Association of MTHFR C677T and A1298C variants with preeclampsia risk and angiogenic imbalance in Tunisian women.

Preeclampsia (PE) is a pregnancy-specific vascular disorder associated with endothelial dysfunction, hypertension, and proteinuria. The methylenetetrahydrofolate reductase (MTHFR) enzyme regulates essential cellular functions in pregnancy owing to its effects on folate metabolism and DNA methylation. Previous studies implicated the association of rs1801133 (C677T; Ala222Val) and rs1801131 (A1298C; Glu429Ala) in the MTHFR gene with PE in different ethnic groups, but with mixed outcomes.

Methods: Study cases comprised 675 Tunisian pregnant women, of whom 350 PE presented with PE, and the remaining 325 normotensive women served as controls. Genotyping of C677T and A1298C variants was performed by real-time PCR.

Results: There was no statistically significant difference in the minor allele frequencies of C677T and A1298C between preeclampsia cases and controls after adjusting for key covariates. In addition, the prevalence of MTHFR C677T and A1298C minor allele homozygote genotypes was significantly higher in PE cases. The association of 1298C/C, but not 677T/T, with PE persisted after adjusting for the main covariates. Carrying the (minor) 677T allele was associated with marginally higher BMI, significantly higher sFlt-1 serum levels, and median sFlt-1/PlGF ratio and sFlt-1/PlGF ratio ≥ 85. Setting the major allele homozygotes (C677/A1298) as a reference, haplotype analysis demonstrated a higher prevalence of C677/C1298 and T677/C1298 haplotypes (P = 0.03) in PE cases compared to controls, which persisted for C677/C1298, but not T677/C1298 after controlling for key covariates.

Discussion: Our results support an association between MTHFR polymorphisms and increased risk of PE, and an imbalance of PE-associated sFLT-1/PlGF.