Contribution of Thymidylate Synthase Enhancer Region (TSER) Polymorphism to Total Plasma Homocysteine Levels in Korean Patients with Recurrent Spontaneous Abortion

Choi, Yoon Kyung; Kang, Myung Seo; Kim, Nam Keun; Kim, Sun Hee; Choi, Dong Hee; An, Myung Ok; Lee, Suman

Abstract

OBJECTIVES
Methylenetetrahydrofolate reductase (MTHFR) mutation are commonly associated with hyperhomocysteinemia, and through their defects in homocysteine metabolism, they have been implicated as a risk factor for recurrent spontaneous abortion. Recent report describe that 28-bp tandem repeat polymorphism in thymidylate synthase enhancer region (TSER) that influence enzyme activity would affect plasma homocysteine level. We have investigated the relationship between TSER genotype and plasma homocysteine level in 54 patients with recurrent spontaneous abortion.
METHODS
Plasma homocysteine level was measured by fluorescent polarizing immunoassay. MTHFR mutation (C677T and A1298C) was identified by PCR-restriction fragment length polymorphism assay and TSER mutation was analyzed by PCR method. The data were analyzed using the program SAS 8.2 for Windows.
RESULTS
Total homocysteine level was significantly higher in MTHFR 677TT genotype (9.80+/-3.87 mumol/L) than MTHFR 677CC genotype (8.14+/-1.74 mumol/L) in Korean patients with unexplained recurrent spontaneous abortion (p=0.0143). However, the plasma homocysteine level was not significantly different in the MTHFR 1298AA (8.42+/-2.65 mumol/L) and 1298CC (6.09+/-0.32 mumol/L; p=0.2058) and, TSER 2R2R (8.61+/-1.68 mumol/L) and 3R3R (8.05+/-2.81 mumol/L; p=0.9319) mutant genotypes, respectively. In this study, we found the combination effects of TSER and MTHFR C677T genotypes. Plasma homocysteine levels were the highest (11.47+/-4.66 mumol/L) in individuals with TSER 3R3R (8.05+/-2.81 mumol/L) and MTHFR 677TT (9.80+/-3.87 mumol/L) genotypes. Individuals with a combination of both TSER 2R2R/2R3R and MTHFR 677CC/CT genotypes (7.69+/-1.77 mumol/L) had lower plasma homocysteine levels than TSER 2R2R (8.61+/-1.68 mumol/L) and MTHR 677CC (8.14+/-1.74 mumol/L) genotypes, respectively. The effect of MTHFR polymorphism in the homocysteine metabolism appears to be stronger than that of TSER polymorphism.
CONCLUSION
Although statistically not significant, we found the elevated level of plasma homocysteine in combined genotypes with TSER and MTHFR (C677T and A1298C) in Korean patients with unexplained habitual abortion. In this study, we reported the possibility that TSER polymorphism is a genetic determinant of plasma homocysteine levels in the Korean patients as well as MTHFR C677T polymorphism. A large prospective study is needed to verify our findings.