Format

Send to

Choose Destination
JAMA. 2016 Oct 4;316(13):1383-1391. doi: 10.1001/jama.2016.14568.

Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.

Author information

1
MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
2
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
3
Navarre Public Health Institute (ISPN), Pamplona, Spain.
4
Navarra Institute for Health Research (IdiSNA) Pamplona, Spain.
5
CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
6
Public Health Division of Gipuzkoa, San Sebastian, Spain.
7
Instituto BIO-Donostia, Basque Government, San Sebastian, Spain.
8
Inserm, CESP, U1018, Villejuif, France.
9
German Institute of Human Nutrition Potsdam-Rehbruecke, Germany.
10
The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
11
Lund University, Malmö, Sweden.
12
Umeå University, Umeå, Sweden.
13
Epidemiology and Prevention Unit, Milan, Italy.
14
German Cancer Research Centre (DKFZ), Heidelberg, Germany.
15
University of Oxford, Oxford, United Kingdom.
16
Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
17
Unit of Preventive Medicine and Public Health, School of Medicine, University of Murcia, Spain.
18
Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
19
Aalborg University Hospital, Aalborg, Denmark.
20
Cancer Research and Prevention Institute (ISPO), Florence, Italy.
21
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
22
Public Health Directorate, Asturias, Spain.
23
School of Public Health, Imperial College London, United Kingdom.
24
Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention (CPO), Torino, Italy.
25
Human Genetics Foundation (HuGeF), Torino, Italy.
26
Andalusian School of Public Health, Granada, Spain.
27
Instituto de Investigación Biosanitaria de Granada (Granada.ibs), Granada, Spain.
28
International Agency for Research on Cancer, Lyon, France.
29
National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands.
30
Danish Cancer Society Research Center, Copenhagen, Denmark.
31
ASP Ragusa, Italy.
32
University Medical Center Utrecht, Utrecht, the Netherlands.
33
Oxford Centre for Diabetes, Endocrinology and Metabolism, and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom.
34
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
35
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, United Kingdom.
#
Contributed equally

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.

PMID:
27701660
PMCID:
PMC5386134
DOI:
10.1001/jama.2016.14568
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center