393. InterPregGen: The discovery and validation of genetic variants associated with pre-eclampsia in mothers and babies

Abstract

30 years of molecular genetic studies of common disorders have demonstrated the need for large, well-powered studies to detect genetic variants with individually small effects on disease susceptibility; pre-eclampsia is no exception. InterPregGen is a collaboration between research groups from Europe and Central Asia seeking to identify DNA sequence variants predisposing to pre-eclampsia. The primary approach is meta-analysis of genome-wide association screening (GWAS) data from over 9000 affected mothers, 6500 offspring, and 370,000 control subjects. Variants with evidence of association with pre-eclampsia are followed-up by targeted genotyping in independent sample collections. In offspring affected by pre-eclampsia there is a highly significant association with a common variant located close to the FLT1 gene, which encodes Fms-like tyrosine kinase 1 and its soluble isoform sFlt-1 (P = 5.38 × 10 - 11 ) . The strongest association was in pregnancies with onset of pre-eclampsia after 34 weeks gestation. Investigation of the maternal genome in pre-eclampsia has highlighted associations with multiple DNA variants which also have confirmed associations with essential hypertension in non-pregnant individuals. In a further 2800 women with non-proteinuric gestational hypertension there is a similar profile of susceptibility variants shared with essential hypertension and pre-eclampsia. Typical of many common complex disorders, there is no single ‘pre-eclampsia gene’. Current parental or fetal genotype data do not enable prediction of preeclampsia in individual pregnancies. However, the results highlight specific biological pathways responsible for pre-eclampsia’s aetiology. Larger studies are essential to identify additional variants and other pathways affecting pre-eclampsia. The genetic findings justify targeted investigation of FLT1 regulation in the placenta, and indicate that raised sFlt-1 has a causal role in pre-eclampsia, and is not just a consequence of the disease. Maternal genotyping results confirm a pathophysiological overlap between essential hypertension, gestational hypertension and pre-eclampsia, and emphasise the imperative for long-term cardiovascular monitoring of women with a history of hypertension in pregnancy.