2. Academic Validation
  3. GDF15 linked to maternal risk of nausea and vomiting during pregnancy

GDF15 linked to maternal risk of nausea and vomiting during pregnancy

  • Nature. 2024 Jan;625(7996):760-767. doi: 10.1038/s41586-023-06921-9.
M Fejzo # 1,  N Rocha # 2,  I Cimino # 2,  S M Lockhart # 2,  C J Petry # 2,  R G Kay 2 3,  K Burling 2 4,  P Barker 2 4,  A L George 3,  N Yasara 5,  A Premawardhena 6 7,  S Gong 8 9,  E Cook 8,  D Rimmington 2,  K Rainbow 2,  D J Withers 2,  V Cortessis 10,  P M Mullin 11,  K W MacGibbon 12,  E Jin 10,  A Kam 11,  A Campbell 13,  O Polasek 14,  G Tzoneva 15,  F M Gribble 2,  G S H Yeo 2,  B Y H Lam 2,  V Saudek 2,  I A Hughes 16,  K K Ong 16 17,  J R B Perry 2 17,  A Sutton Cole 18,  M Baumgarten 18,  P Welsh 19,  N Sattar 19,  G C S Smith # 8 9,  D S Charnock-Jones # 8 9,  A P Coll # 2,  C L Meek # 2,  S Mettananda # 5 20,  C Hayward # 13 21,  N Mancuso # 1 22 23,  S O'Rahilly # 24 25
Affiliations

Affiliations

  • 1 Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 2 Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • 3 Peptidomics and Proteomics Core Facility, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • 4 Core Biochemical Assay Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 5 Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Thalagolla Road, Ragama, Sri Lanka.
  • 6 Adolescent and Adult Thalassaemia Care Center (University Medical Unit), North Colombo Teaching Hospital, Kadawatha, Sri Lanka.
  • 7 Department of Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
  • 8 Department of Obstetrics and Gynaecology, University of Cambridge, NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
  • 9 Centre for Trophoblast Research (CTR), Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • 10 Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 11 Department of Obstetrics and Gynaecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 12 Hyperemesis Education and Research Foundation, Clackamas, OR, USA.
  • 13 Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • 14 Faculty of Medicine, University of Split, Split, Croatia.
  • 15 Regeneron Genetics Center, Tarrytown, NY, USA.
  • 16 Department of Paediatrics, University of Cambridge, Cambridge, UK.
  • 17 MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • 18 Department of Obstetrics and Gynaecology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • 19 School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK.
  • 20 University Paediatrics Unit, Colombo North Teaching Hospital, Ragama, Sri Lanka.
  • 21 MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • 22 Department of Quantitative and Computational Biology, University of Southern California, California, CA, USA.
  • 23 Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, California, CA, USA.
  • 24 Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. [email protected].
  • 25 NIHR Cambridge Biomedical Research Centre, Cambridge, UK. [email protected].
  • # Contributed equally.
PMID: 38092039 DOI: 10.1038/s41586-023-06921-9
Abstract

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

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