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Hum. Reprod. Advance Access published online on July 22, 2006
Human Reproduction, doi:10.1093/humrep/del280
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 4, 2006
Revised May 11, 2006
Accepted May 17, 2006

Article

Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility

Han-Chul Lee 1, Yu-Mi Jeong 1, Sook Hwan Lee 2, Kwang Yul Cha 2, Seung-Hun Song 2, Nam Keun Kim 2, Kyo Won Lee 3, and Suman Lee 4 *

1 Functional Genomics Lab, CHA Research Institute, Bundang Campus, College of Medicine, Pochon CHA University, Kyunggi-Do
2 Genome Research Center for Reproductive Medicine and Infertility, CHA General Hospital, Gangnam-Gu
3 Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
4 Functional Genomics Lab, CHA Research Institute, Bundang Campus, College of Medicine, Pochon CHA University, Kyunggi-Do; Genome Research Center for Reproductive Medicine and Infertility, CHA General Hospital, Gangnam-Gu

* To whom correspondence should be addressed.
Suman Lee, E-mail: suman{at}cha.ac.kr


  Abstract

BACKGROUND: Three typical folate metabolism enzymes--i.e. methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS) and MS reductase (MTRR) in the folate cycle--play a critical role in DNA synthesis and methylation reactions. We evaluated whether polymorphisms of these three enzymes are associated with non-obstructive male infertility. METHOD: Three hundred and sixty patients with non-obstructive infertility and 325 fertile men without any chromosomal abnormalities were included in this study. The single-nucleotide polymorphism (SNP) analysis was performed by pyrosequencing and PCR-restriction fragment length polymorphism (RFLP) analysis RESULTS: The frequencies of MTHFR 677TT and MTRR 66GG genotypes were higher in non-obstructive infertile men compared with those in fertile men. By classifying 360 infertile patients into 174 azoospermia and 186 oligoasthenoteratozoospermia (OAT) subjects, the MTHFR 677TT and MS 2756GG types were significantly associated with the azoospermia group (P = 0.0227 and 0.0063, respectively). The frequency of MTRR 66GG was significant in the OAT group (P = 0.0014 versus fertile males). CONCLUSIONS: By analysis of a large number of subjects and a more specific patient selection, we showed the first genetic evidence that MTHFR C677T, MS A2756G and MTRR A66G genotypes were independently associated with male infertility. Each SNP of the three enzymes may have a different impact on the folate cycle during spermatogenesis.

Keywords: azoospermia/folate metabolism/male infertility/oligoasthenoteratozoospermia/polymorphism.
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