Genetically proxied growth-differentiation factor 15 levels and body mass index

doi:10.1111/bcp.14808

. 2021 Oct;87(10):4036-4039.

doi: 10.1111/bcp.14808. Epub 2021 Mar 19.

Genetically proxied growth-differentiation factor 15 levels and body mass index

Ville Karhunen¹, Susanna C Larsson^{2

3}, Dipender Gill^{1

4

5

6}

Affiliations

¹ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
² Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁴ Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, UK.
⁵ Clinical Pharmacology and Therapeutics Section, Institute for Infection and Immunity, St George's, University of London, London, UK.
⁶ Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, UK.

PMID: 33686698
DOI: 10.1111/bcp.14808

Free article

Genetically proxied growth-differentiation factor 15 levels and body mass index

Ville Karhunen et al. Br J Clin Pharmacol. 2021 Oct.

Free article

. 2021 Oct;87(10):4036-4039.

doi: 10.1111/bcp.14808. Epub 2021 Mar 19.

Authors

Ville Karhunen¹, Susanna C Larsson^{2

3}, Dipender Gill^{1

4

5

6}

Affiliations

¹ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
² Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁴ Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, UK.
⁵ Clinical Pharmacology and Therapeutics Section, Institute for Infection and Immunity, St George's, University of London, London, UK.
⁶ Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, UK.

PMID: 33686698
DOI: 10.1111/bcp.14808

Abstract

Growth-differentiation factor 15 (GDF15) is an inflammatory cytokine involved in energy homeostasis that is being pursued as a drug target for obesity. 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.

Keywords: Mendelian randomization; body mass index; colocalization; growth-differentiation factor 15; type 2 diabetes.

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References

REFERENCES

1. Tsai VWW, Husaini Y, Sainsbury A, et al. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab. 2018;28(3):353-368. https://doi.org/10.1016/j.cmet.2018.07.018
1. Coll AP, Chen M, Taskar P, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020;578(7795):444-448. https://doi.org/10.1038/s41586-019-1911-y
1. Giambartolomei C, Vukcevic D, Schadt EE, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 2014;10(5):e1004383. https://doi.org/10.1371/journal.pgen.1004383
1. Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1-22. https://doi.org/10.1093/ije/dyg070
1. Gill D, Georgakis MK, Walker VM, et al. Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]. Wellcome Open Res. 2021;6(16). 1-19. https://doi.org/10.12688/wellcomeopenres.16544.2

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[1] Tsai VWW, Husaini Y, Sainsbury A, et al. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab. 2018;28(3):353-368. https://doi.org/10.1016/j.cmet.2018.07.018

[2] Tsai VWW, Husaini Y, Sainsbury A, et al. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab. 2018;28(3):353-368. https://doi.org/10.1016/j.cmet.2018.07.018

[3] Coll AP, Chen M, Taskar P, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020;578(7795):444-448. https://doi.org/10.1038/s41586-019-1911-y

[4] Coll AP, Chen M, Taskar P, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020;578(7795):444-448. https://doi.org/10.1038/s41586-019-1911-y

[5] Giambartolomei C, Vukcevic D, Schadt EE, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 2014;10(5):e1004383. https://doi.org/10.1371/journal.pgen.1004383

[6] Giambartolomei C, Vukcevic D, Schadt EE, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 2014;10(5):e1004383. https://doi.org/10.1371/journal.pgen.1004383

[7] Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1-22. https://doi.org/10.1093/ije/dyg070

[8] Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1-22. https://doi.org/10.1093/ije/dyg070

[9] Gill D, Georgakis MK, Walker VM, et al. Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]. Wellcome Open Res. 2021;6(16). 1-19. https://doi.org/10.12688/wellcomeopenres.16544.2

[10] Gill D, Georgakis MK, Walker VM, et al. Mendelian randomization for studying the effects of perturbing drug targets [version 2; peer review: 3 approved, 1 approved with reservations]. Wellcome Open Res. 2021;6(16). 1-19. https://doi.org/10.12688/wellcomeopenres.16544.2

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Genetically proxied growth-differentiation factor 15 levels and body mass index

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Genetically proxied growth-differentiation factor 15 levels and body mass index

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