Elevated plasma adiponectin in risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction: observational and mendelian randomization studies

Abstract

Abstract Background and purpose Adiponectin, an adipocyte-secreted protein-hormone, may play an important protective role in heart failure and associated cardiovascular diseases through insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. We hypothesized that plasma adiponectin is associated observationally and causal, genetically with risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. Methods In the Copenhagen General Population Study (CGPS), 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. 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. Results In observational analyses, 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 was also associated with increased risk of myocardial infarction. 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, while 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 Elevated plasma adiponectin was associated with increased risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. However, genetic evidence did not support causality for those associations.Observational associationObservational and genetic association