Genome-wide association study of nausea and vomiting during pregnancy in Japan: the TMM BirThree Cohort Study.

BACKGROUND: Nausea and vomiting during pregnancy (NVP) and hyperemesis gravidarum (HG), common conditions affecting most pregnant women, are highly heritable and associated with maternal and fetal morbidity. However, the pathologies underlying NVP and HG and their associated loci are scarce. METHODS: We performed genome-wide association studies (GWAS) of NVP in pregnant women (n = 23,040) who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Japan from July 2013 to March 2017. Participants were divided into discovery (n = 9,464) and replication (n = 10,051) stages based on the platform used for their genotyping. Loci that achieved the genome-wide significance level (p < 5.0 × 10- 8) in the discovery stage were selected for genotyping in the replication stage. A meta-analysis integrating the discovery and replication stage results (n = 19,515) was conducted. NVP-related variables were identified as categorical or continuous. RESULTS: GWAS analysis in the discovery phase revealed loci linked to NVP in two gene regions, 11q22.1 (rs77775955) and 19p13.11 (rs749451 and rs28568614). Loci in these two gene regions have also been shown to be associated with HG in a White European population, indicating the generalizability of the GWAS analyses conducted in this study. Of these, only rs749451 and rs28568614 at 19p13.11 reached the genome-wide suggestive level (p < 1.0 × 10- 5) in the replication stage; however, both loci were significant in the meta-analysis. CONCLUSIONS: NVP-related loci were identified in the Japanese population at 11q22.1 and 19p13.11, as reported in previous GWAS. This study contributes new evidence on the generalizability of previous GWAS on the association between genetic background and NVP.

Vitamin D and hyperemesis gravidarum: A mendelian randomization study.

BACKGROUND: The causality between vitamin D and hyperemesis gravidarum remains unknown. Our aim was to investigate the causal effect of vitamin D on hyperemesis gravidarum using the two-sample Mendelian randomization method. METHODS: Independent single nucleotide polymorphisms significantly associated with serum 25-hydroxyvitamin D levels served as instrumental variables. The corresponding effect estimates for hyperemesis gravidarum were obtained from the Finngen Biobank. For Mendelian randomization analysis, inverse variance weighting was used as the primary method. We also used weighted median, MR-Egger regression, simple mode, and weighted mode as complementary methods to inverse variance weighting. The MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis were performed to assess the horizontal pleiotropy, heterogeneity, and stability of the causal association between 25-hydroxyvitamin D levels and hyperemesis gravidarum. RESULTS: We found that an increase in 25-hydroxyvitamin D level was associated with a lower risk of hyperemesis gravidarum [odds ratio (OR): 0.568, 95 % CI: 0.403-0.800, p = 0.001]. The result demonstrates the causal relationship between 25-hydroxyvitamin D level and the risk of hyperemesis gravidarum in the European population. CONCLUSIONS: The large Mendelian randomization analysis suggests that vitamin D may be causally associated with risk of hyperemesis gravidarum.

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

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.

Concentrations of prealbumin and some appetite-controlling hormones in pregnancies associated with hyperemesis gravidarium.

Background Hyperemesis gravidarum, which affects 0.3-2.3% of pregnancies, is defined as excessive vomiting during pregnancy and usually starts in week 4 or 5 of gestation. Symptoms include weight loss, dehydration, ketonaemia, ketonuria, fasting acidosis, alkalosis due to hydrochloric acid loss and hypokalaemia and its exact cause is unknown. The present study was undertaken to investigate the relationship between prealbumin, ghrelin, nesfatin-1 and obestatin concentrations in pregnancies associated with hyperemesis gravidarum. Methods A total of 40 pregnant females with hyperemesis gravidarum and 38 pregnant females without hyperemesis gravidarum as controls were included in this study. Serum concentrations of prealbumin, ghrelin, obestatin and nesfatin-1 were measured. Results There were no significant differences in age, gestational week, gravidity and parity between the two groups. Body mass index was significantly lower in cases than in controls. Serum ghrelin and prealbumin concentrations were significantly lower in cases than in controls ( P <0.05 and P < 0.001, respectively). There was no significant difference in serum concentrations of obestatin and nesfatin-1 between the two groups. There was no significant association between body mass index and serum ghrelin, nesfatin-1, obestatin or prealbumin concentrations in patients with hyperemesis gravidarum. Conclusions Decreased serum concentrations of ghrelin and prealbumin in patients with hyperemesis gravidarum are independent of body mass index. Based on our results, we believe that ghrelin may be considered to play a role in the aetiopathogenesis of hyperemesis gravidarum and that hyperemesis gravidarum may result in disruption of the relationship between nesfatin-1 and ghrelin. In addition, we believe that the measurement of serum prealbumin may be used for assessing nutritional status in pregnancy.

