B4757 - Investigating the contributions of fetal and maternal genetic variation in GDF15 in nausea vomiting and hyperemesis gravid aru - 02/12/2024

B number: 
B4757
Principal applicant name: 
Rachel Freathy | University of Exeter (UK)
Co-applicants: 
Ms Rhian Swarbrick, Dr Rob Beamont, Miss Annika Jaitner
Title of project: 
Investigating the contributions of fetal and maternal genetic variation in GDF15, in nausea, vomiting and hyperemesis gravid aru
Proposal summary: 

References to previously published work in the summary below are given as
PubMed IDs.
Nausea and vomiting during pregnancy (NVP) is estimated to occur in around 70%
of women globally, with 1.1% of women estimated to experience severe cases,
diagnosed as Hyperemesis Gravidarum (HG) (PMID: 23863575). HG is associated
with dehydration and weight loss, which can result in hospitalisation and have
significant detrimental effects for both mother and fetus. These include increased
risk of morbidity, placental complications, small for gestational age birth, maternal
psychological distress and increased risk of developmental delay for offspring
(PMID: 35367190, PMID: 25898368, PMID: 23360164, PMID: 33713683, PMID:
21413857) .
A recent study (PMID: 38092039) made great progress in understanding a major
cause of NVP and HG. Using a variety of analyses, especially of human genetic
data, the authors showed that maternal sensitivity to a protein released from the
placenta called growth differentiation factor 15 (GDF15), is key causal risk factor.
This finding was exciting as it suggested avenues for future research into
prevention or treatment. Evidence for the role of GDF15 included associations of
variants (single letter changes in the DNA code) in the GDF15 gene region with
both risk of NVP or HG, and with GDF15 levels in the blood (PMID: 35218128,
PMID:29563502, PMID: 38092039). The finding that women who have naturally
low levels of GDF15 are more sensitive to the GDF15 released from the placenta
and more susceptible to NVP and HG, raised the possibility that a fetal genetic
variants which increase GDF15 production may also influence HG or NVP risk.
There was some evidence in a small sample that the genotype of the fetus, relative
to the mother, may be associated with the proportion of fetal-placental derived
GDF15 contributing to circulating GDF15, potentially mediating experiences of
nausea and vomiting (PMID: 38092039). However, analyses of maternal and fetal
genotype data in well powered samples are needed to confirm this, which is the
focus of our proposed project. We aim to explore the maternal and fetal genetic
contributions of genetic variants to nausea and vomiting during pregnancy.

Impact of research: 
What do you think the likely impact of your research will be? Advancing understanding on the relationship between maternal and fetal genotypes in their contributions to nausea and vomiting during pregnancy. Contribute to the evidence-base around hyperemesis gravidarum and nausea and vomiting during pregnancy, which could be utilised to identify new predictive biomarkers for early screening or new targets for treatment. We expect this work to result in at least one high impact publication.
Date proposal received: 
Thursday, 28 November, 2024
Date proposal approved: 
Monday, 2 December, 2024
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), hyperemesis gravidarum, nausea and vomiting in pregnancy, Statistical methods, nausea, vomiting, hyperemesis, pregnancy, genetics