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Genetically proxied growth differentiation factor 15 levels and body mass index
  • Ville Karhunen,
  • Susanna Larsson,
  • Dipender Gill
Ville Karhunen
Imperial College London
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Susanna Larsson
Karolinska Institute
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Dipender Gill
St George's University Hospitals NHS Foundation Trust
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Abstract

Growth-differentiation factor 15 (GDF15) is an inflammatory cytokine involved in energy homeostasis. Its circulating levels are acutely increased by the type 2 diabetes medication metformin, resulting in reduced appetite and weight loss. We identified a genetic variant at the GDF15 gene to proxy a small, lifelong increase in circulating GDF15 levels, and leveraged it in colocalization and Mendelian randomization analyses to investigate the effects of chronically elevated GDF15 levels on body mass index (BMI) and type 2 diabetes liability. The results provide human genetic evidence supporting that chronically elevated GDF15 levels increase BMI. There was no genetic evidence to support bi-directional effects, or that chronically elevated GDF15 levels directly affect liability to type 2 diabetes. Our results contrast the BMI lowering effects of an acute increase in GDF15 levels observed after metformin use. These findings have direct implications for informing pharmacological strategies aimed at targeting GDF15 levels for weight loss.

Peer review status:ACCEPTED

04 Jan 2021Submitted to British Journal of Clinical Pharmacology
05 Jan 2021Submission Checks Completed
05 Jan 2021Assigned to Editor
17 Jan 2021Reviewer(s) Assigned
01 Feb 2021Review(s) Completed, Editorial Evaluation Pending
08 Feb 2021Editorial Decision: Revise Major
13 Feb 20211st Revision Received
15 Feb 2021Submission Checks Completed
15 Feb 2021Assigned to Editor
15 Feb 2021Review(s) Completed, Editorial Evaluation Pending
16 Feb 2021Reviewer(s) Assigned
25 Feb 2021Editorial Decision: Accept