Influence of combined methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase enhancer region (TSER) polymorphisms to plasma homocysteine levels in Korean patients with recurrent spontaneous abortion

Abstract

Objectives Methylenetetrahydrofolate reductase (MTHFR) mutations known to be associated with hyperhomocysteinemia may be a risk factor for recurrent spontaneous abortion. Recently 28-bp tandem repeat polymorphism in thymidylate synthase enhancer region (TSER) was reported to affect plasma homocysteine level. We investigated the association between plasma homocysteine level and MTHFR and TSER genotypes. Methods Plasma homocysteine level was measured by fluorescent polarizing immunoassay. MTHFR mutations (C677T and A1298C) were identified by PCR-restriction fragment length polymorphism assay. TSER mutation was analyzed by PCR method. Results Average homocysteine level was significantly higher in MTHFR 677TT genotype (9.80 ± 3.87 μmol/L) than in MTHFR 677CT (7.04 ± 1.99 μmol/L) in MTHFR 677CC genotype (8.14 ± 1.74 μmol/L) in Korean patients with unexplained recurrent spontaneous abortion ( p = 0.0143). While MTHFR 1298AA showed the highest level, plasma homocysteine levels were not significantly different among MTHFR 1298AA (8.42 ± 2.65 μmol/L), 1298AC (6.98 ± 2.44 μmol/L) and 1298CC (6.09 ± 0.32 μmol/L) ( p = 0.2058). There was no significant difference among TSER genotypes (2R2R, 8.61 ± 1.68 μmol/L; 2R3R, 7.84 ± 2.16 μmol/L; 3R3R, 8.05 ± 2.81 μmol/L; p = 0.9319). Among the combined genotypes of MTHFR C677T and TSER, 677TT-3R3R genotype had the highest homocysteine level (11.47 ± 4.66 μmol/L). 1298AA-3R3R had the highest level (8.54 ± 3.05 μmol/L) among the combined genotypes of MTHFR A1298C and TSER. Conclusion Although there was no significant difference found among combined genotypes, 3R3R showed elevated homocysteine levels in MTHFR 677TT and 1298AA in Korean patients with unexplained recurrent spontaneous abortion. Thus TSER polymorphism may be a genetic determinant of plasma homocysteine level in Korean patients as well as MTHFR C677T polymorphism.