The Association Study Between Variants In Apoptosis Pathway And Anti-oxidant Pathway And Idiopathic Male Infertility

Infertility is a world wide problem affecting about10%-15%couples, among which50%cases are caused by male factors. spermatogenesis failure including azoospermia or serve oligospermia is an important reason for male infertility, accounted for10%of infertile cases.Many factors including environment, genetic background, living habits and gene regulations will affect spermatogenesis process. The deletion, mutation, abnormal expressions of genes may result in spermatogenesis failure, leading to oligospermia or azoospermia. Gene polymorphism especially single nucleotide polymorphism (SNP) is most the common human genetic variation. Single nucleotide polymorphism is an important reason for the difference in gene function, more and more researches showed male infertility especially spermatogenesis failure is associated with some SNPs. This study is aimed to clarify whether SNPs in apoptosis pathway and anti-oxidant pathway are associated with male infertility.We chose two key regulating genes in apoptosis pathway, p53and MDM2, and11Tag SNPs in GPX1, CAT, PON1, NQO1, SOD2/MnSOD and SOD3in anti-oxidant pathway based on the gene’s sequences and function, all SNPs are genotyped by the Openarray system. We aimed to study the relationship between apoptosis/anti-oxidant pathway and idiopathic male infertility. The results will contribute to a more comprehensive evaluation of male infertility for genetic susceptibility factors. Part Ⅰ Genetic variants in apoptosis pathway associated with male infertilityHuman p53gene located in17p13.1, transcripted into2.5kb mRNA, coded393amino acids, its protein molecular weight is53kd. It is a transcriptional regulator and tumor suppressor, p53can regulate sperm apoptosis and occupies an important position in the process of spermatogenesis. When the p53acquires abnormal activity, sperm production and fertility rate decline. MDM2is a key regulator of the p53pathway and modulates p53activity. Both proteins have been functionally linked to germ cell apoptosis, which may affect human reproduction, but little is known about polymorphisms in these genes influencing germ cell apoptosis and the risk of male infertility. Thus, this study was designed to test whether three previously described polymorphisms p5372Arg>Pro (rs1042522) and the Ex2+19C>T (rs2287498), and the MDM25’untranslated region (5’UTR)309T>G (rs937283), are associated with idiopathic male infertility in a Chinese population. The three polymorphisms were genotyped using OpenArray assay in a hospital-based case-control study, including580idiopathic infertile patients and580fertile controls from a Chinese Han Population. Our analyses revealed that p53Ex2+119C>T and MDM2309T>G polymorphisms are associated with male infertility. People with Ex2+19C>T (rs2287498)TT genotype have a2.11times higher risk than CC genotype. People with MDM2309T>G (rs937283) GG genotype have a1.55times higher risk than TT genotype. Furthermore, we analysis the additive interaction between p53rs2287498and MDM2rs937283for the development of male infertility(Pinteraction=0.055), but the result is not statistic significant. Part Ⅱ Genetic variants in antioxidant pathway associated with idiopathic male infertilityThis study is aimed to test the hypothesis that polymorphisms in antioxidant pathway are more susceptible to sperm DNA damage and idiopathic male infertility,11single-nucleotide polymorphisms from six antioxidant genes (GPX1, CAT, PON1, NQO1, SOD2/MnSOD, and SODS) in580idiopathic infertility cases and580controls from a Chinese Population are selected, based on case-control study. Genotypes were determined by the OpenArray platform, what’s more, we analysis the relationship between sperm DNA damage and these SNPs. Adjusted OR and95%confidence interval (CI) were estimated using unconditional logistic regression. The results indicated that the PON1Arg192Glu (rs662) and SOD2Vall6Ala (rs4880) variants were associated with a significantly higher risk of idiopathic male infertility. Subjects carrying variants of both loci had a two fold (95%CI:1.42-2.90) increase in the risk of male infertility, indicating a significant gene-gene interaction between the two loci (P for additive/multiplicative interaction=0.016/0.045). In addition, the gene-environment interaction analysis show that PON1Arg192Glu (rs662) and SOD2Vall6Ala (rs4880) variants don’t have a significant interaction with smoking (additive interaction:PPON1=0326, PSOD2=0.566. Multiplicative interaction: PPON1=0.067, PSOD2=0.275). Moreover, linear regression analysis showed that individuals carrying the PON1Arg192Glu (rs662) or SOD2Vall6Ala (rs4880) variants have significantly higher levels of sperm DNA fragmentation and8-OHdG. These datas suggest that genetic variations in antioxidant genes may contribute to oxidative sperm DNA damage and idiopathic male infertility.