Plasma adiponectin levels and risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction: large-scale observational and Mendelian randomization evidence

Abstract

Aims: Adiponectin may play an important protective role in heart failure and associated cardiovascular diseases. We hypothesized that plasma adiponectin is associated observationally and causally, genetically with risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction.

Methods and results: In the Copenhagen General Population Study, we examined 30 045 individuals with plasma adiponectin measurements observationally and 96 903 individuals genetically in one-sample Mendelian randomization analyses using five genetic variants explaining 3% of the variation in plasma adiponectin. In the HERMES, UK Biobank, The Nord-Trøndelag Health Study (HUNT), deCODE, the Michigan Genomics Initiative (MGI), DiscovEHR, and the AFGen consortia, we performed two-sample Mendelian randomization analyses in up to 1 030 836 individuals using 12 genetic variants explaining 14% of the variation in plasma adiponectin.In observational analyses modelled linearly, a 1 unit log-transformed higher plasma adiponectin was associated with a hazard ratio of 1.51 (95% confidence interval: 1.37-1.66) for heart failure, 1.63 (1.50-1.78) for atrial fibrillation, 1.21 (1.03-1.41) for aortic valve stenosis, and 1.03 (0.93-1.14) for myocardial infarction; levels above the median were also associated with an increased risk of myocardial infarction, and non-linear U-shaped associations were more apparent for heart failure, aortic valve stenosis, and myocardial infarction in less-adjusted models. Corresponding genetic, causal risk ratios were 0.92 (0.65-1.29), 0.87 (0.68-1.12), 1.55 (0.87-2.76), and 0.93 (0.67-1.30) in one-sample Mendelian randomization analyses, and no significant associations were seen for non-linear one-sample Mendelian randomization analyses; corresponding causal risk ratios were 0.99 (0.89-1.09), 1.00 (0.92-1.08), 1.01 (0.79-1.28), and 0.99 (0.86-1.13) in two-sample Mendelian randomization analyses, respectively.

Conclusion: Observationally, elevated plasma adiponectin was associated with an increased risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. However, genetic evidence did not support causality for these associations.

Keywords: Adiponectin; Aortic valve stenosis; Atrial fibrillation; Genetic polymorphisms; Heart failure; Myocardial infarction.

Graphical Abstract

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Figure 1

Flowchart for observational and genetic Mendelian randomization analyses. (A) In observational and genetic one-sample Mendelian randomization analyses, the Copenhagen General Population Study was used as the exposure and outcome cohort (pink). (B) In genetic two-sample Mendelian randomization analyses, ADIPOGen was used as the exposure cohort and HERMES, UK Biobank (UKB), The Nord-Trøndelag Health Study (HUNT), deCODE, the Michigan Genomics Initiative (MGI), DiscovEHR, and the AFGen consortia as the outcome cohorts (blue). The supplementary material contains summarized descriptions of the included cohorts. SNPs = single nucleotide polymorphisms. MR = Mendelian randomization.

Figure 2

Observational association of plasma adiponectin with heart failure (HF), atrial fibrillation (AF), aortic valve stenosis (AVS), and myocardial infarction (MI) in the Copenhagen general population study. Hazard ratios (HR) are indicated with a solid red line and a 95% confidence interval (CI) with dashed red lines. The median concentration of plasma adiponectin (16 µg/mL) was used as a reference with a hazard ratio of 1.0 indicated with a horizontal dashed black line. Individuals in the upper 1st percentile for plasma adiponectin (plasma adiponectin ≥50 µg/mL) were included in the analyses but excluded from the graphs for visual purposes. Analyses were multivariable and adjusted for age (as timescale), sex, hypertension, diabetes, use of lipid-lowering drugs, smoking status, socioeconomic status, physical activity, body mass index, waist circumference, non-high-density lipoprotein cholesterol, and plasma high-sensitive C-reactive protein. A fraction of the population is indicated with light blue. N = number of individuals.

Figure 3

Observational association of plasma adiponectin with heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction in the Copenhagen General Population study. The geometric mean with a 95% confidence interval (CI) for plasma adiponectin is indicated with bars and whiskers. Hazard ratios (HR) with 95% CI for heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction are indicated with diamonds and whiskers. Analyses were multivariable and adjusted for age (as timescale), sex, hypertension, diabetes, use of lipid-lowering drugs, smoking status, socioeconomic status, physical activity, body mass index, waist circumference, non-high-density lipoprotein cholesterol, and plasma high-sensitive C-reactive protein. N = number of individuals.

Figure 4

Genetic association of plasma adiponectin with heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction in the Copenhagen General Population study. The geometric mean with a 95% confidence interval (CI) for plasma adiponectin is indicated with bars and whiskers. Odds ratio (OR) with 95% CI for heart failure atrial fibrillation, aortic valve stenosis, and myocardial infarction are indicated with diamonds and whiskers. Analyses for the risk of disease were adjusted for age and sex. The genetic adiponectin score explained 3% of the variation in plasma adiponectin (R²) with an F-value of 797. N = number of individuals.

Figure 5

Observational and genetic one-sample Mendelian randomization of plasma adiponectin with heart failure in clinical subgroups in the Copenhagen General Population Study. Observational analyses were multivariable and adjusted for age, sex, hypertension, diabetes, use of lipid-lowering drugs, smoking status, socioeconomic status, physical activity, body mass index, waist circumference, non-high-density lipoprotein cholesterol, and plasma high-sensitive C-reactive protein. Genetic results are from a Wald-type estimator and analyses were adjusted for age and sex. N = number of individuals. Corresponding data for atrial fibrillation, aortic valve stenosis, and myocardial infarction are shown in Supplementary material online, Figures S10–S12.

Figure 6

Observational and genetic one- and two-sample Mendelian randomization of plasma adiponectin with heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. Observational analyses in the Copenhagen General Population Study (CGPS) were multivariable and adjusted for age, sex, hypertension, diabetes, use of lipid-lowering drugs, smoking status, socioeconomic status, physical activity, body mass index, waist circumference, non-high-density lipoprotein cholesterol, and plasma high-sensitive C-reactive protein. The causal risk ratio with a 95% confidence interval (CI) from one-sample Mendelian randomization (MR) analyses indicated with red diamonds and whiskers were based on the CGPS. The causal risk ratio with 95% CI from two-sample Mendelian randomization analyses indicated with blue diamonds and whiskers was based on HERMES in heart failure; HUNT, deCODE, MGI, DiscovEHR, UKB, and AFGen in atrial fibrillation, and UKB in aortic valve stenosis and myocardial infarction. Genetic information on plasma adiponectin for the two-sample Mendelian randomization was obtained from ADIPOGen. Genetic results are from inverse variance weighted analyses. Results from MR-Egger, weighted median, and weighted mode analyses are shown in Supplementary material online, Figure S13. SNPs = single nucleotide polymorphisms. N = number of individuals.