Detection of Polymorphisms in MTHFD1 G1958A and Its Possible Association with Idiopathic Male Infertility
Vol. 16 No. 06 (2019),
24 December 2019
Purpose: The role of male infertility is important in human infertility pathology. Spermatogenesis is a complex developmental process which is regulated by a number of genes. Methylenetetrahydrofolate dehydrogenase1 (MTHFD1) is involved in the synthesis of purine, pyrimidine, and methionine. The aim of this study was to identify the MTHFD1, G1958A polymorphism and its association with idiopathic male infertility in Iranian population.
Materials and Methods: This case-control study was conducted on 200 Iranian men, 100 cases with idiopathic infertility (experimental group) and 100 normal men (control group). The subjects were assessed for the MTHFD1 G1958A polymorphism, using the polymerase chain reaction-restriction fragment length polymorphism technique (PCR-RFLP). The chi-square test was used to determine the association between MTHFD1 G1958A polymorphism and male infertility, using SPSS software. P ? 0.05 was considered significant.
Results: Totally, the frequency of A allele and AA homozygous genotype was found 51% and 47.3% respectively, with 52.5% and 30% in the experimental group versus 42% and 21% in control group. There was a statistically significant correlation between the frequencies of A allele (95 % CI = 1.028- 2.265, OR = 1.526, p = 0.035) and AA homozygous (% CI = 0.995- 4.494, OR = 2.114, 95 p = 0.05) genotype with the MTHFD1 G1958A polymorphism (P ? 0.05).
Conclusion: These results suggest that the polymorphism in MTHFD1 G1598A gene could be considered as an important genetic disorder associated with the etiology of male infertility.
Ebisch I, Pierik F, De Jong F, et al. Does folic acid and zinc sulphate intervention affect endocrine parameters and sperm characteristics in men? Int J Androl. 2006;29:339-345.
Shefi S, Turek PJ. Definition and current evaluation of subfertile men. Int Braz J Urol. 2006;32:385-397.
Hamada A, Esteves SC, Agarwal A. Unexplained male infertility: potential causes and management. Human Andrology. 2011;1:2-16.
Dohle G, Colpi G, Hargreave T, et al. EAU guidelines on male infertility. Eur Urol. 2005;48:703-711.
Lee H-C, Jeong Y-M, Lee SH, et al. Association study of four polymorphisms in three folate-related enzyme genes with non-obstructive male infertility. Hum Reprod. 2006;21:3162-3170.
Nuti F, Krausz C. Gene polymorphisms/mutations relevant to abnormal spermatogenesis. Reprod Biomed Online. 2008;16:504-513.
Bentivoglio G, Melica F, Cristoforoni P. Folinic acid in the treatment of human male infertility. Fertil Steril. 1993;60:698-701.
Singh K, Jaiswal D. One-carbon metabolism, spermatogenesis, and male infertility. Reprod Sci. 2013;20:622-630.
Wong WY, Merkus HM, Thomas CM, et al. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Fertil Steril. 2002;77:491-498.
Boxmeer JC, Smit M, Weber RF, et al. Seminal plasma cobalamin significantly correlates with sperm concentration in men undergoing IVF or ICSI procedures. J Androl. 2007;28:521-527.
Crha I, Kralikova M, Melounova J, et al. Seminal plasma homocysteine, folate and cobalamin in men with obstructive and non-obstructive azoospermia. J Assist Reprod Genet. 2010;27:533-538.
Lewis S, Aitken R. DNA damage to spermatozoa has impacts on fertilization and pregnancy. Cell Tissue Res. 2005;322:33-41.
Saleh RA, Agarwal A, Nada EA, et al. Negative effects of increased sperm DNA damage in relation to seminal oxidative stress in men with idiopathic and male factor infertility. Fertil Steril. 2003;79:1597-1605.
Weiner AS, Boyarskikh UA, Voronina EN, et al. Polymorphisms in folate-metabolizing genes and risk of idiopathic male infertility: a study on a Russian population and a meta-analysis. Fertil Steril. 2014;101:87-94. e83.
Hum DW, Bell A, Rozen R, et al. Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase. J Biol Chem. 1988;263:15946-15950.
Parle‐McDermott A, Mills JL, Kirke PN, et al. MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae. Am J Med Genet. 2005;132:365-368.
Brody LC, Conley M, Cox C, et al. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am J Hum Genet. 2002;71:1207-1215.
Parle-McDermott A, Pangilinan F, Mills JL, et al. A polymorphism in the MTHFD1 gene increases a mother’s risk of having an unexplained second trimester pregnancy loss. Mol Hum Reprod. 2005;11:477-480.
