Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum

Abstract

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3–2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10−8) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease.

Hyperemesis Gravidarum

“…Additionally, 9% of participants reported having 2 affected family members . A subsequent study by this group identified 2 potential candidate genes, GDF15 and IGFBP7, both of which have roles in early pregnancy which may be implicated in HG …”

Recurrence patterns of hyperemesis gravidarum

“…The lower odds of recurring HG Original Research OBSTETRICS ajog.org associated with smoking is presumably due to its effect on the placenta, for instance inhibiting healthy placental growth and possibly affecting placental proteins that may play a role in HG, such as GDF15 and IGFBP7. 14,21,22 In the univariate analysis, municipality of residence appeared to have an effect on recurring HG: women living in bigger communities experienced recurrent HG more often than women living in smaller communities. However, this finding disappeared in the multivariable analysis.…”

“…14,22 The role of hCG levels in HG remains unclear with statistical evidence both for and against the hypothesis that hCG, or individual susceptibility to hCG, or some of its biochemical isoforms, may cause or aggravate symptoms of HG in some women. 16,23 A detailed analysis of 4372 pregnancies after in vitro fertilization did not show any association between hCG levels and HG 24 and in the light of new evidence that other placental genes may be involved in development of HG, 21 the association between HG and hCG levels may turn out to be incidental. Further studies are needed to fully understand these associations.…”

“…The study group may thus have differed from the general population and possible bias toward overestimation of the recurrence cannot be excluded, or, since their study was small (57 pregnancies after an earlier hyperemetic pregnancy), the difference may stem from general variation. The discovery of potential HG-associated candidate genes 21 has provided a new element for predicting recurrence of HG. For instance, the G allele of the gene GDF15 is more frequently found among HG patients compared to symptom-free women (approximately 80% vs 70%), as well as the A allele of the gene IGFBP7 (approximately 70% vs 65%), and thus examining these associations in the context of recurring hyperemesis will be of interest; in theory, recurrence of hyperemesis may be more common among those with a genetic predisposition to the condition.…”

Management of severe pregnancy sickness and hyperemesis gravidarum

“…Family history of HG leads to a threefold increased chance of the condition occurring among offspring 9. A genome wide association study found that genetic variants of the growth and differentiation factor 15 protein (GDF15) and insulin like growth factor binding protein 7 (IGFBP7) genes were strongly associated with NVP and HG 10. In another study, women with severe NVP symptoms who were taking anti-emetic medications in the second trimester had higher serum concentrations of GDF15 11.…”