Polymorphisms in Folate-Related Enzyme Genes in Idiopathic Infertile Brazilian Men

Abstract

The aim of the study was to analyze the distribution of the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), and methionine synthase (MTR) polymorphisms in idiopathic infertile Brazilian men and fertile men. Case–control study comprising 133 idiopathic infertile Brazilian men with nonobstructive azoospermia ([NOA] n = 55) or severe oligozoospermia ([SO] n = 78) and 173 fertile men as controls. MTHFR C677T, A1298C, and G1793A; MTRR A66G; and MTR A2756G polymorphisms were studied by quantitative polymerase chain reaction (qPCR). The results were analyzed statistically and a P value <.05 was considered significant. Single-marker analysis revealed a significant association among MTHFR C677T polymorphism and both NOA group (P = .018) and SO group (P < .001). Considering the MTHFR A1298C, MTHFR G1793A, and MTRR A66G polymorphisms, no difference was found between NOA group and SO group. Regarding the MTR A2756G polymorphism, a significant difference was found between NOA and controls, P = .017. However, statistical analysis revealed no association between SO group and controls. Combined genotypes of 3 MTHFR polymorphisms did not identify a haplotype associated with idiopathic infertility. The combinatory analysis of the 3 polymorphisms MTHFR, MTRR, and MTR did not show difference between cases and controls. The findings suggest the MTHFR C677T and MTR A2756G polymorphisms could be an important genetic factor predisposing to idiopathic infertility in Brazilian men.

Keywords

male infertility folate homocysteine

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References

O'Flynn O'Brien

Varghese

Agarwal

. The genetic causes of male factor infertility: a review. Fertil Steril. 2010;93(1):1–12.

Ferlin

Arredi

Foresta

. Genetic causes of male infertility. Reprod Toxicol. 2006;22:133–141.

Jacques

Bostom

Wilson

Rich

Rosenberg

Selhub

. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73(3):613–621.

Lucock

. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab. 2000;71(1-2):121–138.

Chen

Karaplis

Ackerman

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.

Agarwal

Prabakaran

Allamaneni

. Relationship between oxidative stress, varicocele and infertility: a meta-analysis. Reprod Biomed Online. 2006;12(5):630–633.

Frosst

Blom

Milos

A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–113.

Forges

Monnier-Barbarino

Alberto

Gueant-Rodriguez

Daval

Gueant

. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update. 2007;13(3):225–238.

Gava

de Oliveira Chagas

Bianco

Methylenetetrahydrofolate reductase polymorphisms are related to male infertility in Brazilian men. Genet Test Mol Biomarkers. 2011;15(3):153–157.

10.

van der Put

Gabreëls

Stevens

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

Am J Hum Genet. 1998;62(5):1044–1051.

11.

Fowler

. Homocysteine: overview of biochemistry, molecular biology, and role in disease processes. Semin Vasc Med. 2005;5(2):77–86.

12.

Toffoli

De Mattia

. Pharmacogenetic relevance of MTHFR polymorphisms. Pharmacogenomics. 2008;9(9):1195–1206.

13.

Shen

Qin

Idiopathic male infertility is strongly associated with aberrant promoter methylation of methylenetetrahydrofolate reductase (MTHFR). PLoS One. 2010;5(11):e13884.

14.

World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction. 14th ed. Cambridge: Cambridge

University

Press; 1999.

15.

Lahiri

Numberger

. A rapid non-enzymatic method for preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991;19(19):5444.

16.

Purcell

Cherny

Sham

. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003;19(1):149–150.

17.

Lee

Jeong

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.

18.

Ravel

Chantot-Bastaraud

Chalmey

Lack of association between genetic polymorphisms in enzymes associated with folate metabolism and unexplained reduced sperm counts. PLoS One. 2009;4(8):e6540.

19.

Montjean

Benkhalifa

Dessolle

Polymorphisms in MTHFR and MTRR genes associated with blood plasma homocysteine concentration and sperm counts. Fertil Steril. 2011;95(2):635–640.

20.

Safarinejad

Shafiei

Safarinejad

. Relationship between genetic polymorphisms of methylenetetrahydrofolate reductase (C677T, A1298C, and G1793A) as risk factors for idiopathic male infertility. Reprod Sci. 2011;18(3):304–315.

21.

Chan

Cushnie

Neaga

Lawrance

Rozen

Trasler

. Strain-specific defects in testicular development and sperm epigenetic patterns in 5,10-methylenetetrahydrofolate reductase-deficient mice. Endocrinology. 2010;151(7):3363–3373.

22.

de Lamirande

Gagnon

. Human sperm hyperactivation in whole semen and its association with low superoxide scavenging capacity in seminal plasma. Fertil Steril. 1993;59(6):1291–1295.

23.

Makker

Agarwal

Sharma

. Oxidative stress & male infertility. Indian J Med Res. 2009; 129(4):357–367.

24.

Abd-Elmoaty

Saleh

Sharma

Agarwal

. Increased levels of oxidants and reduced antioxidants in semen of infertile men with varicocele. Fertil Steril. 2010;94(4):1531–1534.

25.

Rousseaux

Rousseaux-Prevost

. Molecular localization of free thiols in human sperm chromatin. Biol Reprod. 1995;52(5):1066–1072.

26.

Aitken

Harkiss

Buckingham

. Analysis of lipid peroxidation mechanisms in human spermatozoa. Mol Reprod Dev. 1993;35:302–315.

27.

Aitken

De Iuliis

. Origins and consequences of DNA damage in male germ cells. Reprod Biomed Online. 2007;14(6):727–733.

28.

Shamsi

Venkatesh

Kumar

Antioxidant levels in blood and seminal plasma and their impact on sperm parameters in infertile men. Indian J Biochem Biophys. 2010;47(1):38–43.

29.

Neagu

García

Rodríguez

Determination of glutathione peroxidase and superoxide dismutase activities in canine seminal plasma and its relation with sperm quality and lipid peroxidation post thaw. Theriogenology. 2011;75(1):10–16.

30.

Desai

Sabanegh

Jr Kim

Agarwal

. Free radical theory of aging: implications in male infertility. Urology. 2010;75(1):14–19.

31.

Aléssio

Höehr

Siqueira

Polymorphism C776G in the transcobalamin II gene and homocysteine, folate and vitamin B12 concentrations. Association with MTHFR C677T and A1298C and MTRR A66G polymorphisms in healthy children. Thromb Res. 2007;119(5):571–577.

32.

Tavares

Vieira-Filho

Andriolo

Serum total homocysteine levels and the prevalence of folic acid deficiency and C677T mutation at the MTHFR gene in an indigenous population of Amazonia: the relationship of homocysteine with other cardiovascular risk factors. Ethn Dis. 2004;14(1):49–56.