No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation

Hadi Harati; Daniela Zanetti; Abhiram Rao; Stefan Gustafsson; Marco Perez; Erik Ingelsson; Joshua W Knowles

doi:10.1007/s00125-019-4836-y

No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation

Diabetologia. 2019 May;62(5):800-804. doi: 10.1007/s00125-019-4836-y. Epub 2019 Feb 27.

Authors

Hadi Harati¹, Daniela Zanetti², Abhiram Rao³, Stefan Gustafsson⁴, Marco Perez², Erik Ingelsson^{2

5

6}, Joshua W Knowles^{7

8

9}

Affiliations

¹ Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Medicine, Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Drive, CV 273, Stanford, CA, 94305, USA.
³ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁴ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁵ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
⁶ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
⁷ Department of Medicine, Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Drive, CV 273, Stanford, CA, 94305, USA. knowlej@stanford.edu.
⁸ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. knowlej@stanford.edu.
⁹ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA. knowlej@stanford.edu.

Abstract

Aims/hypothesis: Several epidemiological studies have shown an increased risk of atrial fibrillation in individuals with type 2 diabetes or milder forms of dysglycaemia. We aimed to assess whether this relation is causal using a Mendelian randomisation approach.

Methods: Two-sample Mendelian randomisation was used to obtain estimates of the influence of type 2 diabetes, fasting blood glucose (FBG), and HbA_1c on the risk of atrial fibrillation. Instrumental variables were constructed using available summary statistics from meta-analyses of genome-wide association studies (GWAS) for type 2 diabetes and associated phenotypes. Pleiotropic SNPs were excluded from the analyses. The most recent GWAS meta-analysis summary statistics for atrial fibrillation, which included over 1 million individuals (approximately 60,000 individuals with atrial fibrillation) was used for outcome analysis.

Results: Neither type 2 diabetes (OR 1.01 [95% CI 0.98, 1.03]; p = 0.37), nor FBG (OR 0.95 [95% CI 0.82, 1.09] per mmol/l; p = 0.49) or HbA_1c (OR 1.01 [95% CI, 0.85, 1.17] per mmol/mol [%]; p = 0.88) were associated with atrial fibrillation in Mendelian randomisation analyses. We had >80% statistical power to detect ORs of 1.08, 1.06 and 1.09 or larger for type 2 diabetes, FBG and HbA_1c, respectively, for associations with atrial fibrillation.

Conclusions/interpretation: This Mendelian randomisation analysis does not support a causal role of clinical significance between genetically programmed type 2 diabetes, FBG or HbA_1c and development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective strategy for atrial fibrillation prevention.

Data availability: The datasets analysed during the current study are available from the following repository: Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al (2018) GWAS summary statistics for AF (N=60,620 AF cases and 970,216 controls). Center for Statistical Genetics: http://csg.sph.umich.edu/willer/public/afib2018/nielsen-thorolfsdottir-willer-NG2018-AFib-gwas-summary-statistics.tbl.gz.

Keywords: Atrial fibrillation; Genome-wide association; Mendelian randomisation; Type 2 diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Atrial Fibrillation / complications
Atrial Fibrillation / genetics
Atrial Fibrillation / physiopathology*
Blood Glucose / metabolism*
Diabetes Mellitus, Type 2 / complications
Diabetes Mellitus, Type 2 / genetics
Diabetes Mellitus, Type 2 / physiopathology*
Genome-Wide Association Study
Genotype
Glycated Hemoglobin / analysis
Humans
Insulin / blood
Mendelian Randomization Analysis
Phenotype
Polymorphism, Single Nucleotide
Risk Factors

Substances

Blood Glucose
Glycated Hemoglobin A
Insulin
hemoglobin A1c protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding