Strong Association of 677 C>T Substitution in the MTHFR Gene with Male Infertility - A Study on an Indian Population and a Meta-Analysis

Abstract

BackgroundMethylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies.Methodology/Principal FindingsWe undertook genotyping on a total of 837 individuals including well characterized infertile (N = 522) and confirmed fertile (N = 315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included ‘Pubmed’, ‘Ovid’ and ‘Google Scholar’. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p = 0.0025) and genotypes (CT+TT) (p = 0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p = 0.000), 1.310 (p = 0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility.Conclusions/Significance677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

“…Many studies have revealed discrepant findings between Caucasians and Asians. 21,35,51 It seems most likely that this is related to dietary factors, such as folic acid intake; however; caution should be applied when generalizing the following recommendations to the Asian-American population.…”

“…20 The potential associations between MTHFR genotype status and a number of medical complications have been evaluated using methodologies such as case-control, cohort, Mendelian randomization, and meta-analysis. A modest positive association has been found between the MTHFR "thermolabile" polymorphism and many different medical complications, including, but not limited to, thromboembolic disease (in non-North-American populations only), 21,22 stroke, [23][24][25][26][27] aneurysm, 28 peripheral artery disease, 29 migraine, 30 hypertension, 31,32 recurrent pregnancy loss, 33,34 male infertility, 35,36 risk for offspring with neural tube defects, 37,38 certain cancers, [39][40][41] neuropsychiatric disease, 42 and chemotherapy toxicity. 43,44 …”

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.…”

“…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.…”

The role of epigenetics in idiopathic male infertility

“…Recently, some copy number variations (CNV) have been described to be associated with severe oligozoospermia or Sertoli-cell-only (SCO) syndrome or both [6]. In addition, some autosomal deletions, rare X-linked CNV, DNA repair mechanism defects, Y-linked syndromes, and some single nucleotide polymorphisms (SNPs) have been found to be associated with male factor infertility [7][8][9][10][11][12][13]. Although some specific mutations have been identified, other factors responsible for the sperm defects remain unknown.…”