GFRAL genetic variations and circulating GFRAL in hyperemesis gravidarum

Hyperemesis gravidarum, the most severe form of nausea and vomiting in pregnancy, is linked to variants in GDF15 and its receptor GFRAL . This study combined exome and targeted sequencing, genotyping, immunoassays, and clinical data to characterize GFRAL sequence variation and circulating soluble GFRAL (sGFRAL) in pregnancy. Rare GFRAL variants were identified in patients with hyperemesis gravidarum and in asymptomatic pregnancies. A common variant was associated with symptoms persisting beyond 27 weeks' gestation. sGFRAL was frequently detectable in early pregnancy, with dynamic changes across gestation and inverse correlation with weight loss, and subsequently more common in hyperemesis gravidarum. In silico promoter analysis suggested progesterone-dependent repression of GFRAL transcription, concordant with sGFRAL downregulation in controls after week 6. In contrast, women with hyperemesis gravidarum maintained soluble receptor levels. These findings implicate genetic and post-translational regulation of GFRAL in pregnancy sickness and support further evaluation of sGFRAL as a biomarker and mechanistic readout.