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Epigenetic Shifts in MTNR1A, MTNR1B and Fn14 and Their Links to Preeclampsia Risk
Sana Kashif Shahid1, Syeda Sadia Fatima2, Sabah Farhat2
1Department of Physiology, Fazaia Ruth Pfau Medical College, Air University, Karachi, Sindh, Pakistan.
Background:
Preeclampsia (PE) is a complex pregnancy disorder associated with early placental hypoxia, oxidative stress, and impaired angiogenic signaling. Melatonin and soluble tumor necrosis factor like weak inducer of apoptosis (sTWEAK) contribute to antioxidant and vascular pathways, whereas their receptors, melatonin receptor 1A (MTNR1A), melatonin receptor 1B (MTNR1B), and fibroblast growth factor-inducible 14 (Fn14), may be subject to epigenetic regulation. This study assessed serum melatonin and sTWEAK levels in parallel with promoter methylation of MTNR1A, MTNR1B, and Fn14 in early gestation.
Methods:
A mixed design cohort was recruited between 13 and 20 weeks of gestation. A total of 198 pregnant women were categorized as pregnant control, high risk, or preeclamptic at enrollment time. Serum melatonin and sTWEAK were measured by enzyme-linked immunosorbent assay (ELISA). Promoter methylation of MTNR1A, MTNR1B, and Fn14 was assessed using methylation-specific PCR with semi quantitative densitometry.
Results:
Serum sTWEAK levels were significantly lower in high-risk and preeclamptic women, whereas melatonin levels showed a downward trend without reaching statistical significance. Promoter methylation of MTNR1A and Fn14 was elevated in both high-risk and preeclamptic groups, whereas MTNR1B showed no notable differences. Multivariate analysis revealed that lower sTWEAK (OR 0.837; 95% confidence interval [CI] 0.782-0.896; p < 0.001) and higher Fn14 methylation (OR 0.935; 95% CI 0.882-0.992; p = 0.027) were independently associated with hypertensive outcomes. Additionally, higher Fn14 methylation in early pregnancy was observed in high-risk women who later developed hypertensive disorders.
Conclusion:
Early pregnancy hypermethylation of MTNR1A and Fn14, but not MTNR1B, was observed in high-risk and PE women and co-occurred with a significantly reduced sTWEAK level and non-significantly reduced serum melatonin, suggesting epigenetic modulation of antioxidant and angiogenic pathways in women at risk for PE. These findings establish associations rather than causation and require validation using quantitative assays in multicenter cohorts before clinical translation.
