Role of 677C→T polymorphism a single substitution in methylenetetrahydrofolate reductase (MTHFR) gene in North Indian infertile men

Abstract

Failure or severe difficulty in conceiving a child is surprisingly common, worldwide problem. Half of these cases are due to male factors with defects in sperm (1 in 15 men) being the single most common cause. Also about 60-75 % of male infertility cases are idiopathic, since the molecular mechanisms underlying the defects remain unknown. DNA methylation is crucial for spermatogenesis and high methylenetetrahydrofolate reductase (MTHFR) activity in adult testis than other organs in mouse, signifies its critical role in spermatogenesis. According to recent findings there is a correlation of epigenetic regulation of several imprinted genes with disturbed spermatogenesis and fertility. Consequently any change in the MTHFR gene sequence can modify the spermatogenesis including transmission of infertility to the carriers. The aim of the study is to analyze the distribution of the single nucleotide polymorphism C677T in the MTHFR gene in 637 North Indian infertile patients and 364 fertile North Indian men as controls by using PCR-RFLP technique and Chi Square test for statistical analysis. The average MTHFR 677CC, 677CT, 677TT genotype frequencies of total infertile men were 70.17, 24.17, 5.65 % in infertile men and 75.27, 21.7, 2.74 % in controls, respectively. The average frequency of the MTHFR 677T allele was 17.73 % in infertile men as compared to 13.59 % in controls. The statistical difference was significant. Disease risk was found 2.27-folds increased in patients who were carrying T allele. We found an association of C677T polymorphism with male infertility and that it may be a genetic risk factor for male infertility in North Indian population.

Evaluation of DNA methylation at imprinted DMRs in the spermatozoa of oligozoospermic men in association withMTHFRC677T genotype

“…Previous epidemiological studies have suggested ethnicity as a factor, where only certain ethnic populations revealed an association between this SNP and male infertility (Gupta et al, 2011;Chellat et al, 2012;Naqvi et al, 2014;Gong et al, 2015). The men in this study, however, were not evaluated for ethnicity.…”

“…A total of eight samples from fertile men, eight with moderate (5-15 million spermatozoa/mL), 20 with severe (1-5 million spermatozoa/mL), and eight with very severe (<1 million spermatozoa/mL) oligozoospermia were analyzed. PCR amplification was carried out in 25 lL reactions: 0.625 U HotStarTaq DNA polymerase (Qiagen), 19 PCR Buffer (Qiagen), 0.2 mM dNTPs, 0.5 lM forward and reverse primers (Naqvi et al, 2014), and 250-300 ng of DNA. The following cycling conditions were used: 95°C for 15 min; 44 cycles of 95°C for 45 sec, 65°C for 1 min, and 72°C for 1.5 min; and a final extension of 72°C for 5 min.…”

“…The persistence of altered DNA methylation patterns in the germline may therefore increase the risk for infertility. Indeed, the MTHFR C677T SNP has been more frequently found in many populations of infertile men (Gupta et al, 2011;Naqvi et al, 2014;Gong et al, 2015). However, to date, studies on DNA methylation in the spermatozoa of infertile men with oligozoospermia in association with the MTHFR C677T SNP have been limited.…”

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

“…A number of studies have evaluated the association of MTHFR gene polymorphism with male infertility [13, 38-40, 22, 27, 17, 16, 18, 29, 25, 41, 28, 42, 26, 21, 23]. The MTHFR C677T polymorphism was reported to be associated with male infertility in the German [42], Indian [26,18,17,38], Korean [23], Chinese [19] and Italian populations [41]. In contrast, Stuppia et al [28] and Ebisch et al [21] did not find any statistically significance of C677T variation in infertile men from Italy and the Netherlands.…”

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.…”