title: 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.
abstract: 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 B(12), 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 B(12) 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.
authors.affiliation: CSIRO Human Nutrition, Adelaide, Australia. varinderpal.dhillon@csiro.au
authors.forename: Varinderpal S
authors.initials: VS
authors.lastname: Dhillon
authors.forename: Mohd
authors.initials: M
authors.lastname: Shahid
authors.forename: Syed Akhtar
authors.initials: SA
authors.lastname: Husain
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005492:Folic Acid / Q000097:blood; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics*; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007194:India; D007248:Infertility, Male / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012307:Risk Factors; D017384:Sequence Deletion; D014805:Vitamin B 12 / Q000097:blood; D044465:White People / Q000235:genetics; D000097584:DNA Methyltransferase 3B
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D004248:DNA (Cytosine-5-)-Methyltransferases; D004272:DNA, Mitochondrial; D003849:Deoxyguanosine; D005492:Folic Acid; D005982:Glutathione Transferase; D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12; D000097584:DNA Methyltransferase 3B