A 2005 study showed that women with a first-degree relative who had a pre-eclamptic birth are twice as likely to develop it themselves. Furthermore, men related to someone with affected birth have an increased risk of fathering a pre-eclamptic pregnancy. Fetuses affected by pre-eclampsia have a higher chance of later pregnancy complications including growth restriction, prematurity, and stillbirth.The onset of pre-eclampsia is thought to be caused by several complex interactions between genetics and environmental factors. Our current understanding of the specifically heritable cause involves an imbalance of angiogenic factors in the placenta. Angiogenesis involves the growth of new blood vessels from existing vessels, and an imbalance during pregnancy can affect the vascularization, growth, and biological function of the fetus. The irregular expression of these factors is thought to be controlled by multiple loci on different chromosomes. Research on the topic has been limited because of the heterogeneous nature of the disease. Maternal, paternal, and fetal genotypes all play a role as well as complex epigenetic factors such as whether the parents smoke, maternal age, sexual cohabitation, and obesity. Currently, there is very little understanding behind the mechanisms of these interactions. Due to the polygenic nature of pre-eclampsia, a majority of the studies that have been conducted thus far on the topic have utilized genome-wide association studies.One known effector of pre-eclampsia is the fetal loci FLT1. Located on chromosome 13 in the q12 region, FLT1 codes for Fms-like tyrosine kinase 1, an angiogenic factor expressed in fetal trophoblasts.
Furthermore, ZNF831 (zinc finger protein 831) and its loci on chromosome 20q13 were identified as another significant factor in pre-eclampsia. The risk allele rs259983 is also associated with both pre-eclampsia and hypertension, further evidence that the two traits are possibly linked. While the current understanding suggests that maternal alleles are the main hereditary cause of pre-eclampsia, paternal loci have also been implicated. In one study, paternal DLX5 (Distal-Less Homeobox 5) was identified as an imprinted gene. Located on chromosome 7 in the q21 region, DLX5 serves as a transcription factor often linked with the developmental growth of organs. When paternally inherited, DLX5 and its SNP rs73708843 are shown to play a role in trophoblast proliferation, affecting vascular growth and nutrient delivery.Besides specific loci, several important genetic regulatory factors contribute to the development of pre-eclampsia. Micro RNAs, or miRNAs, are noncoding mRNAs that down-regulate posttranscriptional gene expression through RNA-induced silencing complexes. In the placenta, miRNAs are crucial for regulating cell growth, angiogenesis, cell proliferation, and metabolism. These placental-specific miRNAs are clustered in large groups, mainly on chromosomes 14 and 19, and irregular expression of either is associated with an increased risk of an affected pregnancy. For instance, miR-16 and miR-29 are vascular endothelial growth factors (VEGFs) and play a role in upregulating sFLT-1. In particular, the overexpression of miRNA miR-210 has been shown to induce hypoxia, which affects spiral artery remodeling, an important part of the pathogenesis of pre-eclampsia.