O-5: The Influence of Genetic Polymorphism On Idiopathic Male Infertility

Background: Infertility is a multifactorial disorder affecting one in ten couples, and in 50% of infertile couples, the male factor due to deteriorated semen quality is a major cause. In about 30% of infertile men seeking help for their problem, the etiology and pathogenesis are not yet known and their condition is considered idiopathic. Through animal studies conducted recently, hundreds of genes have been found to be related to impaired spermatogenesis and reported as possible pathogenic mechanisms for idiopathic male infertility; however, their human counterparts need to be investigated in infertile patients. This study aims to examine if there is an association between endothelial nitric oxide synthase (eNOS) T-786C, G894T, and 4a/b gene; glutathione-S-transferase (GSTM1, GSTT1, GSTP1) gene; estrogen receptors alpha, and beta (ESR1, ESR2) gene; the (TAAAA)n repeat and Asp327Asn in the sex hormone-binding globulin (SHBG) gene; Methylenetetrahydrofolate reductase (C677T, A1298C, and G1793A) gene; and the follicle stimulating hormone (FSH) receptor gene Thr 307 -Ala and Asn 680 -Ser polymorphisms as risk factors for idiopathic male infertility. Materials and Methods: Genotypes for all gene polymorphisms were identified by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Reproductive hormones were measured and at least two semen analyses were performed in each subject. Results: Multivariate regression analysis showed an increase in risk to infertility in the patients with null genotype of GSTM1 (OR: 2.18; 95% CI: 1.64-3.32; p<0.001) or GSTT1 (OR: 1.88; 95% CI:1.12-2.52; p<0.04). There was a significant difference between the group of infertile patients with azoospermia and oligoasthenoteratozoospermia (OAT) when compared by genotype distribution (-786CC vs. 786TT, 894TT vs. 894GG, and 4aa vs. 4bb) (all p<0.01). Significant differences were observed in the frequency distribution of Pvull and XbaI in the ESR-α gene and RsaI and Alul in the ER-β gene between patients and controls. The variant Asp/Asn genotype was associated with a more than 50% reduced risk of infertility (OR: 0.46, 95% CI: 0.25-0.80, p=0.001). Genotype analysis demonstrated six SHBG (TAAAA)n alleles with 6-11 repeats. The 677T allele carriers (TC or TT) had a significantly increased risk of infertility compared with the CC homozygotes (OR:1.60, 95% CI:1.21- 2.75, and OR:2.68, 95% CI:1.84-3.44, respectively). No significant association between codon 680 and codon 307 genotypes and infertility was observed (p=0.076 and p=0.073, respectively). Conclusion: These results support the hypothesis of increased risk of GSTM1 or GSTT1null genotypes, eNOS genotypes, ESR-α, and ER-β variants, SHBG Asp237Asn and (TAAAA) n polymorphisms, MTHFR C677T polymorphism, and for developing infertility. We did not observe any significant association of FSH-R genotype frequencies with any of the sperm characteristics analysed in either group.