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

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.

SUBMITTER: Fejzo MS

PROVIDER: S-EPMC6464816 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Fejzo Marlena Schoenberg MS Myhre Ronny R Colodro-Conde Lucía L MacGibbon Kimber W KW Sinsheimer Janet S JS Reddy M V Prasad Linga MVPL Pajukanta Päivi P Nyholt Dale R DR Wright Margaret J MJ Martin Nicholas G NG Engel Stephanie M SM Medland Sarah E SE Magnus Per P Mullin Patrick M PM

Molecular and cellular endocrinology 20160920

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 e ...[more]

PMID: 27663074

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Project description:BACKGROUND:Nausea and vomiting occur 50-90% during the first trimester of pregnancy. However, patients with hyperemesis gravidarum (HG) may be hospitalized at an incidence rate of 0.8-2% before the 20th week of gestational age. The symptoms generally start during the 5-6th gestational weeks, reaching the highest degree during the 9th week, and decline after the 16-20th weeks of gestation. Clinical findings are proportional to the severity of the disease and severe HG is characterized with dehydration, electrolyte imbalance, and nutritional deficiency as a result of vomiting. METHODS:The study population consisted of two groups of pregnant volunteers at 5-12?weeks of gestation: a severe HG group and a control group. The HG severity was scored using the Pregnancy-Unique Quantification of Emesis (and nausea) (PUQE).The serum levels of the maternal Ca, parathyroid hormone (PTH), Na, K, blood urea nitrogen(BUN), creatinine, vitamin D(25OHD3), and the maternal urine NTx levels were compared between the groups. RESULTS:In total, 40 volunteers were enrolled in this study: 20 healthy pregnant volunteers and 20 with severe HG. There were no statistically significant differences between the maternal characteristics. The first trimester weight loss of ?5?kg was significantly higher in the severe HG group (p?<?0.001), while the control group had a significantly higher sunlight exposure ratio than the severe HG group (p?=?0.021). The urine NTx levels were significantly higher in the severe HG group (39.22?±?11.68NTx/Cre) than in the control group(32.89?±?8.33NTx/Cre) (p?=?0.028).The serum Ca, PTH, Na, K, BUN, and creatinine levels were similar between the groups (p?=?0.738, p?=?0.886, p?=?0.841, p?=?0.957, p?=?0.892, and p?=?0.824, respectively). In the severe HG group, the serum 25OHD3 levels were significantly lower than in the control group (p?<?0.001). CONCLUSIONS:The data from this study indicated that severe HG is associated with increased urine NTx levels. However, large-scale studies are required to understand the clinical significance of this finding, as well as the long-term consequences of elevated urine NTx levels and the underlying mechanisms. TRIAL REGISTRATION:NCT02862496 Date of registration: 21/07/2016.

Dataset Information

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

Publications

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

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