NEW YORK (GenomeWeb) – A genome-wide association study published online today in Nature Communications suggests an extreme form of nausea and vomiting during pregnancy known as hyperemesis gravidarum (HG) may stem from alterations in pathways that mediate placenta formation and appetite, rather than genes involved in pregnancy-related hormone pathways.
Researchers from the University of California at Los Angeles, the University of Southern California, 23andMe, and elsewhere tapped into data from 23andMe participants consented for research, comparing array- and imputation-based genotyping profiles from thousands of women with or without severe nausea and vomiting of pregnancy (NVP).
By comparing relatively nausea-free pregnancies with those requiring intravenous fluid for extreme sickness, the team identified two hyperemesis gravidarum candidate loci on chromosomes 4 and 19 that coincided with IGFBP7 and GDF15 genes implicated in appetite and placenta formation, as well as a chronic form of weakness and body wasting called cachexia. The associations were supported through replication testing on thousands more women from 23andMe and other studies, including those diagnosed with HG.
"It has long been assumed that the pregnancy hormones, human chorionic gonadotropin or estrogen, were the likely culprits of extreme nausea and vomiting, but our study found no evidence to support this," first and corresponding author Marlena Fejzo, a hematology and oncology researcher affiliated with UCLA and USC, said in a statement.
Past studies indicate that up to 2 percent of pregnancy may be affected by HG — a condition that gained attention during Kate Middleton's illness-prone pregnancies and claimed the life of writer Charlotte Brontë, according to some accounts. Since effective prevention and treatment strategies for HG are lacking, the team delved into the genetic underpinnings of HG and NVP in an effort to understand and eventually mitigate their negative effects on maternal and fetal health.
"While the absence of NVP is associated with a higher risk of miscarriage," the authors wrote, "having the most severe form of nausea and vomiting (HG) is also associated with poor fetal outcomes including preterm birth, neurodevelopmental delay, and vitamin K deficient embryopathy."
For the first stage of the study, the researchers focused on self-reported NVP in female 23andMe participants, comparing SNP patterns that were imputed or directly genotyped using custom Illumina arrays in 1,306 women treated with fluids by IV due to extreme NVP and 15,756 women who did not experience NVP.
After focusing in on the top two loci at chromosomes 4 and 19 in this cohort, the team compared SNP patterns in 53,731 more female 23andMe participants who described their NVP severity as slight, moderate, severe, very severe, or non-existent — an analysis that again led to the chromosome 4 region in and around IGFBP7 and GDF15 on chromosome 19.
Ties to the genes were further shored up through analyses on two replication cohorts, the researchers reported. One group was comprised of 789 women with IV-treated HG and 581 women who experienced NVP but did not require treatment, while another included 103 women who received "total parenteral nutrition" treatment for HG and 143 controls who were reportedly NVP-free over two or more pregnancies.
The team saw further support for these associations through Taqman-based genotyping in the replication cohorts, though the variants profiled did not reach genome-wide significance.
By digging into the sites further using expression, regulatory clues, and in silico functional analyses, the researchers earmarked GDF15 and IGFBP7 as the most suspicious genes at the loci, highlighting potential ties between HG, NVP, and pathways related to processes including placentation, appetite regulation, and chronic wasting.
"Since GDF15 and IGFBP7 levels are up-regulated during placentation and cachexia, and down-regulated prior to miscarriage, serum concentrations of GDF15 and IGFBP7 should now be studied in pregnant women with or without HG," the authors wrote. "If GDF15 and IGFBP7 prove to be relevant, it is conceivable that drugs targeting these proteins may have clinical utility in treating HG."