Studies On The Association Of XPC Gene Polymorphisms And Spermatogenic Failure

Infertility affects approximately 10% of couples attempting pregnancy and this rate is on the rise, with the man responsible in approximately half of the cases. Several factors have been proposed for male infertility and spermatogenic failure is confirmed to be a significant one, which typified by idiopathic non-obstructive azoospermia or oligozoospermia.spermatogenic failure is a complex disease which environmental,genetic factors and their interaction can affect it. But in the same environment, a variation in individual genetic susceptibility is generally assumed to be an important cause. The genetic etiology of spermatogenic failure have been identified and studied recently such as Y-chromosome microdeletions, chromosomal abnormalities, mutations and deletion of some genes.In male reproductive process, spermatogenesis is indispensable and a continuum of cellular differentiation in which three principal phases can be discerned: spermatogonia renewal and proliferation, meiosis, and spermiogenesis. Multiple genes are required and implicated in the process of spermatogenesis, and damage to the expression and function of these genes can lead to spermatogenic failure. Polymorphism especially single nucleotide polymorphisms (SNPs) are the most common genetic variants which can change the production and activity of the gene. Recently, several studies have found the association of SNPs with spermatogenic failure.An integrated DNA repair system exists in spermatogenesis which can repair a series of DNA damage in germ cell. Xeroderma pigmentosum complementation group C (XPC) is an important gene and is required for normal spermatogenesis. In this study, we investigated the SNPs in XPC gene on the risk of spermatogenic failure and the potential association between the SNPs and the semen quality in the Han-Chinese population. XPC Ala499Val(OT) and Lys939Gln(A>C) SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in three groups of the patients of spermatogenic failure (172 patients of idiopathic non-obstructive azoospermia , 25 patients of idiopathic severe oligozoospermia, 149 patients of idiopathic oligozoospermia) and 228 fertile men. Conventional semen analysis of patients of idiopathic oligozoospermia was examined by using computer-aided semen analysis (CASA) systems. Univariate and multivariate logistic regression analysis were performed to estimate the association between the SNPs and risk of spermatogenic failure and control the potential confouding factors such as age, smoking status, and alcohol use. Rank testing was used to analysis the distribution of sperm concentration and the total sperm count by different genotypes. For the XPC Ala499Val(C>T) polymorphism, the frequencies of the CC, CT, and TT genotypes were 29.1%, 49.4%, and 21.5% among the idiopathic azoospermic patients and 41.2%, 43.9%, and 14.9% among the controls. Significant difference was identified between the azoospermic patients and the controls (P=0.029). Increased risk of idiopathic azoospermia was associated with the XPC variant genotypes (CT or TT) of Ala499Val(C>T) [adjusted odds ratio (OR) = 1.67, 95% confidence interval (CI) = 1.04-2.68 for CT heterozygote and adjusted OR = 2.03, 95% CI = 1.10-3.75 for TT homozygote] compared with CC homozygous wide-type. The Lys939Gln(A>C) polymorphism was not related to idiopathic azoospermia. The combined risk alleles analysis and haplotype analysis showed the 499T-939C haplotype had a significantly increased risk of idiopathic azoospermia (OR=7.97; 95% CI=3.51-18.07) compared with other haplotypes and the ORs increased as the number of the risk alleles increased. The individuals with 2-4 risk alleles had a significantly higher risk of idiopathic azoospermia (adjusted OR=1.72, 95% CI=1.06-2.79, P = 0.018) than those with 0-1 risk alleles. No association was observed between these two SNPs and the risk of idiopathic severe oligozoospermia or oligozoospermia. In patients of idiopathic oligozoospermia, the association between different genotypes and semen quality was not found.The results suggested that XPC Ala499Val (C>T) polymorphism is correlated with high risk of idiopathic azoospermia and may be a potential genetic risk factor in idiopathic azoospermia in the Han-Chinese population. Further study with larger samples and more functional analysis are needed to elucidate the biological mechanism of these polymorphisms of XPC gene in idiopathic azoospermia.