Exploration of the Beneficial Role of Circulating Adiponectin Levels on Cardiovascular Disease Risk Reveals T-cadherin as a Putative Target for Therapeutic Intervention
Evangelos Pavlos Myserlis1, Dipender Gill2, Marios Georgakis3, Vasileios-Arsenios Lioutas4, Magdy Selim4, Jonathan Rosand5, Chirantan Banerjee1, Christopher Anderson6
1Department of Neurology, Medical University of South Carolina, 2Imperial College London, 3Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-University (LMU) Hospital, 4Department of Neurology, Beth Israel Deaconess Medical Center, 5Department of Neurology, Massachusetts General Hospital, 6Department of Neurology, Brigham and Women's Hospital
Objective:
To explore whether circulating adiponectin may be causally associated with lower cardiovascular disease (CVD) risk, and provide mechanistic insights of this association, leveraging large-scale genomics data.
Background:
Prior studies have suggested that obesity is associated with increased CVD risk. We have previously shown that apart from traditional vascular risk factor modification, circulating adiponectin may lie in the pathway between body fat and CVD risk, suggesting that targeting adipose tissue-specific factors may provide additional vascular benefit.
Design/Methods:
We followed a mendelian randomization (MR) approach, focusing on the gene that encodes adiponectin, ADIPOQ. We constructed two genomic instruments: a cis-instrument, selecting genome-wide significant, independent (r2≤0.1) variants near the ADIPOQ gene from a GWAS of circulating adiponectin (n=~38,600), and a trans-instrument, selecting genome-wide significant, independent (r2≤0.01) variants across the genome, excluding ADIPOQ, to explore whether ADIPOQ-independent mechanisms that increase circulating adiponectin are associated with CVD risk. Using these instruments, we performed MR on all stroke (AS) (n=110,182), ischemic stroke (IS) (n=86,668), and coronary artery disease (CAD) (n=181,522), using GWAS of the respective traits. Effect sizes were expressed as per standard deviation of circulating adiponectin levels.
Results:
The cis-instrument consisted of 14 variants. Higher genetically proxied, ADIPOQ-mediated circulating adiponectin levels were associated with lower CAD (OR=0.62, 95% CI: 0.43-0.87), but not AS or IS risk. The trans-instrument consisted of 21 variants. Higher genetically proxied, ADIPOQ-independent circulating adiponectin levels were associated with lower AS, IS, and CAD risk (OR 0.46, 0.39, 0.11; 95% CI: 0.32-0.67, 0.25-0.62, 0.03-0.37 respectively). Variants near the CDH13 gene region (~43.1% variance explained by the trans-instrument) were associated with both AS and CAD risk (OR 0.55, 0.32; 95% CI: 0.34-0.90, 0.17-0.60 respectively).
Conclusions:
Higher ADIPOQ-independent circulating adiponectin levels may be causally associated with decreased stroke and CAD risk. Whether T-cadherin-mediated increases in circulating adiponectin may represent a viable therapeutic target for CVD warrants further research.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.