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


METHODS
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.
Lee
Han-Chul
HC
Functional Genomics Lab, CHA Research Institute, Bundang Campus, College of Medicine, Pochon CHA University, Kyunggi-Do, Republic of Korea.
Jeong
Yu-Mi
YM
Lee
Sook Hwan
SH
Cha
Kwang Yul
KY
Song
Seung-Hun
SH
Kim
Nam Keun
NK
Lee
Kyo Won
KW
Lee
Suman
S
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000328:Adult; D000368:Aged; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005492:Folic Acid / Q000378:metabolism*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007248:Infertility, Male / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase