Genetic Risk Factors in Preeclampsia Pathophysiology

Preeclampsia arises from a complex interplay of maternal, fetal and placental genetic influences that converge on pathways governing vascular adaptation, trophoblast invasion and immune tolerance. Familial clustering and twin studies point to heritable components, with both maternal and paternal genomes contributing to disease susceptibility. Key genetic factors include polymorphisms in the renin–angiotensin–aldosterone system (RAAS), variations in endothelial nitric oxide synthase (eNOS/NOS3) affecting nitric oxide bioavailability, mutations in coagulation genes predisposing to thrombophilia, and alterations in matrix metalloprotease genes that regulate extracellular matrix remodelling. These variants disrupt endothelial function, impair spiral artery transformation and tip the balance of angiogenic mediators toward an anti-angiogenic state. Unraveling these genetic risk factors has global significance for early screening, stratified antenatal care and the development of targeted interventions to reduce maternal and perinatal morbidity.

Research from Nature Portfolio

Recent investigations have dissected the contribution of nitric oxide synthase gene variants to preeclampsia susceptibility. A 2023 case–control study in a West African cohort demonstrated that specific eNOS polymorphisms correlate with altered circulating nitric oxide levels and confer differential risk, while a meta-analysis spanning multiple populations reaffirmed the association of G894T and T-786C NOS3 alleles with endothelial dysfunction in preeclampsia. Parallel research utilising renin–angiotensin–aldosterone system gene profiling in expectant mothers identified AGT and AGTR1 variants interacting with maternal age to modulate risk of hypertensive disorders of pregnancy.

Genetic Risk Factors in Preeclampsia Pathophysiology publication trend

The graph below shows the total number of articles in genetic risk factors in preeclampsia pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Single-nucleotide polymorphism (SNP): a variant at a single DNA base pair among individuals that may alter gene function or expression.

Endothelial dysfunction: impaired performance of the vascular endothelium in regulating vessel tone and barrier function, central to preeclampsia.

Trophoblast invasion: the process by which specialised placental cells migrate into maternal uterine tissue to establish adequate blood supply.

Renin–angiotensin–aldosterone system (RAAS): hormonal cascade controlling blood pressure and fluid balance with genetic variants influencing vascular responses in pregnancy.

Nitric oxide synthase (eNOS): enzyme producing nitric oxide, a vasodilator critical for maintaining placental blood flow.

Thrombophilia: a genetic predisposition to excessive blood clotting, often linked to mutations in coagulation factor genes.

References

1. Genetic Appraisal of RAAS-Associated SNPs: REN (rs16853055), AGT (rs3789678) and ACE (rs4305) in Preeclamptic Women Living with HIV Infection. Current Hypertension Reports (2024).
2. Association between endothelial nitric oxide synthase (eNOS) gene variants and nitric oxide production in preeclampsia: a case–control study in Ghana. Scientific Reports (2023).
3. Associations between nitric oxide synthase 3 gene polymorphisms and preeclampsia risk: a meta-analysis. Scientific Reports (2016).
4. Renin–angiotensin–aldosterone system gene polymorphisms in gestational hypertension and preeclampsia: A case–control gene-association study. Scientific Reports (2016).
5. Association between Thrombophilia Gene Polymorphisms and Preeclampsia: A Meta-Analysis. PLOS ONE (2014).
6. Association of Maternal and Fetal Single‐Nucleotide Polymorphisms in Metalloproteinase (MMP1, MMP2, MMP3, and MMP9) Genes with Preeclampsia. Disease Markers (2018).