title: Significant impact of the MTHFR polymorphisms and haplotypes on male infertility risk.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  PCR-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.
  
  
  RESULTS
  c.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.
  
  
  CONCLUSIONS
  Among 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.
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Lucknow, India.
authors.forename: Nishi
authors.initials: N
authors.lastname: Gupta
authors.forename: Saumya
authors.initials: S
authors.lastname: Sarkar
authors.forename: Archana
authors.initials: A
authors.lastname: David
authors.forename: Pravin Kumar
authors.initials: PK
authors.lastname: Gangwar
authors.forename: Richa
authors.initials: R
authors.lastname: Gupta
authors.forename: Gita
authors.initials: G
authors.lastname: Khanna
authors.forename: Satya Narayan
authors.initials: SN
authors.lastname: Sankhwar
authors.forename: Anil
authors.initials: A
authors.lastname: Khanna
authors.forename: Singh
authors.initials: S
authors.lastname: Rajender
mesh_terms: D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)