Abstract Details

Title Exploration of the Beneficial Role of Circulating Adiponectin Levels on Cardiovascular Disease Risk Reveals T-cadherin as a Putative Target for Therapeutic Intervention

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) S30 - Stroke Risk Factors, Outcomes, and Prevention (3:30 PM-3:42 PM)

Poster/Presentation
Number 001

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.

Authors/Disclosures
Evangelos Pavlos Myserlis, MD (Department of Neurology) PRESENTER	The institution of Dr. Myserlis has received research support from ��ɫ��. Dr. Myserlis has received personal compensation in the range of $500-$4,999 for serving as a AAN Resident Scholarship to the Annual Meeting Recipient with ��ɫ��.
Dipender P. Gill, MBBS, PhD	Dr. Gill has received personal compensation for serving as an employee of Sequoia Genetics Ltd. Dr. Gill has stock in Apollo Therapeutics. The institution of Dr. Gill has received research support from Medical Research Council.
Marios Georgakis	Marios Georgakis has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Tourmaline Bio.
Vasileios-Arsenios Lioutas, MD (Beth Israel Deaconess Medical Center, Department of Neurology)	Dr. Lioutas has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Qmetis. Dr. Lioutas has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mindray. The institution of Dr. Lioutas has received research support from NIH. The institution of Dr. Lioutas has received research support from Alzheimer's Association.
Magdy H. Selim, MD, PhD (Beth Israel Deaconess Med. Ctr.)	Dr. Selim has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. The institution of Dr. Selim has received research support from NIH/NINDS. Dr. Selim has received publishing royalties from a publication relating to health care.
Jonathan Rosand, MD (Massachusetts General Hospital)	Dr. Rosand has received personal compensation for serving as an employee of Massachusetts General Hospital. Dr. Rosand has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly and Co. Dr. Rosand has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Rosand has received research support from NIH. The institution of Dr. Rosand has received research support from American Heart Association. Dr. Rosand has received personal compensation in the range of $0-$499 for serving as a Peer reviewer with National Institutes of Health. Dr. Rosand has a non-compensated relationship as a Trustee with Columbia University that is relevant to AAN interests or activities.
Chirantan Banerjee, MD, MPH (Medical University of South Carolina)	Dr. Banerjee has nothing to disclose.
Christopher D. Anderson, MD, PhD, FAAN (Brigham and Women's Hospital)	The institution of Dr. Anderson has received research support from Bayer AG. The institution of Dr. Anderson has received research support from American Heart Association. The institution of Dr. Anderson has received research support from National Institutes of Health. An immediate family member of Dr. Anderson has received publishing royalties from a publication relating to health care.

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