Significant impact of the MTHFR polymorphisms and haplotypes on male infertility risk.
Significant impact of the MTHFR polymorphisms and haplotypes on male infertility risk.
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DOI：
10.1371/journal.pone.0069180
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rajender S
中科院分区：
文献类型：
--
作者：
Gupta N;Sarkar S;David A;Gangwar PK;Gupta R;Khanna G;Sankhwar SN;Khanna A;Rajender S
亚甲基四氢叶酸还原酶（MTHFR）将5，10-亚甲基四氢叶酸转化为5-甲基四氢叶酸，并影响参与核苷酸合成、DNA修复、基因组稳定性、甲基库维持和基因调控的细胞周期的活性。基因受损的MTHFR活性已被认为会影响男性生育能力。本研究旨在探讨MTHFR基因c.203G>A、c.1298A>C和c.1793G>A多态性对不孕风险的影响。采用PCR-RFLP和DNA测序技术对630例不育男性和250例生育男性的MTHFR基因进行了SNPs分型。采用卡方检验对基因型数据进行统计学比较。使用Haploview软件评估SNPs之间的连锁不平衡和常见单倍型的频率。测定总同型半胱氨酸（tHcy）和叶酸的生化水平。对2734例病例和2737例对照的10个研究的数据进行Meta分析。c.203G>A和c.1298A>C与不孕风险无关。c.1793G>A对不孕有保护作用（P = 0.0008）。 c.677C>T和c.1793G>A均呈显著LD（D'= 0.9）。 叶酸和tHcy水平与男性不育无相关性。对所有已发表研究的c.1298A>C数据进行汇总估计，包括我们的数据，显示该多态性与男性不育（比值比= 1.035，P = 0.56）、无精子症（比值比= 0.97，P = 0.74）或少弱畸形精子症（比值比= 0.92，P = 0.29）无关。 检测到8种频率超过1%的单倍型，其中CCGA对不孕症有保护作用（p = 0.02），但在应用Bonferroni校正后，未发现后者的显著性。 在MTHFR基因多态性中，c.203G>A和c.1298A>C不影响不育风险，而c.1793G>A对不育具有保护作用。单倍型分析表明，MTHFR基因座上的危险因素不会在DNA串上延伸太长。
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. 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. 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. 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.
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