Background: Folate metabolism plays an important role in appropriate cellular function, DNA methylation, repair, and synthesis. C677T and A1298C variants of methylenetetrahydrofolate reductase (MTHFR) play a role in reduced plasma folate and increase the susceptibility to various multifactorial disorders.
Aim and objective: The present study was aimed to detect the association of C677T polymorphism and A1298C polymorphism in the MTHFR gene with male infertility.
Materials and methods: In the current study, we analyzed a group of 50 infertile men with a clinical history of nonobstructive azoospermia or severe oligozoospermia. For the control group, we also analyze 50 fertile men. Cytogenetic analysis revealed a normal male karyotype in 50 cases of infertile men, which further subjected to molecular analysis. The expected genotype and allele frequencies were calculated for both infertile men and controls. These frequencies were tested when the study group followed Hardy–Weinberg equilibrium. The interaction between the MTHFR genotypes was calculated using the odds ratio for mutant genotypes as compared to the wild types. To evaluate the risk of the different genotypes, 95% confidence intervals (CI) were calculated.
Results: The A1298C polymorphism of the MTHFR gene was present at a statistically increased significance in infertile men.
Interpretation and conclusion: We concluded that MTHFR C677T gene polymorphism is not associated with male infertility whereas A1298C gene polymorphism showed a significant increase in male infertility. To better understanding the causes of male infertility, future studies to be conducted in a large population to obtain a better understanding of the complex gene-to-gene interactions.
Hirsh A. Male subfertility. BMJ 2003;327(7416):669–672. DOI: 10.1136/bmj.327.7416.669.
Jarvi K, Lo K, Fischer A, et al. CUA guideline: the workup of azoospermic males. Can Urol Assoc J 2010;4(3):163–167. DOI: 10.5489/cuaj.10050.
Miyamoto T, Minase G, Okabe K, et al. Male infertility and its genetic causes. J Obstet Gynaecol Res 2015;41(10):1501–1505. DOI: 10.1111/jog.12765.
Shen O, Liu R, Wu W, et al. Association of the methylenetetrahydrofolate reductase gene A1298C polymorphism with male infertility: a meta-analysis. Ann Hum Genet 2012;76(1):25–32. DOI: 10.1111/j.1469-1809.2011.00691.x.
Waseem AS, Singh V, Makker GC, et al. AZF deletions in Indian populations: original study and meta-analyses. J Assist Reprod Genet 2020;37(2):459–469. DOI: 10.1007/s10815-019-01661-0.
Dohle GR, Halley DJ, Van Hemel JO, et al. Genetic risk factors in infertile men with severe oligozoospermia and azoospermia. Hum Reprod 2002;17(1):13–16. DOI: 10.1093/humrep/17.1.13.
Ravel C, Chantot-Bastaraud S, Chalmey C, et al. Lack of association between genetic polymorphisms in enzymes associated with folate metabolism and unexplained reduced sperm counts. PloS One 2009;4(8):e6540. DOI: 10.1371/journal.pone.0006540.
Ni W, Li H, Wu A, et al. Lack of association between genetic polymorphisms in three folate-related enzyme genes and male infertility in the Chinese population. J Assist Reprod Genet 2015;32(3):369–374. DOI: 10.1007/s10815-014-0423-9.
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10(1):111–113. DOI: 10.1038/ng0595-111.
Goyette P, Pai A, Milos R, et al. Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome 1998;9(8):652–656. DOI: 10.1007/s003359900838.
Chen Z, Karaplis AC, Ackerman SL, et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 2001;10(5):433–443. DOI: 10.1093/hmg/10.5.433.
Kelly TLJ, Neaga OR, Schwahn BC, et al. Infertility in 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation. Biol Reprod 2005;72(3):667–677. DOI: 10.1095/biolreprod.104.035238.
Bezold G, Lange M, Peter RU. Homozygous methylenetetrahydrofolate reductase C677T mutation andmale infertility. New Engl J Med 2001;344(15):1172–1173. DOI: 10.1056/NEJM200104123441517.
Ebisch IMW, van Heerde WL, Thomas CMG, et al. C677T methylenetetrahydrofolate reductase polymorphisminterferes with the effects of folic acidand zinc sulftate on sperm concentration. Fertil Steril 2003;80(5):1190–1194. DOI: 10.1016/S0015-0282(03)02157-5.
Stuppia L, Gatta V, Scarciolla O, et al. The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility in Italy. Jendocrinol Invest 2003;26(7):620–622. DOI: 10.1007/BF03347018.
Singh K, Singh SK, Sah R, et al. MutationC677T in the methylenetetrahydrofolate reductase gene is associated with male infertility in an Indian population. Int J Androl 2005;28(2):115–119. DOI: 10.1111/j.1365-2605.2004.00513.x.
Park JH, Lee HC, Jeong Y-M, et al. MTHFR C677T polymorphism associates with unexplained infertile male factors. J Assis Reprod Genet 2005;22(9-10):361–368. DOI: 10.1007/s10815-005-6795-0.
Lee HC, Jeong YM, Lee SH, et al. Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility. Hum Reprod 2006;21(12):3162–3170. DOI: 10.1093/humrep/del280.
Zhou-Cun A, Yang Y, Si-Zhong Z, et al. Single nucleotide polymorphism C677T in the methylenetetrahydrofolate reductase gene might be a genetic risk factor for male infertility for Chinese men with azoospermia or severe oligozoospermia. Asian J Androl 2007;9(1):57–62. DOI: 10.1111/j.1745-7262.2007.00225.x.
Varinderpal SD, Mohd S, Syed AH. Associations of MTFR DNMT3b 4977 bp deletion in mtDNA and GSTM1 deletion, and aberrant CpG island hypermethylayion of GSTM1in non-obstructive infertility in Indian men. Mol Hum Reprod 2007;13(4):213–222. DOI: 10.1093/molehr/gal118.
Robertson KD, Wolfe AP. DNA methylation in health and disease. NatRev Genet 2000;1(1):11–19. DOI: 10.1038/76862.
Siegfried Z, Eden S, Mendelsohn M, et al. Gene silencing in mammalian cells and the spread of DNA methylation. Nat Genet 1999;22(2):203–206. DOI: 10.1038/9727.
Kumar J, Das SK, Sharma P, et al. Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population. J Hum Genet 2005;50(12):655–663. DOI: 10.1007/s10038-005-0313-1.