• PMID: 25908656
• Gene Name: USP8
• Condition: Male infertility
• Association: Associated
• Mutation: rs7867029, rs7174015, rs12870438 and rs724078
• Population size: 917
• Population details: 917 (791 fertile men, 76 patients with azoospermia, 50 patients with oligozoospermia)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: PSAT, USP8, EPSTI1, MAS1L, UBD
• Other associated phenotypes: Male infertility

An association study of four candidate loci for human male fertility traits with male infertility

Sato Y, Tajima A, Tsunematsu K, Nozawa S, Yoshiike M, Koh E, Kanaya J, Namiki M, Matsumiya K, Tsujimura A, Komatsu K, Itoh N, Eguchi J, Imoto I, Yamauchi A, Iwamoto T.

STUDY QUESTION: Are the four candidate loci (rs7867029, rs7174015, rs12870438 and rs724078) for human male fertility traits, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with male infertility in a Japanese population? SUMMARY ANSWER: rs7867029, rs7174015 and rs12870438 are significantly associated with the risk of male infertility in a Japanese population. WHAT IS KNOWN ALREADY: Recently, a GWAS of a Hutterite population in the USA revealed that 41 single-nucleotide polymorphisms (SNPs) were significantly correlated with family size or birth rate. Of these, four SNPs (rs7867029, rs7174015, rs12870438 and rs724078) were found to be associated with semen parameters in ethnically diverse men from Chicago. STUDY DESIGN, SIZE, DURATION: This is a case-control association study in a total of 917 Japanese subjects, including 791 fertile men, 76 patients with azoospermia and 50 patients with oligozoospermia. PARTICIPANTS/MATERIALS, SETTING, METHODS: Azoospermia was diagnosed on the basis of semen analysis (the absence of sperm in ejaculate), serum hormone levels and physical examinations. Oligozoospermia was defined as a sperm concentration of <20 × 10(6)/ml. We excluded patients with any known cause of infertility (i.e. obstructive azoospermia, varicocele, cryptorchidism, hypogonadotropic hypogonadism, karyotype abnormalities or complete deletion of AZF a, b or c). The SNPs rs7867029, rs7174015, rs12870438 and rs724078 were genotyped using DNA from peripheral blood samples and either restriction fragment length polymorphism PCR or TaqMan probes. Genetic associations between the four SNPs and male infertility were assessed using a logistic regression analysis under three different comparative models (additive, recessive or dominant). MAIN RESULTS AND THE ROLE OF CHANCE: The genotypes of all four SNPs were in Hardy-Weinberg equilibrium in the fertile controls. The SNPs rs7867029 and rs7174015 are associated with oligozoospermia [rs7867029: odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.07-2.68, P = 0.024 (log-additive); rs7174015: OR = 6.52, 95% CI = 1.57-27.10, P = 0.0099 (dominant)] and rs12870438 is associated with azoospermia (OR = 10.90, 95% CI = 2.67-44.60, P = 0.00087 (recessive)] and oligozoospermia [OR = 8.54, 95% CI = 1.52-47.90, P = 0.015 (recessive)]. The association between rs7174015 and oligozoospermia under a dominant model and between rs12870438 and azoospermia under additive and recessive models remained after correction for multiple testing. There were no associations between rs724078 and azoospermia or oligozoospermia. LIMITATIONS, REASONS FOR CAUTION: Even though the sample size of case subjects was not very large, we found that three SNPs were associated with the risk of male infertility in a Japanese population. WIDER IMPLICATIONS OF THE FINDINGS: The three infertility-associated SNPs may be contributing to a quantitative reduction in spermatogenesis. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T. I.) and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare. CI - © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Sato, Youichi AU - Sato Y AD - Department of Pharmaceutical Information Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8505, Japan youichi.sato@tokushima-u.ac.jp atajima@med.kanazawa-u.ac.jp. FAU - Tajima, Atsushi AU - Tajima A AD - Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan youichi.sato@tokushima-u.ac.jp atajima@med.kanazawa-u.ac.jp. FAU - Tsunematsu, Kouki AU - Tsunematsu K AD - Department of Pharmaceutical Information Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8505, Japan. FAU - Nozawa, Shiari AU - Nozawa S AD - Department of Urology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan. FAU - Yoshiike, Miki AU - Yoshiike M AD - Department of Urology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan. FAU - Koh, Eitetsue AU - Koh E AD - Department of Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan. FAU - Kanaya, Jiro AU - Kanaya J AD - Department of Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan. FAU - Namiki, Mikio AU - Namiki M AD - Department of Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan. FAU - Matsumiya, Kiyomi AU - Matsumiya K AD - Department of Urology, Osaka Police Hospital, Osaka 543-0035, Japan. FAU - Tsujimura, Akira AU - Tsujimura A AD - Department of Urology, Graduate School of Medicine, Faculty of Medicine, Osaka University, Osaka 565-0871, Japan. FAU - Komatsu, Kiyoshi AU - Komatsu K AD - Department of Urology, Harasanshinkai Hospital, Fukuoka 812-0033, Japan. FAU - Itoh, Naoki AU - Itoh N AD - Department of Urology, Sapporo Medical University, Sapporo 060-8543, Japan. FAU - Eguchi, Jiro AU - Eguchi J AD - Department of Urology, Nagasaki University, Nagasaki 852-8523, Japan. FAU - Imoto, Issei AU - Imoto I AD - Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan. FAU - Yamauchi, Aiko AU - Yamauchi A AD - Department of Pharmaceutical Information Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8505, Japan.