Mol. Hum. Reprod. Advance Access originally published online on February 2, 2007
Molecular Human Reproduction 2007 13(4):213-222; doi:10.1093/molehr/gal118
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Associations of MTHFR DNMT3b 4977 bp deletion in mtDNA and GSTM1 deletion, and aberrant CpG island hypermethylation of GSTM1 in non-obstructive infertility in Indian men
1 CSIRO Human Nutrition, Adelaide, Australia 2 Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, India
3 To whom correspondence should be addressed at: Genome Health and Nutrigenomics Laboratory, CSIRO Human Nutrition, Gate 13, Kintore Avenue, PO Box 10041, Adelaide, SA 5000, Australia. E-mail: varinderpal.dhillon{at}csiro.au
Methylenetetrahydrofolate (MTHFR) and DNMT3b play imperative roles in DNA synthesis and de novo methylation. GSTM1 is involved in detoxification of carcinogens. Mitochondrial DNA deletion has been associated with lower motility in human sperm. We analysed if polymorphisms in MTHFR (C677T and A1298C) and DNMT3b (C46359T) are associated with non-obstructive male infertility. We also analysed if folate, vitamin B12, homocysteine (Hcy), 8'-hydroxy-2'-deoxygnanosine (8-OHdG) levels, dietary folate intake and mtDNA deletion (4977 bp) affects fertility, such interactions are modified by deletion and methylation of GSTM1. In this case–control study, we included 179 oligoasthenoteratozoospermia patients and 200 fertile men. Single-nucleotide polymorphism analysis was performed by PCR-restriction fragment length polymorphism. The MTHFR (C677T and A1298C) and DNMT3b (C46359T) frequencies did not differ significantly in two groups. GSTM1 in association with mtDNA 4977 deletion is significantly associated with infertility. Plasma folate and vitamin B12 levels are decreased and total Hcy is elevated in infertile men. GSTM1 methylation status was investigated by methylation-specific PCR. Methylation is significantly correlated with GSTM1 reduced/loss of expression in infertile men. Infertile men have significantly higher 8-OHdG levels. Dietary folate intake is not linked with GSTM1 methylation. Low folate intake in association with CT + TT genotypes (C677T) has significant protective effect on GSTM1 methylation. Results indicate that micronutrients, 8-OHdG levels, mtDNA deletion and GSTM1 promoter methylation are frequent alterations in infertility.
Key words: CpG island hypermethylation/DNMT3b/GSTM1/infertility/mtDNA/MTHFR
Submitted on November 13, 2006; resubmitted on December 21, 2006; accepted on January 2, 2007.