905: Hormone receptor genes PGR and GFRAL linked to hyperemesis gravidarum


      Most pregnancies are complicated by nausea and vomiting of pregnancy (NVP) and 18% of women with NVP require medication. The severest form of NVP, Hyperemesis Gravidarum (HG), occurs in 2% of pregnant women. It accounts for 285,000 hospitalizations in the US annually and can cause brain, renal, and liver dysfunction, esophageal rupture, and post-partum post-traumatic stress. HG is associated with a 4-fold increased risk of adverse fetal outcome including low birth weight, preterm birth, and a 3-fold increased risk of neurodevelopmental delay. It is highly heritable. Our recent genome-wide association (GWAS) and replication study identified the placenta, appetite, and cachexia genes GDF15 and IGFBP7 as being associated with HG.
      Objective: In our GWAS study, hormone receptor genes PGR and GFRAL were also found to be significant. We performed a replication study to validate the genome-wide association linking PGR and GFRAL to HG.

      Study Design

      Study design: DNA from 789 women treated for HG and 606 women with normal or no nausea and vomiting of pregnancy were genotyped using a Taqman platform. Genotypes of risk alleles for PGR and GFRAL were compared between cases and controls using


      Results: Risk alleles for PGR and GFRAL were significantly associated with HG (Table 1).
      TABLE 1. Replication results confirm the PGR and GFRAL associations with HG published previously
      Figure thumbnail fx1
      Ns are based on total participants successfully genotyped.


      Conclusion: Evidence suggests abnormal levels of the hormone GDF15 are associated with HG. Validation of the GDF15 receptor gene GFRAL as a genetic risk factor for HG provides further support that the GDF15-GFRAL pathway is involved in disease etiology. Additionally, the progesterone receptor PGR, like GDF15, plays a role in the developing placenta and gastrointestinal mobility. Our findings validate PGR as a genetic risk factor for HG. GDF15 inhibitors have proven successful in restoring body weight and appetite in animal models of cachexia, making this a promising strategy for treating NVP and HG. Therapeutics targeting GFRAL and PGR should also be investigated.