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Association of methylenetetrahydrofolate reductase (MTHFR 677C>T) and thymidylate synthase (TSER and TS 1494del6) polymorphisms with premature ovarian failure in Korean women

Rah, HyungChul DVM, PhD1,2; Jeon, Young Joo MS1,2; Choi, Youngsok PhD1,3; Shim, Sung Han PhD1,3; Yoon, Tae Ki MD, PhD3; Choi, Dong Hee MD, PhD4; Cha, Sun Hee MD, PhD4; Kim, Nam Keun PhD1,2

doi: 10.1097/gme.0b013e3182556b08
Original Articles

Objective The aim of our study was to investigate whether methylenetetrahydrofolate reductase (MTHFR) gene variant (MTHFR 677C>T) and thymidylate synthase (TS) gene variants (TS enhancer region [TSER] and TS 1494del6) confer a risk for premature ovarian failure (POF).

Methods We genotyped 136 POF patients and 236 controls among Korean women for the three single nucleotide polymorphism sites using polymerase chain reaction restriction fragment length polymorphism analysis. Differences in the MTHFR 677C>T, TSER, and TS 1494del6 genotype frequencies between POF patients and controls were compared, and odds ratios (ORs) and 95% CIs were determined as a measure of the strength of the association between genotypes and POF.

Results The MTHFR 677CT and CT + TT variant genotypes were more frequent in POF patients than in controls (OR, 2.249; 95% CI, 1.317-3.843; and OR, 2.132; 95% CI, 1.268-3.585, respectively). The combined genotype frequencies of MTHFR 677CT + TT/TSER 3R3R and 677CT + TT/TS 1494del6 del6/del6 were higher in patients than in controls (OR, 2.300; 95% CI, 1.219-4.337; and OR, 3.314; 95% CI, 1.623-6.767, respectively). The T-3R-del6 and T-2R-del6 (MTHFR 677C>T/TSER/TS 1494del6) haplotypes were more frequent in patients (OR, 1.450; 95% CI, 1.050-2.002; and OR, 2.911; 95% CI, 1.191-7.117, respectively), whereas the C-2R-del6 haplotype was less frequent in patients (OR, 0.372; 95% CI, 0.152-0.912). The T-del6 (MTHFR 677/TS 1494del6) haplotype frequency was higher among patients (OR, 1.653; 95% CI, 1.206-2.266), whereas the C-del6 haplotype frequency was lower among patients (OR, 0.700; 95% CI, 0.516-0.950). We did not find an association between TSER or TS 1494del6 polymorphisms and POF.

Conclusions Our data suggest that the MTHFR 677T allele may increase the risk for POF, which could lead to the development of novel genetic markers for predicting the risk of POF in patients.

From the 1Department of Biomedical Science, College of Life Science and 2Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam, South Korea; 3Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, South Korea; and 4Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam, South Korea.

Received January 16, 2012; revised and accepted March 5, 2012.

Funding/support: This work was partly supported by the Priority Research Centers Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (2009-0093821) and by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare, and Family Affairs, Republic of Korea (A084923).

Financial disclosure/conflicts of interest: None reported.

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Address correspondence to: Nam Keun Kim, PhD, Institute for Clinical Research, CHA Bundang Medical Center, CHA University, 351 Yatapdong, Bundang-gu, Seongnam 463-712, South Korea. E-mail:

©2012The North American Menopause Society