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CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2018; 78(09): 866-870
DOI: 10.1055/a-0661-0287
GebFra Science
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Evidence GDF15 Plays a Role in Familial and Recurrent Hyperemesis Gravidarum

GDF15 spielt eine Rolle bei erblicher und wiederkehrender Hyperemesis gravidarum
Marlena S. Fejzo
1   Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
2   Department of Maternal-Fetal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
,
Daria Arzy
1   Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
,
Rayna Tian
1   Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
,
Kimber W. MacGibbon
3   Hyperemesis Education and Research Foundation, Damascus, OR, USA
,
Patrick M. Mullin
2   Department of Maternal-Fetal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
› Author Affiliations
Further Information

Publication History

received 13 July 2018
revised 18 July 2018

accepted 18 July 2018

Publication Date:
14 September 2018 (online)

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Abstract

Introduction Hyperemesis gravidarum (HG), a pregnancy complication characterized by severe nausea and vomiting in pregnancy, occurs in up to 2% of pregnancies. It is associated with both maternal and fetal morbidity. HG is highly heritable and recurs in approximately 80% of women. In a recent genome-wide association study, it was shown that placentation, appetite, and the cachexia gene GDF15 are linked to HG. The purpose of this study was to explore whether GDF15 alleles linked to overexpression of GDF15 protein segregate with the condition in families, and whether the GDF15 risk allele is associated with recurrence of HG.

Methods We analyzed GDF15 overexpression alleles for segregation with disease using exome-sequencing data from 5 HG families. We compared the allele frequency of the GDF15 risk allele, rs16982345, in patients who had recurrence of HG with its frequency in those who did not have recurrence.

Results Single nucleotide polymorphisms (SNPs) linked to higher levels of GDF15 segregated with disease in HG families. The GDF15 risk allele, rs16982345, was associated with an 8-fold higher risk of recurrence of HG.

Conclusion The findings of this study support the hypothesis that GDF15 is involved in the pathogenesis of both familial and recurrent cases of HG. The findings may be applicable when counseling women with a familial history of HG or recurrent HG. The GDF15-GFRAL brainstem-activated pathway was recently identified and therapies to treat conditions of abnormal appetite are under development. Based on our findings, patients carrying GDF15 variants associated with GDF15 overexpression should be included in future studies of GDF15-GFRAL-based therapeutics. If safe, this approach could reduce maternal and fetal morbidity.

Zusammenfassung

Einleitung Hyperemesis gravidarum (HG), das übermäßige und anhaltende Erbrechen während der Schwangerschaft, kommt in 2% aller Schwangerschaften vor. Sie geht mit einer Erhöhung der mütterlichen und der fetalen Morbidität einher. HG ist stark vererbbar und tritt bei ungefähr 80% aller betroffenen Frauen erneut auf. In einer kürzlich durchgeführten genomweiten Assoziationsstudie konnte gezeigt werden, dass es einen Zusammenhang zwischen Plazentation, Appetit, dem Kachexie-Gen GDF15 und HG gibt. Unsere Studie wollte untersuchen, ob GDF15-Allele, die mit einer Überexpression des GDF15-Proteins einhergehen, sich in Familien zusammen mit HG vererben, und ob das GDF15-Risikoallel mit wiederkehrender HG assoziiert ist.

Methoden Die Exom-Sequenzierungsdaten von 5 Familien mit HG wurden dahingehend analysiert, ob in diesen Familien auch das GDF15-Überexpressions-Allel vererbt wurde. Die Häufigkeit des GDF15-Risikoallels rs16982345 bei Patientinnen mit wiederkehrender HG wurde mit der Häufigkeit bei Frauen ohne wiederkehrende HG verglichen.

Ergebnisse SNPs, die im Verbund mit größeren Mengen an GDF15 auftraten, vererbten sich gemeinsam mit HG in von HG betroffenen Familien. Das GDF15-Risikoallel rs16982345 ging mit einem 8-fach höheren Risiko für das Wiederauftreten von HG einher.

Schlussfolgerung Die Ergebnisse dieser Studie sprechen dafür, dass GDF15 an der Pathogenese von erblicher sowie wiederkehrender HG beteiligt ist. Das Wissen um diesen Zusammenhang könnte bei der Beratung von Frauen mit erblicher oder wiederkehrender HG von Nutzen sein. Vor Kurzem wurde der hirnstammaktivierte GDF15-GFRAL-Weg identifiziert, und es wird aktuell an Therapien zur Behandlung von abnormem Appetitverlust gearbeitet. Gestützt auf die Ergebnisse unsere Untersuchung sollten Patientinnen mit GDF15-Varianten, die mit der Überexpression von GDF15 assoziiert sind, an zukünftigen Studien zu GDF15-GFRAL-gestützten Therapeutika teilnehmen. Sollten sich diese als sicher erweisen, könnte das ein Weg sein, um die HG-bedingte mütterliche und fetale Morbidität zu verringern.

Key words

hyperemesis gravidarum - nausea and vomiting of pregnancy - GDF15 - GFRAL - genetic

Schlüsselwörter

Hyperemesis gravidarum - Schwangerschaftsübelkeit und -erbrechen - GDF15 - GFRAL - genetisch
 

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