Popp RA, Farcas MF, Trifa AP, et al. The Methylenetetrahydrofolate Dehydrogenase (MTHFD 1) gene G1958A polymorphism and idiopathic male infertility in a Romanian population group. Clujul Med 2012;85:54-58.
Organisation WH. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interactionCambridge university press; 1999.
Kim JH, Jeon YJ, Lee BE, et al. Association of methionine synthase and thymidylate synthase genetic polymorphisms with idiopathic recurrent pregnancy loss. Fertil Steril. 2013;99:1674-1680. e1673.
Crişan TO, Trifa A, Farcaş M, et al. The MTHFD1 c. 1958 G> A polymorphism and recurrent spontaneous abortions. J Matern Fetal Neonatal Med. 2011;24:189-192.
Fowdar JY, Lason MV, Szvetko AL, et al. Investigation of homocysteine-pathway-related variants in essential hypertension. Int J Hypertens. 2012;2012.
Neagos D, Cretu R, Tutulan–Cunita A, et al. Methylenetetrahydrofolate dehydrogenase (MTHFD) enzyme polymorphism as a maternal risk factor for trisomy 21: a clinical study. J Med Life. 2010;3:454.
Zheng J, Lu X, Liu H, et al. MTHFD1 polymorphism as maternal risk for neural tube defects: a meta-analysis. Neuro Sc. 2015;36:607-616.
Hol FA, Put NM, Geurds M, et al. Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate‐dehydrogenase, methenyltetrahydrofolate‐cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects. Clin Genet. 1998;53:119-125.
Zhang H, Ma H, Li L, et al. Association of methylenetetrahydrofolate dehydrogenase 1 polymorphisms with cancer: a meta-analysis. PLoS One. 2013;8:e69366.
Aston KI, Krausz C, Laface I, et al. Evaluation of 172 candidate polymorphisms for association with oligozoospermia or azoospermia in a large cohort of men of European descent. Hum Reprod. 2010;25:1383-1397.
Park JH, Lee HC, Jeong Y-M, et al. MTHFR C677T polymorphism associates with unexplained infertile male factors. J Assist Reprod Genet. 2005;22:361-368.
Stuppia L, Gatta V, Scarciolla O, et al. The methylenetethrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility in Italy. J Endocrinol Invest. 2003;26:620-622.
Ebisch IM, van Heerde WL, Thomas CM, et al. C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. Fertil Steril. 2003;80:1190-1194.
Murphy LE, Mills JL, Molloy AM, et al. Folate and vitamin B12 in idiopathic male infertility. Asian J. Androl. 2011;13:856.
Dohle G, Halley D, Van Hemel J, et al. Genetic risk factors in infertile men with severe oligozoospermia and azoospermia. Hum Reprod. 2002;17:13-16.
Khatami M, Ratki FM, Tajfar S, et al. Relationship of the MTHFD1 (rs2236225), eNOS (rs1799983), CBS (rs2850144) and ACE (rs4343) gene polymorphisms in a population of Iranian pediatric patients with congenital heart defects. Kaohsiung J Med Scis. 2017;33:442-448.
Rasti M, Tavasoli P, Monabati A, et al. Association between HIC1 and RASSF1A promoter hypermethylation with MTHFD1 G1958A polymorphism and clinicopathological features of breast cancer in Iranian patients. Iran Biomed J. 2009;13:199.
Balkan M, Atar M, Erdal ME, et al. The possible association of polymorphisms in MTHFR, MTRR, and MTHFD1 genes with male infertility. Int Med J 2013;20:404-408.
Ariel M, Cedar H, McCarrey J. Developmental changes in methylation of spermatogenesis–specific genes include reprogramming in the epididymis. Nat Genet. 1994;7:59.
Kurzawski M, Wajda A, Malinowski D, et al. Association study of folate-related enzymes (MTHFR, MTR, MTRR) genetic variants with non-obstructive male infertility in a Polish population. Genetics and molecular biology 2015;38:42-47.
Carrell DT. Epigenetics of the male gamete. Fertil Steril. 2012;97:267-274.
Bezold G, Lange M, Peter RU. Homozygous methylenetetrahydrofolate reductase C677T mutation and male infertility. N Engl J Med. 2001;344:1172-1173.
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;76:25-32.
Toffoli G, De Mattia E. Pharmacogenetic relevance of MTHFR polymorphisms. Pharmacogenomics. 2008; 9:1195–1206.
- Abstract Viewed: 519 times
- pdf/4647 Downloaded: 168 times