Lack of Association between Genetic Polymorphisms in Enzymes Associated with Folate Metabolism and Unexplained Reduced Sperm Counts

Abstract

BackgroundThe metabolic pathway of folate is thought to influence DNA stability either by inducing single/double stranded breaks or by producing low levels of S-adenosyl-methionine leading to abnormal gene expression and chromosome segregation. Polymorphisms in the genes encoding enzymes in the folate metabolism pathway show distinct geographic and/or ethnic variations and in some cases have been linked to disease. Notably, the gene Methylenetetrahydrofolate reductase (MTHFR) in which the homozygous (TT) state of the polymorphism c.665C>T (p.A222V) is associated with reduced specific activity and increased thermolability of the enzyme causing mild hyperhomocysteinemia. Recently several studies have suggested that men carrying this polymorphism may be at increased risk to develop infertility.Methodology/Principal FindingsWe have tested this hypothesis in a case/control study of ethnic French individuals. We examined the incidence of polymorphisms in the genes MTHFR (R68Q, A222V and E429A), Methionine synthase reductase MTRR; (I22M and S175L) and Cystathionine beta-synthase (CBS; G307S). The case population consisted of DNA samples from men with unexplained azoospermia (n = 70) or oligozoospermia (n = 182) and the control population consisted of normospermic and fertile men (n = 114). We found no evidence of an association between the incidence of any of these variants and reduced sperm counts. In addition haplotype analysis did not reveal differences between the case and control populations.Conclusions/SignificanceWe could find no evidence for an association between reduced sperm counts and polymorphisms in enzymes involved in folate metabolism in the French population.

Lack of association between genetic polymorphisms in three folate-related enzyme genes and male infertility in the Chinese population

“…The frequency of the MTHFR A1298C variant allele also differs across populations, the frequency of the C allele is less frequent among Chinese than among Caucasians [20]. Lack of association between MTHFR A1298C and male infertility was observed in French, Indian, Korean and Moroccan populations [17,13,24,16]. Our results are in concordance with previous studies.…”

“…Impaired folate status has been associated with several pathologies such as cardiovascular, neurodegenerative diseases and pregnancy complications [32]. Recent studies suggest that the key enzymes in folate metabolism are critical for male spermatogenesis [24,33]. Impaired folate status causes DNA hypomethylation that disrupts gene expression by inducing uracil misincorporation during DNA synthesis thereby leading to errors in DNA repair, strand breakage and chromosomal anomalies.…”

“…Montjean et al reported that no association was found between MTHFR (A1286C, C677T, and G203A), MTRR (A66G and C524T) genetic variants and sperm counts in French population [43]. Ravel et al failed to detect an association between among three variants in MTHFR (G203A, C665T, and A1286C), two variants in MTRR (A66G and C524T), a mutation in the CBS gene (G919A) and reduced sperm counts in infertile individuals of French ethnic origin [24]. On the other hand, Lee et al [13] investigated the relationship between polymorphisms of three folate metabolism enzymes (MTHFR C677T and A1298C, MTR A2756G, and MTRR A66G) and nonobstructive Korean male infertility.…”

“…A large number of molecular epidemiological studies have been conducted to evaluate the role of the three folate-related enzyme gene (MTHFR, MTR and MTRR) polymorphisms in male infertility [11,13,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. However, the association between polymorphism and the risk of male infertility is still controversial.…”

Association between C677T and A1298C polymorphisms of the MTHFR gene and risk of male infertility: a meta-analysis

“…Overall, 24 case-control articles (Bezold et al, 2001;Ebisch et al, 2003;Stuppia et al, 2003;Park et al, 2005;Lee et al, 2006;Paracchini et al, 2006;A et al, 2007;Dhillon et al, 2007;Sun et al, 2007;Ravel et al, 2009;Singh et al, 2005Singh et al, , 2010Gava et al, 2011;Liu, 2011;Qiu et al, 2011;Safarinejad et al, 2011;Eloualid et al, 2012;Vani et al, 2012;Karimian and Colagar, 2014;Li et al, 2014a,b;Mfady et al, 2014;Naqvi et al, 2014;Ni et al, 2015) were included in this meta-analysis. There were 21 studies of C677T with 4505 cases and 4024 controls, and 13 studies of A1298C with 2785 cases and 3094 controls.…”