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

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.

No increased risk of psychological/behavioral disorders in siblings of women with hyperemesis gravidarum (HG) unless their mother had HG.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, is characterized by prolonged maternal stress, undernutrition and dehydration. Maternal stress and malnutrition of pregnancy are linked to poor neonatal outcome and associated with poor adult health, and we recently showed that in utero exposure to HG may lead to increased risks of psychological and behavioral disorders in the offspring. In addition, we have shown familial aggregation of HG, which is strong evidence for a genetic component to the disease. In this study, we compare the rates of psychological and behavioral disorders in 172 adults with and 101 adults without a sibling with HG. The rate of emotional/behavioral disorders is identical (15%) in both groups. The results suggest that the etiology of HG is not likely to include genetic factors associated with emotional and behavioral disorders. In addition, this study provides evidence that the increased incidence of psychological/behavioral disorders among offspring of women with HG is attributable to the HG pregnancy itself, rather than to confounding genetic factors linked to HG.

Familial aggregation of hyperemesis gravidarum.

OBJECTIVE: This study was undertaken to determine whether there is familial aggregation of hyperemesis gravidarum (HG), making it a disease amenable to genetic study. STUDY DESIGN: Cases with severe nausea and vomiting in a singleton pregnancy treated with intravenous hydration and unaffected friend controls completed a survey regarding family history. RESULTS: Sisters of women with HG have a significantly increased risk of having HG themselves (odds ratio, 17.3; P = .005). Cases have a significantly increased risk of having a mother with severe nausea and vomiting; 33% of cases reported an affected mother compared to 7.7% of controls (P < .0001). Cases reported a similar frequency of affected second-degree maternal and paternal relatives (18% maternal lineage, 23% paternal lineage). CONCLUSION: There is familial aggregation of HG. This study provides strong evidence for a genetic component to HG. Identification of the predisposing gene(s) may determine the cause of this poorly understood disease of pregnancy.

Recurrence of hyperemesis gravidarum across generations: population based cohort study.

OBJECTIVE: To estimate the risk of hyperemesis gravidarum (hyperemesis) according to whether the daughters and sons under study were born after pregnancies complicated by hyperemesis. DESIGN: Population based cohort study. SETTING: Registry data from Norway. PARTICIPANTS: Linked generational data from the medical birth registry of Norway (1967-2006): 544 087 units of mother and childbearing daughter and 399 777 units of mother and child producing son. MAIN OUTCOME MEASURE: Hyperemesis in daughters in mother and childbearing daughter units and hyperemesis in female partners of sons in mother and child producing son units. RESULTS: Daughters who were born after a pregnancy complicated by hyperemesis had a 3% risk of having hyperemesis in their own pregnancy, while women who were born after an unaffected pregnancy had a risk of 1.1% (unadjusted odds ratio 2.9, 95% confidence interval 2.4 to 3.6). Female partners of sons who were born after pregnancies complicated by hyperemesis had a risk of 1.2% (1.0, 0.7 to 1.6). Daughters born after a pregnancy not complicated by hyperemesis had an increased risk of the condition if the mother had hyperemesis in a previous or subsequent pregnancy (3.2 (1.6 to 6.4) if hyperemesis had occurred in one of the mother's previous pregnancies and 3.7 (1.5 to 9.1) if it had occurred in a later pregnancy). Adjustment for maternal age at childbirth, period of birth, and parity did not change the estimates. Restrictions to firstborns did not influence the results. CONCLUSIONS: Hyperemesis gravidarum is more strongly influenced by the maternal genotype than the fetal genotype, though environmental influences along the maternal line cannot be excluded as contributing factors.

Patients with a history of hyperemesis gravidarum have similar symptoms during egg stimulation and develop ovarian hyperstimulation syndrome: case series.

OBJECTIVE: To investigate the symptoms and outcomes of ovarian stimulation in patients with a history of hyperemesis gravidarum. DESIGN: Retrospective case series. SETTING: Research laboratory of a university hospital. PATIENT(S): Participants in an ongoing study on hyperemesis gravidarum that reported ovarian stimulation for gestational surrogacy. INTERVENTION(S): Review of medical records. MAIN OUTCOME MEASURE(S): Pregnancy history, symptoms, estradiol level and mature oocyte number in cases, and nausea and vomiting level reported in surrogate. RESULT(S): Three cases in their early thirties with a history of hyperemesis gravidarum presented with severe nausea and vomiting during ovarian stimulation and ovarian hyperstimulation syndrome. Gestational carriers reported normal nausea and vomiting of pregnancy. CONCLUSION(S): This series provides lessons for in vitro fertilization for cases with a history of hyperemesis gravidarum and their gestational carriers as well as insight into the cause of hyperemesis gravidarum and its potential role in fertility. A link between hyperemesis gravidarum and an evolutionary advantage of increased fertility suggests a novel theory to explain the selection for nausea and vomiting in pregnancy.

