Effect of folate-cycle gene polymorphisms (MTHFR, MTRR) on fertility, pregnancy outcomes, and on congenital outcomes in newborn
Folate metabolism plays a critical role in DNA synthesis, repair, and methylation, which are essential for reproductive function and fetal development. Polymorphisms in folate-cycle genes, particularly MTHFR and MTRR, may impair enzyme activity, leading to elevated homocysteine levels and adverse reproductive and neonatal outcomes. This study aimed to evaluate the association of these gene polymorphisms with infertility, pregnancy complications, and congenital anomalies in newborns. A case–control study was conducted including 360 participants divided into three groups: women with infertility (n = 120), women with adverse pregnancy outcomes (n = 120), and mothers of newborns with congenital anomalies (n = 120). An age-matched control group of healthy women (n = 120) was included. Genomic DNA was extracted from peripheral blood, and genotyping for MTHFR C677T, MTHFR A1298C, and MTRR A66G was performed using PCR-RFLP and real-time PCR. Serum folate, vitamin B12, and plasma homocysteine levels were measured. Statistical analyses included chi-square tests, ANOVA, and logistic regression to determine associations. Mutant genotypes of MTHFR (677TT, 1298CC) and MTRR (66GG) were significantly more prevalent in all case groups compared to controls. Participants with mutant genotypes exhibited lower serum folate and vitamin B12 levels and higher homocysteine concentrations (p < 0.001). Logistic regression revealed that MTHFR 677TT (OR = 2.8), MTHFR 1298CC (OR = 2.1), and MTRR 66GG (OR = 2.4), as well as low folate intake and elevated homocysteine, were independent risk factors for adverse reproductive and neonatal outcomes. Neural tube defects and congenital heart defects were significantly associated with MTHFR TT and MTRR GG genotypes, respectively. Folate-cycle gene polymorphisms, particularly in MTHFR and MTRR, are strongly associated with infertility, adverse pregnancy outcomes, and congenital anomalies. These genetic risks are exacerbated by inadequate folate intake, emphasizing the importance of preconception screening, nutritional interventions, and folic acid supplementation to improve reproductive and neonatal outcomes.
