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?rs7867029, rs7174015 and rs12870438 are significantly associated with the risk of
male infertility in a Japanese population.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.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.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).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.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.The three infertility-associated SNPs may be contributing to a quantitative reduction
in spermatogenesis.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.