Hypomethylation of the Soluble Fms-like Tyrosine Kinase 1 (sFlt-1) Gene Promoter Region and Elevated sFlt-1 Placental Expression as Risk Factors for Preeclampsia

Anak Agung Ngurah Jaya Kusuma (Maternal Fetal Medicine Division, Department of Obstetrics and Gynecology, Prof. Dr. I.G.N.G. Ngoerah General Hospital, Jl. Diponegoro, Denpasar 80113)
I Made Darmayasa (Social Obstetrics and Gynecology Division, Department of Obstetrics and Gynecology, Prof. Dr. I.G.N.G. Ngoerah General Hospital, Jl. Diponegoro, Denpasar 80113,)
I Gede Mega Putra (Urogynecology Division, Department of Obstetrics and Gynecology, Prof. Dr. I.G.N.G. Ngoerah General Hospital, Jl. Diponegoro, Denpasar 80113)
Anom Suardika (Reproductive Endocrinology and Infertility Division, Department of Obstetrics and Gynecology, Prof. Dr. I.G.N.G. Ngoerah General Hospital, Jl. Diponegoro, Denpasar 80113)
Evert Solomon Pangkahila (Maternal Fetal Medicine Division, Department of Obstetrics and Gynecology, Prof. Dr. I.G.N.G. Ngoerah General Hospital, Jl. Diponegoro, Denpasar 80113,)
Vidya Saraswati Putri Duarsa (Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Udayana/Prof. Dr. I.G.N.G. Ngoerah General Hospital, Jl. P.B. Sudirman, Denpasar 80232,)
William William (Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Udayana/Prof. Dr. I.G.N.G. Ngoerah General Hospital, Jl. P.B. Sudirman, Denpasar 80232,)

The Indonesian Biomedical Journal
Vol 17, No 4 (2025)

BACKGROUND: Preeclampsia significantly contributes to maternal and fetal morbidity and mortality worldwide, marked by an imbalance of angiogenic factors, particularly increased soluble Fms-like tyrosine kinase-1 (sFlt-1), leading to endothelial dysfunction. Epigenetic regulation, including DNA methylation of the sFlt-1 promoter, has been suggested to influence sFlt-1 expression, but the data in Indonesian population are limited. This study was perfmed to determine whether hypomethylation of the sFlt-1 promoter and elevated placental sFlt-1 expression are associated with increased risk of preeclampsia.METHODS: A case-control study was conducted involving 30 women with preeclampsia and 30 normotensive pregnant women. Subjects were selected based on eligibility criteria that included singleton pregnancy and gestational age of ≥37 weeks. DNA methylation of the sFlt-1 promoter was assessed using methylation-specific polymerase chain reaction (PCR), and sFlt-1 expression was measured by enzyme-linked immunosorbent assay (ELISA). Statistical analyses, including Mann-Whitney U, Chi-square tests, Receiver-operating characteristic (ROC) curve analysis, and multivariate logistic regression, were performed to evaluate the relationship between methylation levels, gene expression, and preeclampsia risk.RESULTS: The preeclampsia group had significantly lower methylation levels of sFlt-1 promoter and higher placental sFlt-1 expression (both p<0.001). Hypomethylation of sFlt-1 promoter (adjusted odd ratio (AOR): 21.18; 95% CI: 2.49–179.72; p=0.005), high sFlt-1 expression (AOR: 12.55; 95% CI: 1.95–80.83; p=0.008), and obesity (AOR: 11.15; 95% CI: 2.01–61.78; p=0.006) were identified as independent risk factors for preeclampsia.CONCLUSION: Hypomethylation of sFlt-1 promoter and elevated placental sFlt-1 expression are significant independent risk factors for preeclampsia. These findings suggest that hypomethylation of sFlt-1 promoter and elevated placental sFlt-1 expression may serve as potential epigenetic biomarkers for early detection and targeted intervention in preeclampsia.KEYWORDS: preeclampsia, sFlt-1, gene expression, hypomethylation, placenta, risk factor