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

      Objective

      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 medcalc.org/calc/odds_ratio.php.

      Results

      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 https://www.nature.com/articles/s41467-018-03258-0.
      Figure thumbnail fx1
      Ns are based on total participants successfully genotyped.

      Conclusion

      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.