Abstract
BackgroundMethylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate and affects the activity of cellular cycles participating in nucleotide synthesis, DNA repair, genome stability, maintenance of methyl pool, and gene regulation. Genetically compromised MTHFR activity has been suggested to affect male fertility. The objective of the present study was to find the impact on infertility risk of c.203G>A, c.1298A>C, and c.1793G>A polymorphisms in the MTHFR gene.MethodsPCR-RFLP and DNA sequencing were used to genotype the common SNPs in the MTHFR gene in 630 infertile and 250 fertile males. Chi-square test was applied for statistical comparison of genotype data. Linkage disequilibrium between the SNPs and the frequency of common haplotypes were assessed using Haploview software. Biochemical levels of total homocysteine (tHcy) and folic acid were measured. Meta-analysis on c.1298A>C polymorphism was performed using data from ten studies, comprising 2734 cases and 2737 controls.Resultsc.203G>A and c.1298A>C were found to be unrelated to infertility risk. c.1793G>A was protective against infertility (P = 0.0008). c.677C>T and c.1793G>A were in significant LD (D’ = 0.9). Folic acid and tHcy level did not correlate with male infertility. Pooled estimate on c.1298A>C data from all published studies including our data showed no association of this polymorphism with male infertility (Odds ratio = 1.035, P = 0.56), azoospermia (Odds ratio = 0.97, P = 0.74), or oligoasthenoteratozoospermia (Odds ratio = 0.92, p = 0.29). Eight haplotypes with more than 1% frequency were detected, of which CCGA was protective against infertility (p = 0.02), but the significance of the latter was not seen after applying Bonferroni correction.ConclusionAmong MTHFR polymorphisms, c.203G>A and c.1298A>C do not affect infertility risk and c.1793G>A is protective against infertility. Haplotype analysis suggested that risk factors on the MTHFR locus do not extend too long on the DNA string.
Highlights
Infertility is the inability of a couple to conceive even after one year of regular, unprotected intercourse
Etiological factors acting at pre-testicular, testicular, or post-testicular level may alter sperm production and/or function [4,5]. Genetic factors, such as Y-chromosomal microdeletions, chromosomal anomalies, and copy number variations (CNVs) in the genes involved in testicular function have been identified to be causative or risk factors for male infertility [6]
A study on adult mouse showed that the key enzyme of the folate pathway is five times more active in testes in comparison to other organs, suggesting its critical role in spermatogenesis [7]
Summary
Infertility is the inability of a couple to conceive even after one year of regular, unprotected intercourse. Etiological factors acting at pre-testicular, testicular, or post-testicular level may alter sperm production and/or function [4,5]. Genetic factors, such as Y-chromosomal microdeletions, chromosomal anomalies, and copy number variations (CNVs) in the genes involved in testicular function have been identified to be causative or risk factors for male infertility [6]. Folate metabolic pathway plays important roles in cellular physiology by participating in nucleotide synthesis, DNA repair and methylation, and maintenance and stability of the genome. Methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate and affects the activity of cellular cycles participating in nucleotide synthesis, DNA repair, genome stability, maintenance of methyl pool, and gene regulation. The objective of the present study was to find the impact on infertility risk of c.203G.A, c.1298A.C, and c.1793G.A polymorphisms in the MTHFR gene
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