Menopause: The Journal of The North American Menopause Society Vol. 19, No. 11, pp. 1260/1266 DOI: 10.1097/gme.0b013e3182556b08 * 2012 by The North American Menopause Society Association of methylenetetrahydrofolate reductase (MTHFR 677C9T) and thymidylate synthase (TSER and TS 1494del6) polymorphisms with premature ovarian failure in Korean women HyungChul Rah, DVM, PhD, 1,2 Young Joo Jeon, MS, 1,2 Youngsok Choi, PhD, 1,3 Sung Han Shim, PhD, 1,3 Tae Ki Yoon, MD, PhD, 3 Dong Hee Choi, MD, PhD, 4 Sun Hee Cha, MD, PhD, 4 and Nam Keun Kim, PhD 1,2 Abstract Objective: The aim of our study was to investigate whether methylenetetrahydrofolate reductase (MTHFR) gene variant (MTHFR 677C9T) 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 677C9T, 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 677C9T/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. Key Words: Premature ovarian failure Y Primary ovarian insufficiency Y Methylenetetrahydrofolate reductase Y Thymidylate synthase Y Single nucleotide polymorphism. P remature ovarian failure (POF) or primary ovarian insuf- ficiency is defined as the cessation of ovarian function by amenorrhea and elevated gonadotropin levels (serum follicle-stimulating hormone [FSH] 940 IU/L) before the age of 40 years. The prevalence of POF is estimated at about 1% of women younger than 40 years. 1 The multiple causes contributing to POF occurrence include X chromosome ab- normalities, iatrogenic origins, autoimmune causes, autosomal gene aberrations, and genomic imbalances; however, the cause of POF remains undetermined in most cases. Because 15% to 30% of POF cases have been shown to be familial, suggesting a genetic etiology, 2<5 more than a dozen gene products have been identified for their key roles at various states of ovarian folliculogenesis and after ovulation in mouse models, 6 and variants of more than 50 human genes have been reported to be associated with POF (Table, Supplemental Digital Content 1, http://links.lww.com/MENO/A36). 7 However, no genes involved in one-carbon metabolism have yet been associated with POF. Received January 16, 2012; revised and accepted March 5, 2012. From the 1 Department of Biomedical Science, College of Life Science and 2 Institute for Clinical Research, CHA Bundang Medical Center, CHA University, Seongnam, South Korea; 3 Fertility Center of CHA Gangnam Medical Center, CHA University, Seoul, South Korea; and 4 Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam, South Korea. 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. Supplemental digital content is available for this article. Direct URL cita- tions appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.menopause.org). Address correspondence to: Nam Keun Kim, PhD, Institute for Clinical Research, CHA Bundang Medical Center, CHA University, 351 Yatap- dong, Bundang-gu, Seongnam 463-712, South Korea. E-mail: nkkim@ cha.ac.kr 1260 Menopause, Vol. 19, No. 11, 2012 Copyright © 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.