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Human Genetics

, Volume 132, Issue 12, pp 1405–1411 | Cite as

HLA-DPB1*04:01 allele is associated with non-obstructive azoospermia in Japanese patients

  • Timothy A. Jinam
  • Hirofumi Nakaoka
  • Kazuyoshi Hosomichi
  • Shigeki Mitsunaga
  • Hiroyuki Okada
  • Atsushi Tanaka
  • Kenichi Tanaka
  • Ituro InoueEmail author
Original Investigation

Abstract

Azoospermia is defined by absence of sperm in the semen and can either be caused by obstruction of the seminal tract (obstructive azoospermia) or by defects in spermatogenesis (non-obstructive azoospermia, NOA). Previous studies reported that specific alleles and single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region were associated with NOA in East Asians. We attempt to expand upon previous findings by genotyping more HLA genes and to replicate SNP associations by focusing on Japanese NOA patients. HLA typing of six genes (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) was done on 355 NOA patients using SSO-Luminex assay while genotyping of two previously reported SNPs (rs498422 and rs3129878) was done on 443 patients and 544 fertile males using TaqMan assay. Association between the HLA alleles and SNP with NOA was assessed with Chi squared and logistic regression tests. We found that HLA-DPB1*04:01 [corrected p value, P c 7.13 × 10−6; odds ratio (OR) 2.52], DRB1*13:02 (P c 4.93 × 10−4, OR 1.97), DQB1*06:04 (P c 8.94 × 10−4, OR 1.91) and rs3129878 (p value 3.98 × 10−4; OR 1.32) showed significant association with NOA, however, these loci are in linkage disequilibrium with each other. The conditional logistic regression tests showed that DPB1*04:01 is independently associated with NOA, confirming the involvement of the HLA region in the etiology of NOA in Japanese patients.

Keywords

Human Leukocyte Antigen Varicocele Human Leukocyte Antigen Class Male Infertility Conditional Logistic Regression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors would like to thank to Ms. Satoh (NIG) and Ms. Okudaira (Tokai University) for their technical assistances. This work was supported by the Grant-in-Aid for Scientific Research on Innovative Areas (22133002), and “Genome Science” (No.221S0002) from Ministry of Education, Culture, Sports, Science and Technology of Japan (K.H, I.I).

Supplementary material

439_2013_1347_MOESM1_ESM.pdf (131 kb)
Supplementary material (PDF 130 kb)

