**5. Polymorphism of genes that affect spermatogenesis**

Except xenobiotic detoxification gene polymorphisms, another target group of genes that are most probably involved in development of male infertility is genes take part in spermatogenesis. This group includes genes with different functions such as endocrine regulation of spermatogenesis (i.e., androgen receptor (AR), follicle-stimulating hormone receptor (FSHR) and Estrogen receptor α and β), specific spermatogenic functions (i.e., deleted azoospermia-like (DAZL), Ubiquitin carboxyl-terminal hydrolase 26 (USP26), protamine-1 (PRM1) and gonadotrophin-regulated testicular helicase (GRTH)), regulation of cell functions such as metabolism, cell cycle and mutation repair (i.e., mtDNA polymerase γ (POLG) and Methylene tetrahydrofolate reductase (MTHFR)) and Y-chromosome haplogroups. Y-chromosome abnormalities are the best studied, while data about association of male infertility with the other spermatogenesis regulation genes remain contradictory. For example, the spermatogenesis locus azoospermia factor c (AZFc) region partial deletion (gr/gr deletions, which include DAZ (Deleted in azoospermia) genes) is regarded as classical Y-chromosome mutation. Its role in male infertility was proven by several studies, although it is present in normospermic men as well [16, 23]. Here are some examples of the other probable risk factors obtained by meta-analysis [23]. One of gene candidates, which is regarded as the most probable risk factor of male infertility, is MTHFR, which encodes methylenetetrahydrofolate reductase—one of the key enzymes in folate metabolism. The C → T substitution in the position 667 changes an alanine to a valine (Ala222Val) and decreases activity of enzyme, thus leading to the decrement of spermatogenesis. FSHR SNP showed a significant association with seminal fluid abnormalities only in the case when both the exon 10 SNPs and SNP of promoter at position 29 are present. G197 T SNP in PRM1 gene, which encodes DNA-binding protein, responsible for packing of DNA into the sperm head, may by a novel risk factor for patients with a normal sperm count but elevated levels of sperm DNA fragmentation and/or teratozoospermia. Studying of the genes affecting spermatogenesis also demonstrated significant influence of ethnicity on the association of polymorphisms and the risk of male infertility. Thus, AR repeat length polymorphism with repeat number more than 23 is a risk factor for Asiatic but not the European population. T54A mutation in exon 3 of DAZL gene was significantly associated with oligospermia or azoospermia in the Chinese population, while in Japanese or Caucasian populations, such an association was not established. The POLG gene, which encodes mtDNA polymerase γ and thus important for mitochondria functioning, has common 10-fold repeated CAG motif in the first exon. It is known that mitochondria are one of the main determinants of sperm motility, and their altered regulation may be connected with asthenozoospermia (which is characterized by reduced sperm motility). Nevertheless, only one study [24] among four considered [24–27] established that the absence of this allele was significantly associated with male infertility. These results may not be relevant enough, as far as the sample size was not sufficiently big, (verum group included 99 infertile men, while control, 98 fertile men). In spite of the increased interest in the genetic causes of male infertility, there are no clear predictive and diagnostic criteria, except few polymorphisms such as AZF gr/gr deletions (OR 1.81, 1.46–2.24 CI, P < 0.00001) and MTHFR 677C → T (OR 1.39, 1.15–2.69 95% CI, P = 0.0006) [16]. The only way to build an adequate picture of reasons standing behind idiopathic male infertility is application of methods based on whole genome analysis, taking into account environmental factors.
