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The technical developments and expanded indications for testicular sperm extraction (TESE) with intracytoplasmic sperm injection (ICSI) provide great advantages for patients with non-obstructive azoospermia. Such success, however, also means that genetic abnormalities in non-obstructive azoospermia can be transmitted to the next generation, demonstrating the importance of being able to understand the genetic background of non-obstructive azoospermia. We have previously reported that human leukocyte antigens (HLA)-A33 and -B44 in the HLA class I region and the HLA-DRB1*1302 allele in the HLA class II region are linked to susceptibility to non-obstructive azoospermia in Japanese men. However, strong linkage of HLA-DRB1*1302 with HLA-A33 and -B44 is also evident in the Japanese population. Thus, uncertainty prevails as to whether the HLA class I or class II molecule is more directly associated with non-obstructive azoospermia. In the present study, we performed association analysis with 21 polymorphic microsatellite markers identified near the HLA genes to map the gene involved in the development of non-obstructive azoospermia more precisely. Microsatellite markers located in the HLA class I region or the class III region showed no statistically significant association with this disorder, although once again the HLA-A33 and -B44 alleles showed a significant association. In contrast, some of the microsatellite markers in the HLA class II region and at the HLA-DRB1 and -DQB1 loci displayed strong associations with non-obstructive azoospermia. Taken together, our previous and present data suggest that the critical region for development of non-obstructive azoospermia is near the HLA-DRB1 and -DQB1 segments in the HLA class II region.

We previously reported that the HLA-A33, -B13, and -B44 antigens, which are major histocompatibility complex class I molecules, are involved in the susceptibility of nonobstructive azoospermia in Japanese men. In this report, HLA-DR antigens, which are class II molecules, are investigated by advanced DNA typing in addition to classical serological typing to study a more complex genotype of HLA-DRB2. Genotyping was performed by the polymerase chain reaction-sequence-specific primer (PCR-SSP) method of analysis and/or by a commercial rapid assay based on the polymerase chain reaction (PCR), followed by reverse dot-blot hybridization of PCR products (the Inno-LiPA assay). The allele frequencies of the HLA-DR13 antigen and the -DRB1*1302 allele were significantly higher in Japanese subjects with nonobstructive azoospermia compared with a control group of healthy Japanese men, and these alleles were associated with relative risks for nonobstructive azoospermia of 4.2 and 4.9, respectively. If we suppose this strong linkage to both HLA class I and II antigens is due to linkage disequilibrium, it may suggest the existence of a novel gene involved in spermatogenesis in the class III region, which is located between the class I and class II regions and contains several genes other than HLA.

Purpose: Approximately 15 to 20% of infertile men have azoospermia. In the Y chromosome a deletion, termed the azoospermic factor, has been found in some cases of idiopathic azoospermia. We investigate the relationship of factors in autosomal chromosomes (HLA class I antigens) to spermatogenesis failure in idiopathic azoospermia., Materials and Methods: We evaluated 65 infertile Japanese men with idiopathic azoospermia. The frequency of the HLA allele reported in 1,216 healthy Japanese men was used as a control. HLA class I typing was performed by the National Institutes of Health standard serological method or polymerase chain reaction-sequence specific primer analysis. Allele frequencies were calculated. We determined statistical significance in the frequency of each allele in patients and controls using the chi-square test. The relationship of HLA antigens to idiopathic azoospermia was expressed as relative risk., Results: In Japanese men with idiopathic azoospermia the frequency of HLA-A33, B13 and B44 was significantly increased compared with controls. The relative risk of HLA-B44 was 8.4, an extremely high value compared with that of other diseases and HLA antigens., Conclusions: We suggest that HLA class I antigens are important genetic markers that represent a risk factor for idiopathic azoospermia.