References

  1. Colorado IA, Acquatella H, Catalioti F, Fernandez MT, Layrisse Z (2000) HLA class II DRB1, DQB1, DPB1 polymorphism and cardiomyopathy due to Trypanosoma cruzi chronic infection. Hum Immunol 61:320–325PubMedCrossRefGoogle Scholar
  2. Excoffier L, Lischer HEL (2010) Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour 10:564–567PubMedCrossRefGoogle Scholar
  3. Excoffier L, Laval G, Balding D (2003) Gametic phase estimation over large genomic regions using an adaptive window approach. Hum Genomics 1:7–19PubMedCrossRefGoogle Scholar
  4. Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR (2011) Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucl Acid Res 39:D913–D919CrossRefGoogle Scholar
  5. Gough SCL, Simmonds MJ (2007) The HLA region and autoimmune disease: associations and mechanisms of action. Curr Genomics 8:453–465PubMedCrossRefGoogle Scholar
  6. Ha H, Howard CA, Yeom YI, Abe K, Uehara H, Artzt K, Bennett D (1991) Several testis-expressed genes in the mouse t-complex have expression differences between wild-type and t-mutant mice. Dev Genet 12:318–332PubMedCrossRefGoogle Scholar
  7. Hamada AJ, Esteves SC, Agarwal A (2013) A comprehensive review of genetics and genetic testing in azoospermia. Clinics 68(Suppl 1):39–60PubMedCrossRefGoogle Scholar
  8. Hu Z, Xia Y, Guo X, Dai J, Li H, Hu H, Jiang Y, Lu F, Wu Y, Yang X, Li H, Yao B, Lu C, Xiong C, Li Z, Gui Y, Liu J, Zhou Z, Shen H, Wang X, Sha J (2011) A genome-wide association study in Chinese men identifies three risk loci for non-obstructive azoospermia. Nat Genet 44:183–186PubMedCrossRefGoogle Scholar
  9. Jamsai D, Grealy A, Stahl PJ, Schlegel PN, McLachlan RI, Morand E, O’Bryan MK (2013) Genetic variants in the human glucocorticoid-induced leucine zipper (GILZ) gene in fertile and infertile men. Andrology 1:451–455PubMedCrossRefGoogle Scholar
  10. Jarow JP, Espeland MA, Lipshultz LI (1989) Evaluation of the azoospermic patient. J Urol 142:62–65PubMedGoogle Scholar
  11. Kauppi L, Sajantila A, Jeffreys AJ (2003) Recombination hotspots rather than population history dominate linkage disequilibrium in the MHC class II region. Hum Mol Genet 12:33–40PubMedCrossRefGoogle Scholar
  12. Khattri A, Bhushan SS, Sireesha V, Gupta NJ, Chakravarty BN, Deendayal M, Prasad S, Singh L, Thangaraj K (2011) The TNP1 haplotype—GCG is associated with azoospermia. Int J Androl 34:173–182PubMedCrossRefGoogle Scholar
  13. Klein J, Sato A (2000) The HLA system. N Engl J Med 343:702–709PubMedCrossRefGoogle Scholar
  14. Lee JY, Dada R, Sabanegh E, Carpi A, Agarwal A (2011) Role of genetics in azoospermia. Urology 77:598–601PubMedCrossRefGoogle Scholar
  15. Luo H, Chen M, Cui Z, Yang R, Xu PC, Zhou XJ, Zhao MH (2011) The association of HLA-DQB1, -DQA1 and -DPB1 alleles with anti- glomerular basement membrane (GBM) disease in Chinese patients. BMC Nephrol 12:21PubMedCrossRefGoogle Scholar
  16. Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine (2001) Infertility: report on evaluation of the azoospermic male. American Urological Association, American Society for Reproductive MedicineGoogle Scholar
  17. Matsuzaka Y, Makino S, Okamoto K, Oka A, Tsujimura A, Matsumiya K, Takahara S, Okuyama A, Sada M, Gotoh R, Nakatani T, Ota M, Katsuyama Y, Tamiya G, Inoko H (2002) Susceptibility locus for non-obstructive azoospermia is localized within the HLA-DR/DQ subregion: primary role of DQB1*0604. Tissue Antigens 60:53–63PubMedCrossRefGoogle Scholar
  18. Mazarakis ND, Nelki D, Lyon MF, Ruddy S, Evans EP, Freemont P, Dudley K (1991) Isolation and characterization of a testis expressed developmentally regulated gene from the distal inversion of the mouse t-complex. Development 111:561–571PubMedGoogle Scholar
  19. Mitsunaga S, Suzuki Y, Kuwana M, Sato S, Kaneko Y, Homma Y, Narita A, Kashiwase K, Okudaira Y, Inoue I, Kulski JK, Inoko H (2012) Associations between six classical HLA loci and rheumatoid arthritis: a comprehensive analysis. Tissue Antigens 80:16–25PubMedCrossRefGoogle Scholar