High prevalence of severe nausea and vomiting of pregnancy and hyperemesis gravidarum among relatives of affected individuals.

OBJECTIVE: The goal of this study was to determine the prevalence of severe nausea and vomiting of pregnancy/hyperemesis gravidarum among relatives of affected individuals. STUDY DESIGN: Family history data were obtained on 1224 self-reported cases of hyperemesis gravidarum. Cases completed an online survey administered by the Hyperemesis Education and Research Foundation between 2003 and 2006. RESULTS: Approximately 28% of cases reported their mother had severe nausea and vomiting or hyperemesis gravidarum while pregnant with them. Of the 721 sisters with a pregnancy history, 137 (19%) had hyperemesis gravidarum. Among the most severe cases, those requiring total parenteral nutrition or nasogastric feeding tube, the proportion of affected sisters was even higher, 49/198 (25%). Nine percent of cases reported having at least two affected relatives including sister(s), mother, grandmother, daughters, aunt(s), and cousin(s). CONCLUSION: There is a high prevalence of severe nausea and vomiting of pregnancy/hyperemesis gravidarum among relatives of hyperemesis gravidarum cases in this study population. Because the incidence of hyperemesis gravidarum is most commonly reported to be 0.5%, this study provides strong but preliminary evidence for a genetic component to extreme nausea and vomiting of pregnancy.

Consanguinity and the risk of hyperemesis gravidarum in Norway.

BACKGROUND: Hyperemesis gravidarum (HG) is a condition that occurs in the first half of pregnancy, and is manifested by severe vomiting, electrolyte disturbances and weight loss. Previous studies have suggested the potential role of genetic factors in the aetiology of HG. We hypothesise that consanguineous relations between parents increase the risk of HG due to the increased risk of homozygosity in HG-associated alleles in a fetus. Moreover, we examine whether ethnic variations in the occurrence of HG can be attributed to consanguinity. METHODS: All Norwegian, Pakistani and Turkish primiparous women with singleton pregnancies registered in the Norwegian Medical Birth Registry (MBRN) from 1967 to 2005 comprised the sample. Data on HG and potential confounders were obtained from MBRN. Multiple logistic regression was used to study associations between the degrees of relationship between women and their partners and the prevalence of HG. Crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: The prevalence of HG was 0.9, 2.2 and 1.9% in Norwegian, Pakistani and Turkish women, respectively. Norwegian (OR =0.93; 95% CI: 0.42-2.09), Pakistani (OR =1.08; 95% CI: 0.68-1.74) and Turkish (OR =1.08; 95% CI: 0.44-2.67) women related to their partners as first cousins had similar risks of HG as non-related women after adjustment for potential confounders. CONCLUSIONS: Consanguinity was not associated with HG in this study. The differences in the occurrence of HG between Norwegian, Pakistani and Turkish women are not attributed to consanguinity.

Abnormal stimulation of the thyrotrophin receptor during gestation.

Pregnancy induces physiological alterations in thyroid function which may make difficult the interpretation of results of thyroid hormone measurement. A state of hyperstimulation of the thyroid gland is common in early pregnancy. In a few cases, thyroid hormone values will deviate from the normal range, which corresponds to the gestational transient thyrotoxicosis. This syndrome is closely associated with hyperemesis gravidarum. The relationship between the two syndromes, demonstrated by epidemiological studies, has been illustrated by an exceptional case of familial recurrent gestational thyrotoxicosis presenting as hyperemesis gravidarum due to hypersensitivity of the thyrotrophin receptor to hCG. However, the exact mechanisms of hyperemesis gravidarum have not yet been identified. Gestational transient thyrotoxicosis has to be distinguished from Graves' disease, because the latter is associated with potential maternal and fetal complications when thyrotoxicosis is not controlled, whereas the former has usually a favourable outcome. The existence of other cases of thyroid hypersensitivity or hCG endowed with abnormal thyrotrophic activity is suspected. They may be identified only by assessment of the thyroid function in cases of hyperemesis gravidarum. The identification of these cases would be helpful to understand the mechanisms of specificity of glycoprotein hormone receptors.