Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Research leading to these results was conducted as part of the InterPregGen study, which received funding from the European Union Seventh Framework Programme under grant agreement no. 282540 and was supported by Wellcome Trust grant 098051. Some data used for the research were obtained from THL Biobank. We thank all study participants for their generous participation at THL Biobank. Part of this work was conducted using the UK Biobank Resource under application number 24711. A full list of acknowledgments appears in Supplementary Note 3. Publisher Copyright: © 2020, The Author(s).Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.Peer reviewe

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

: Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10(-11)) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.<br/

Disentangling fetal and maternal susceptibility for pre-eclampsia: a British multicenter candidate-gene study.

The Genetics of Pre-Eclampsia (GOPEC) collaboration aims to identify genetic factors in U.K. families affected by pre-eclampsia. A number of genetic studies have reported associations with pre-eclampsia, but attempts to replicate these findings have yielded inconsistent results. We describe the results of extensive genotyping of seven candidate genes previously reported as conferring susceptibility to pre-eclampsia. Six hundred fifty-seven women affected by pre-eclampsia and their families were genotyped at 28 single-nucleotide polymorphisms in the genes encoding angiotensinogen, the angiotensin receptors, factor V Leiden variant, methylene tetrahydrofolate reductase, nitric oxide synthase, and TNFalpha. Genotypes were analyzed by the transmission/disequilibrium test. Genotype risk ratios (GRRs) associated with maternal genotypes had a range of 0.70-1.16; GRRs associated with fetal genotypes had a range of 0.72-1.11. No GRR achieved the prespecified criteria for statistical significance (posterior probability &gt;.05). We conclude that none of the genetic variants tested in this large study of strictly defined pre-eclamptic pregnancies confers a high risk of disease. The results emphasize the importance of conducting rigorously designed studies of adequate size to provide precise genetic risks with narrow confidence intervals, if overreporting of false-positive results is to be avoided

Babies, pre-eclamptic mothers and grandparents: a three-generation phenotyping study.

OBJECTIVES: Pre-eclampsia (PE) is associated with an increased incidence of cardiovascular disease in later life. Daughters of PE mothers have an increased risk of developing the disease; recent epidemiological data suggest a (grand)paternal contribution. We have directly studied the parents of 673 women with stringently defined PE in relation to their daughters' disease. METHODS: (Grand)parental medical history, current medication and blood pressure (using an Omron 705 automated monitor) were recorded, with obstetric history for the grandmother, including directly verified pregnancy hypertension. RESULTS: The age of the 649 participating grandmothers was 55.5 +/- 7.5 years (mean +/- SD) and that of the 542 participating grandfathers was 58.0 +/- 7.3 years. Essential hypertension (EHT) requiring therapy was present in 23.4% of the grandmothers and 22.8% of the grandfathers. Patients had moderate to severe PE; a quarter were delivered before 34 weeks' gestation. A third of the babies had birthweights below the third centile; the perinatal mortality rate was 2.1%. Grandparental absolute systolic pressures and EHT status were highly significant determinants of maternal systolic pressure during gestation (F = 11.8, P &lt; 0.001; F = 8.91, P = 0.003, respectively); maternal body mass index (BMI) had less effect. A similar, less marked, pattern was seen for diastolic pressure (F = 6.01, P = 0.014; F = 11.50, P &lt; 0.0001). Grandmaternal EHT did not influence her daughter's systolic or diastolic pressure (P &gt; 0.2 for both). CONCLUSIONS: A paternal, but not maternal, history of EHT is associated with increased risks of non-pregnant hypertension in the children, the risk being greater in daughters than sons. Pregnancy may unveil or exacerbate this effect, possibly reflecting underlying endothelial vulnerability

Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis.

BACKGROUND: Pre-eclampsia is thought to have a polygenic basis, but the identification of susceptibility genes and the quantification of associated risks have been elusive owing to lack of replication from published genetic association studies. OBJECTIVE: To perform a systematic review and meta-analysis of genetic association studies to evaluate the evidence for the associations of various candidate genes with pre-eclampsia. METHODS: For inclusion, studies had to involve unrelated subjects and examine the associations between pre-eclampsia (excluding publications without a measurement of proteinuria) and any candidate variant. Authors were contacted to obtain unpublished data when necessary. A meta-analysis was conducted for all variants with three or more independent samples available. Summary odds ratios (ORs), 99% confidence intervals (CIs) and P-values were calculated using random effects models. RESULTS: Data from 192 genetic association studies met the selection criteria and were included in 25 independent meta-analyses. There was some evidence of association for F5 rs6025 (OR = 1.74; 99% CI 1.43-2.12), F2 rs1799963 (OR = 1.72; 99% CI 1.31-2.26), ACE rs4646994 (OR = 1.17; 99% CI 0.99-1.40), AGT rs699 (OR = 1.26; 99% CI 1.00-1.59) and AGTR1 rs5186 (OR = 1.22; 99% CI 0.96-1.56), but only the first two associations reached moderate epidemiological credibility. Possible bias resulting from small study size and poor reporting of individual studies were the most important factors affecting the reported associations. CONCLUSION: To date, candidate gene studies in pre-eclampsia have not robustly documented any associations with strong epidemiological credibility. Large-scale replication of the most promising associations, exhibited by two genetic variants, and incorporation of agnostic high-throughput data may improve our genetic knowledge base for this complex phenotype