  20. Miura H, Tsujimura A, Nishimura K, Kitamura M, Kondoh N, Takeyama M, Fujioka H, Sada M, Tsuji T, Matsumiya K, Takahara S, Okuyama A (1998) Susceptibility to non-obstructive azoospermia in Japanese men is linked to HLA class I antigen. J Urol 159:1939–1941PubMedCrossRefGoogle Scholar
  21. Nakaoka H, Mitsunaga S, Hosomichi K, Shyh-Yuh L, Sawamoto T, Fujiwara T, Tsutsui N, Suematsu K, Shinagawa A, Inoko H, Inoue I (2013) Detection of ancestry informative HLA alleles confirms the admixed origins of Japanese population. PLoS ONE 8:e60793PubMedCrossRefGoogle Scholar
  22. Okada H, Tajima A, Shichiri K, Tanaka A, Tanaka K, Inoue I (2008) Genome-wide expression of azoospermia testes demonstrates a specific profile and implicates ART3 in genetic susceptibility. PLoS Genet 4:e26PubMedCrossRefGoogle Scholar
  23. Pelliccione F, d’Angeli A, Cinque B, Falone S, Micillo A, Francavilla F, Amicarelli F, Gandini L, Francavilla S (2011) Activation of the immune system and sperm DNA fragmentation are associated with idiopathic oligoasthenoteratospermia in men with couple subfertility. Fertil Steril 95:2676–2679PubMedCrossRefGoogle Scholar
  24. Reijo R, Lee TY, Salo P, Alagappan R, Brown LG, Rosenberg M, Rozen S, Jaffe T, Straus D, Hovatta O, de la Chapelle A, Silber S, Page DC (1995) Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet 10:383–393PubMedCrossRefGoogle Scholar
  25. Robinson J, Waller MJ, Parham P, de Groot N, Bontrop R, Kennedy LJ, Stoehr P, Marsh SGE (2003) IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucl Acids Res 31:311–314PubMedCrossRefGoogle Scholar
  26. Takao T, Tsujimura A, Sada M, Goto R, Koga M, Miyagawa Y, Matsumiya K, Yamada K, Takahara S, Okuyama A (2004) Susceptibility gene for non-obstructive azoospermia in the HLA class II region: correlations with Y chromosome microdeletion and spermatogenesis. Int J Androl 27:37–41PubMedCrossRefGoogle Scholar
  27. Tsujimura A, Ota M, Katsuyama Y, Sada M, Miura H, Matsumiya K, Gotoh R, Nakatani T, Okuyama A, Takahara S (2002) Susceptibility gene for non-obstructive azoospermia located near HLA-DR and -DQ loci in the HLA class II region. Hum Genet 110:192–197PubMedCrossRefGoogle Scholar
  28. Tsujimura A, Fujita K, Komori K, Tanjapatkul P, Miyagawa Y, Takada S, Matsumiya K, Sada M, Katsuyama Y, Ota M, Okuyama A (2006) Associations of homologous RNA-binding motif gene on the X chromosome (RBMX) and its like sequence on chromosome 9 (RBMXL9) with non-obstructive azoospermia. Asian J Androl 8:213–218PubMedCrossRefGoogle Scholar
  29. Zhao H, Xu J, Zhang H, Sun J, Sun Y, Wang Z, Liu J, Ding Q, Lu S, Shi R, You L, Qin Y, Zhao X, Lin X, Li X, Feng J, Wang L, Trent JM, Xu C, Gao Y, Zhang B, Gao X, Hu J, Chen H, Li G, Zhao J, Zou S, Jiang H, Hao C, Zhao Y, Ma J, Zheng SL, Chen ZJ (2012) A genome-wide association study reveals that variants within the HLA region are associated with risk for nonobstructive azoospermia. Am J Hum Genet 90:900–906PubMedCrossRefGoogle Scholar
  30. Zhou DX, Zhang J, Wang HX, Wang XF, Tian Z, Zhao WB, Han SP, Zhang J, Huo YW, Tian H (2011) Association study of HLA-B alleles with idiopathic male infertility in Han population of China. J Assist Reprod Genet 28:979–985PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Timothy A. Jinam
    • 1
  • Hirofumi Nakaoka
    • 1
  • Kazuyoshi Hosomichi
    • 1
  • Shigeki Mitsunaga
    • 2
  • Hiroyuki Okada
    • 3
  • Atsushi Tanaka
    • 4
  • Kenichi Tanaka
    • 5
  • Ituro Inoue
    • 1
    Email author
  1. 1.Division of Human GeneticsNational Institute of GeneticsMishimaJapan
  2. 2.Department of Molecular Life SciencesTokai University School of MedicineIseharaJapan
  3. 3.Department of Obstetrics and GynaecologyJyoetsu General HospitalJyoetsuJapan
  4. 4.St. Mother’s HospitalKitakyushuJapan
  5. 5.Department of Obstetrics and GynaecologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan

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