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Elevated Circulating Follistatin Associates with Increased Risk of Mortality and Cardiometabolic Disorders
32 Pages Posted: 20 Apr 2023
More...Abstract
Background and Aims: Previous study showed that elevated circulating hepatokine follistatin (FST) associates with an increased risk of type 2 diabetes by inducing adipose tissue insulin resistance. Here we explore further the relationships between plasma FST levels with mortality and health outcomes.
Methods: The population-based Malmö Diet Cancer cardiovascular cohort (n=4733, age 45-68 years) was used to study plasma FST in relation to incidence of health outcomes, by linkage with national patient registers. Cox regression analysis was used to assess the associations of plasma FST and outcomes, with adjustments for multiple potential confounding factors.
Findings: During the mean follow-up time of 22.64±5.84 years in 4,733 individuals, 526 had incident stroke, 432 had ischemic stroke, 530 had incident coronary events (CE), 339 had incident heart failure (HF), 320 had incident chronic kidney disease (CKD) and 1,843 individuals died. Hazard ratio (HR) per SD increase in FST levels adjusted for multiple risk factors was 1.05 (95%CI: 1.00-1.11, p=0.036) for mortality; 1.10 (95%CI: 1.00-1.20, p=0.042) for stroke; 1.13 (95%CI: 1.03-1.25, p=0.014) for ischemic stroke; 1.16 (95%CI: 1.03-1.30, p=0.015) for HF; and 1.38 (95%CI: 1.12-1.70, p=0.003) for a diagnosis of CKD.
Interpretation: Elevated circulating FST associates with an increased risk of mortality and HF, which partly may be mediated by diabetes. FST also associated with stroke, ischemic stroke, CE and CKD, independently of established risk factors including diabetes.
Funding: This study was supported by the Swedish Research Council, Strategic Research Area Exodiab, Dnr 2009-1039; and the Swedish Foundation for Strategic Research Dnr IRC15-0067. We also acknowledge support from a Lund University Infrastructure grant: "Malmö Population-Based cohorts" (STYR 2019/2046). The research was supported with a project grant from the Crafoord Foundation (Crafoordska stiftelsen) grant to Y.D.M.; and the Swedish Heart and Lung Foundation (20140078).
Declaration of Interest: Y.D.M. is the founder of Lundoch Diagnostics (www.lundoch.com), which developed an AI- driven blood test for the early risk detection of type 2 diabetes using FST and other measurements. G.E. is member of the scientific advisory board of Lundoch Diagnostics.
Ethical Approval: All data were pseudonymized during the analysis and no identity information being revealed. The written consent was obtained from all participants. The study conforms to the principles of the Declaration of Helsinki and was approved by the Ethical Committee at Lund University, Lund, Sweden (LU 51-90; LU 2009/633).
Keywords: Follistatin, mortality, heart failure, stroke, ischemic stroke, coronary events, chronic kidney disease
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