title: An association study of four candidate loci for human male fertility traits with male infertility.
abstract: OBJECTIVE
  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?
  
  
  CONCLUSIONS
  rs7867029, rs7174015 and rs12870438 are significantly associated with the risk of male infertility in a Japanese population.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  The three infertility-associated SNPs may be contributing to a quantitative reduction in spermatogenesis.
  
  
  BACKGROUND
  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.
authors.affiliation: 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.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Sato
authors.affiliation: 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.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.affiliation: Department of Pharmaceutical Information Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8505, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Tsunematsu
authors.affiliation: Department of Urology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Shiari
authors.initials: S
authors.lastname: Nozawa
authors.affiliation: Department of Urology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Yoshiike
authors.affiliation: Department of Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan.
authors.forename: Eitetsue
authors.initials: E
authors.lastname: Koh
authors.affiliation: Department of Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kanaya
authors.affiliation: Department of Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Namiki
authors.affiliation: Department of Urology, Osaka Police Hospital, Osaka 543-0035, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Matsumiya
authors.affiliation: Department of Urology, Graduate School of Medicine, Faculty of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tsujimura
authors.affiliation: Department of Urology, Harasanshinkai Hospital, Fukuoka 812-0033, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Komatsu
authors.affiliation: Department of Urology, Sapporo Medical University, Sapporo 060-8543, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Itoh
authors.affiliation: Department of Urology, Nagasaki University, Nagasaki 852-8523, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Eguchi
authors.affiliation: Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.affiliation: Department of Pharmaceutical Information Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8505, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Yamauchi
authors.affiliation: Department of Urology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan Center for Infertility and IVF, International University of Health and Welfare Hospital, Nasushiobara 329-2763, Japan.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Iwamoto
mesh_terms: D001213:Asian / Q000235:genetics*; D053713:Azoospermia / Q000235:genetics; D016022:Case-Control Studies; D005298:Fertility / Q000235:genetics*; D005787:Gene Frequency; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D007564:Japan / Q000208:ethnology; D008297:Male; D009845:Oligospermia / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D005819:Genetic Markers
keywords: Japanese population; azoospermia; case–control association study; male infertility; oligozoospermia