Two Genes Linked to Severe Nausea and Vomiting in Pregnancy Interview with:

Marlena Fejzo, PhD Aassociate researche David Geffen School of Medicine UCLA.

Dr. Fejzo

Marlena Fejzo, PhD
Aassociate researche
David Geffen School of Medicine
UCLA. What is the background for this study?

Response: Most women experience some nausea and vomiting of pregnancy, and the worst 2% are diagnosed with Hyperemesis Gravidarum which is associated with poor maternal and fetal outcomes. I had HG in 2 pregnancies. In my second pregnancy my HG was so severe that I could not move without vomiting and did not keep any food or water down for 10 weeks. I was put on a feeding tube, but ultimately lost the baby in the second trimester. I am a medical scientist by training so I looked into what was known about HG. At the time, very little was known, so I decided to study it. I partnered with the Hyperemesis Education and Research Foundation (HER) and we did a survey on family history of .Hyperemesis Gravidarum that provided evidence to support a role for genes. I collected saliva samples from HG patients and their unaffected acquaintances to do a DNA study. Then I partnered with the personal genetics company, 23andMe to do a genome scan and validation study, which identified 2 genes, GDF15 and IGFBP7, linked to HG. What are the main findings?

Response: 23andMe has genotyped and collected survey data on nausea and vomiting of pregnancy in over 50,000 women.  Using this data, first we compared the DNA from women hospitalized with . Hyperemesis Gravidarum to DNA from women with no nausea and vomiting of pregnancy to look for differences. From that we found evidence that the DNA is different in HG patients around the genes GDF15 and IGFBP7. When we compared the DNA not just from pregnant women at the extreme ends of the nausea spectrum, but at all levels from none, slight, moderate, severe, to very severe nausea and vomiting, again, significant differences were found in the DNA around GDF15 and IGFBP7. We then tested these DNA differences around GDF15 and IGFBP7 in the separate set of patients, the patients I collected with HG treated by intravenous fluids, and compared them to those in patients with none or normal nausea and vomiting of pregnancy. The variation around GDF15 and IGFBP7 was confirmed in this separate set of patients, validating the findings from the 23andMe dataset. What should readers take away from your report?

Response: We found two genes that are involved in the development of the placenta and play a role in appetite are associated with Hyperemesis Gravidarum. Interestingly, GDF15 and IGFBP7 have already been shown to play a role in cachexia, a condition that is characterized by similar symptoms to HG, loss of appetite and muscle wasting. Cachexia kills 20% of cancer patients. Therefore inhibitors of this protein are currently being developed by several groups and have already proven to improve appetite in mice. Therefore, I am very hopeful that our findings will lead to novel therapies to treat .Hyperemesis Gravidarum, if they are safe in pregnancy. What recommendations do you have for future research as a result of this work?

Response: The next step is to determine whether the levels of GDF15 and IGFBP7 are abnormal in HG patients. We have already shown that and presented it at the ICHG conference last October, but we need researchers to focus on looking at GDF15 and IGFBP7 at different time points during pregnancy (our study was done at 12 weeks gestation). Then we can focus on identifying new and safe therapies that adjust the levels of these proteins/pathways during pregnancy. There are also other potential genes identified in the GWAS that were not tested for replication. Research should focus on replicating the findings in different populations and validating the additional targets. Is there anything else you would like to add? 

Response: This study should put an end to the unfortunate misconception that Hyperemesis Gravidarum is “all in your head” which has resulted in poor treatment, contributed to adverse maternal and fetal outcomes, and caused therapeutic termination in some women with HG.

The study was supported, in part, by 23andMe and the participants of 23andMe who volunteered to complete an online survey. Funding came from the Hyperemesis Education and Research Foundation; the Paul and Janice B Plotkin Family Foundation; and grants from the National Cancer Institute/National Institutes of Health and the National Human Genome Research Institute. Fejzo has no disclosures, but co-authors from 23andMe own stock options in 23andMe. 


Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum

Marlena S. Fejzo, Olga V. Sazonova, J. Fah Sathirapongsasuti, Ingileif B. Hallgrímsdóttir, Vladimir Vacic, Kimber W. MacGibbon, Frederic P. Schoenberg, Nicholas Mancuso, Dennis J. Slamon, Patrick M. Mullin & 23andMe Research Team
Nature Communicationsvolume 9, Article number: 1178 (2018)
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