Evidence GDF15 Plays a Role in Familial and Recurrent Hyperemesis Gravidarum

Abstract

Introduction Hyperemesis gravidarum (HG), a pregnancy complication characterized by severe nausea and vomiting in pregnancy, occurs in up to 2% of pregnancies. It is associated with both maternal and fetal morbidity. HG is highly heritable and recurs in approximately 80% of women. In a recent genome-wide association study, it was shown that placentation, appetite, and the cachexia gene GDF15 are linked to HG. The purpose of this study was to explore whether GDF15 alleles linked to overexpression of GDF15 protein segregate with the condition in families, and whether the GDF15 risk allele is associated with recurrence of HG. Methods We analyzed GDF15 overexpression alleles for segregation with disease using exome-sequencing data from 5 HG families. We compared the allele frequency of the GDF15 risk allele, rs16982345, in patients who had recurrence of HG with its frequency in those who did not have recurrence. Results Single nucleotide polymorphisms (SNPs) linked to higher levels of GDF15 segregated with disease in HG families. The GDF15 risk allele, rs16982345, was associated with an 8-fold higher risk of recurrence of HG. Conclusion The findings of this study support the hypothesis that GDF15 is involved in the pathogenesis of both familial and recurrent cases of HG. The findings may be applicable when counseling women with a familial history of HG or recurrent HG. The GDF15-GFRAL brainstem-activated pathway was recently identified and therapies to treat conditions of abnormal appetite are under development. Based on our findings, patients carrying GDF15 variants associated with GDF15 overexpression should be included in future studies of GDF15-GFRAL-based therapeutics. If safe, this approach could reduce maternal and fetal morbidity.

Keywords: GDF15; GFRAL; genetic; hyperemesis gravidarum; nausea and vomiting of pregnancy.

Fig. 1

Three of five HG families show segregation of alleles at GDF15 locus associated with increased expression of GDF15. The index case is labeled with an “A” in each family. a  Family 1 is of English/Irish/Swedish/Welsh descent. Case 1A reported IV fluid, total parenteral nutrition, antiemetic medication, home health care, and a > 5% weight loss due to HG. Her cousin (1B) reported normal NVP with no weight loss and no medication to treat NVP. Her aunt (1C) reported antiemetic medication and weight loss due to HG, and her great aunt (1D) reported antiemetic medication and unrelenting nausea that kept her bedridden for 6 months due to HG. b  Family 2 is of English/German/Scottish/Irish descent. Case 2A reported IV fluid, hospitalization, > 5% weight loss, and antiemetic medication to treat her HG. Her aunt (2B) reported IV fluid, hospitalization, weight loss, and antiemetic medication to treat her HG. Her cousin (affected auntʼs daughter, [2C]) reported antiemetic medication and a 24-pound weight loss in the first trimester due to HG. Participant 2F, the unaffected sister of 2C, reported 2 easy pregnancies with no weight loss nor treatment for NVP. c  Family 3 is of English/Irish descent. Case 3A reported IV fluid, hospitalization, > 10% weight loss, and antiemetic medication to treat HG. One affected sister (3B) reported IV fluid, hospitalization, and antiemetic medication to treat HG. The other affected sister (3C) reported IV fluid, hospitalization, weight loss, and antiemetic medication to treat HG. The unaffected aunt (3E) reported mild NVP with no medication or weight loss.