Genetic analysis of hyperemesis gravidarum reveals association with intracellular calcium release channel (RYR2)

Mol Cell Endocrinol. 2017 Jan 5:439:308-316. doi: 10.1016/j.mce.2016.09.017. Epub 2016 Sep 20.

Abstract

Hyperemesis Gravidarum (HG), severe nausea/vomiting in pregnancy (NVP), can cause poor maternal/fetal outcomes. Genetic predisposition suggests the genetic component is essential in discovering an etiology. We performed whole-exome sequencing of 5 families followed by analysis of variants in 584 cases/431 controls. Variants in RYR2 segregated with disease in 2 families. The novel variant L3277R was not found in any case/control. The rare variant, G1886S was more common in cases (p = 0.046) and extreme cases (p = 0.023). Replication of G1886S using Norwegian/Australian data was supportive. Common variants rs790899 and rs1891246 were significantly associated with HG and weight loss. Copy-number analysis revealed a deletion in a patient. RYR2 encodes an intracellular calcium release channel involved in vomiting, cyclic-vomiting syndrome, and is a thyroid hormone target gene. Additionally, RYR2 is a downstream drug target of Inderal, used to treat HG and CVS. Thus, herein we provide genetic evidence for a pathway and therapy for HG.

Keywords: Hyperemesis gravidarum; Nausea; Pregnancy; RYR2; Vomiting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Australia
  • Calcium / metabolism*
  • Cohort Studies
  • Exome / genetics
  • Family
  • Female
  • Gene Deletion
  • Gene Dosage
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Hyperemesis Gravidarum / genetics*
  • Intracellular Space / metabolism*
  • Male
  • Norway
  • Parenteral Nutrition
  • Pedigree
  • Pregnancy
  • Ryanodine Receptor Calcium Release Channel / genetics*
  • Sequence Analysis, DNA
  • United States

Substances

  • Ryanodine Receptor Calcium Release Channel
  • Calcium