧University of Cambridge; MRC Epidemiology Unit
- Isobel D. Stewart🇬🇧University of Cambridge; MRC Epidemiology Unit
- Sara M. Willems🇬🇧University of Cambridge; MRC Epidemiology Unit
- Jian’an Luan🇬🇧University of Cambridge; MRC Epidemiology Unit
- Eva Ardanáz🇪🇸Instituto de Salud Pública de Navarra; Navarre Institute of Health Research; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
- Larraitz Arriola🇪🇸Basque Government; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
- Beverley Balkau🇫🇷Inserm; Centre de recherche en Epidémiologie et Santé des Populations
- Heiner Boeing🇩🇪German Institute of Human Nutrition
- Panos Deloukas🇬🇧Wellcome Sanger Institute
- Nita G. Forouhi🇬🇧University of Cambridge; MRC Epidemiology Unit
- Paul W. Franks🇸🇪Lund University; Skåne University Hospital
- Sara Grioni
- Rudolf Kaaks🇩🇪German Cancer Research Center
- Timothy J. Key🇬🇧University of Oxford
- Carmen Navarro🇪🇸Instituto Murciano de Investigación Biosanitaria; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública; Universidad de Murcia
- Peter M. Nilsson🇸🇪Lund University; Skåne University Hospital
- Kim Overvad🇩🇰Aarhus University; Aalborg University Hospital
- Domenico Palli
- Salvatore Panico🇮🇹Federico II University Hospital; University of Naples Federico II
- Jose-Ramón Quirós🇪🇸Gobierno del Principado de Asturias
- Elio Ríboli🇬🇧Imperial College London
- Olov Rolandsson🇸🇪Umeå University
- Carlotta Sacerdote🇮🇹Italian institute for Genomic Medicine; University of Turin
- Elena Salamanca‐Fernández🇪🇸Instituto de Investigación Biosanitaria de Granada; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública; Andalusian School of Public Health
- Nadia Slimani🇫🇷Centre international de recherche sur le cancer
- Annemieke M. W. Spijkerman🇳🇱National Institute for Public Health and the Environment
- Anne Marie Tjønneland🇩🇰Danish Cancer Society
- Rosario Tumino
- Daphne L. van der A🇳🇱National Institute for Public Health and the Environment
- Yvonne T. van der Schouw🇳🇱University Medical Center Utrecht
- Mark I. McCarthy🇬🇧Centre for Human Genetics; University of Oxford; Oxford Centre for Diabetes, Endocrinology and Metabolism
- Inês Barroso🇬🇧Wellcome Sanger Institute
- Stephen O’Rahilly🇬🇧University of Cambridge; Wellcome/MRC Institute of Metabolic Science
- David B. Savage🇬🇧University of Cambridge; Wellcome/MRC Institute of Metabolic Science
- Naveed A. Sattar🇬🇧University of Glasgow
- Claudia Langenberg🇬🇧University of Cambridge; MRC Epidemiology Unit
- Robert A. Scott🇬🇧University of Cambridge; MRC Epidemiology Unit
- Nicholas J. Wareham🇬🇧 · autor de correspondenciaUniversity of Cambridge; MRC Epidemiology Unit
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial.
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