Association Of Polymorphisms In FAS And FASLG Genes With Susceptibility To Idiopathic Azoospermia Or Severe Oligozoospermia

As WHO reported, human infertile problems affect 10%～15% ofcouples worldwide, half of which are due to male factors. The etiology of30% of male infertility has not been established. Recently studies haveshown that germ cell apoptosis is a biological progress involved invarious stages of mammalian testicular development. Moreover, it hasbeen proposed that excessive or inadequate germ cell apoptosis may bothresult in spermatogenesis impairment. By cross-linking with FAS,FASLG can trigger apoptotic signaling, mediating apoptosis of variouscell types. Recently, much attention has been paid to FAS/FASLG as a keysystem regulating germ cell apoptosis in testis.Gene polymorphisms, especially SNPs, are the most common humangenetic variations. Recently, more and more studies have indicated thatmale infertility, especially spermatogenesis impairment, may beassociated with some gene SNPs. FAS-1377G/A, -670A/G and FASLG-844C/T SNPs can influence the expression of FAS or FASLG and thenresult in germ cell apoptosis, leading to spermatogenesis impairment. Therefore, we hypothesized that FAS-1377G/A, -670A/G and FASLG-844C/T SNPs were associated with idiopathic azoospermia or severeoligozoospermia. To test this hypothesis, we performed a case-controlstudy and investigated the association of idiopathic azoospermia or severeoligozoospermia with independent role or combined effect of these SNPs.This study recruited 203 infertile men with idiopathic azoospermia orsevere oligozoospermia as cases and 246 proven fathers as controls. Wegenotyped FAS-1377G/A, -670A/G and FASLG -844C/T SNPs byPCR-RFLP methods, and calculated the relative risk (RR≈OR) ofidiopathic azoospermia or severe oligozoospermia among differentgenotypes. The results of the study are as follows: (1) Frequencies ofFASLG o844CC, CT and TT genotypes were 58.1%, 31.5% and 10.4%,respectively, among infertile cases and 58.5%, 37.4% and 4.1%,respectively, among fathered controls; the differences of genotypedistributions were statistically significant between cases and controls(P=0.024). The results obtained from logistic regression model haveshown that men with FASLG -844TT genotype had an increased risk ofidiopathic azoospermia or severe oligozoospermia compared with thosewith CC genotype (OR 2.56, 95% CI 1.10-6.33), the risk even higherbenig compared with (CC+CT) genotypes. (2) The genotype distributinnsof FAS -1377G/A and -670A/G SNP were not significantly differentbetween infertile cases and fathered controls. (3) FAS gene haplotype analysis and FAS and FASLG gene multiloci combined analysis revealedthat the distributions of haplotype-related genotypes of FAS -1377G/Aand -670A/G were not significantly different between infertile cases andfathered controls, and that the distributions of combined genotypes ofFAS and FASLG SNPs were not significantly different between cases andcontrols, either.Thus, we drew a preliminary conclusion that FASLG gene -844C/TSNP may be a genetic predisposing factor for idiopathic azoospermia orsevere oligozoospermia among Han Chinese men, and that FAS-1377G/Aand -670A/G SNPs were both not a independent risk factor for idiopathicazoospermia or severe oligozoospermia, and that haplotype-relatedgenotypes of FAS gene and combined genotypes of FAS and FASLGSNPs were not associated with idiopathic azoospermia or severeoligozoospermia. However, this study needs to be further tested amongdifferent human races and to be followed by functional investigation.