Institute of Toxicology, Nanjing Medical University, Nanjing, China.
Hum Reprod. 2013 Sep;28(9):2440-9. doi: 10.1093/humrep/det234. Epub 2013 May 21.
What are the genetic causes for the predisposition of certain Y chromosome haplogroups (Y-hgs) to spermatogenic impairment?
The AZFc(azoospermia factor c)/DAZ (deleted in azoospermia) duplications might underlie the susceptibility of Y-hg K* to spermatogenic impairment.
The roles of Y chromosomal genetic background in spermatogenesis are controversial and vary among human populations. Individuals in predisposed Y-hgs may carry some genetic factors, which might be a potential genetic modifier for the Y-hg-specific susceptibility to spermatogenic impairment.
STUDY DESIGN, SIZE, DURATION: A total of 2444 individuals with azoospermia or oligozoospermia and 2456 healthy controls were recruited to this study from March 2004 and January 2011.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a two-stage association study to investigate the risk and/or protective Y-hgs for spermatogenic impairment. In addition, the genetic causes for the predisposition of certain Y-hg to spermatogenic impairment were investigated. Deletion typing and DAZ gene copy number quantification were performed for individuals in predisposed Y-hgs.
Y-hgs K* and O3e* showed significantly different distribution between cases and controls consistently in two-stage studies. Combined analyses identified significant predisposition to non-obstructive azoospermia in Y-hg K* [odds ratio (OR) 8.58; 95% confidence interval (CI) 3.31-22.28; P = 1.40 × 10⁻⁵], but a protecting effect in Y-hg O3e* (OR 0.64; 95% CI 0.53-0.78; P = 4.20 × 10⁻⁵). Based on the dynamic nature of the Y chromosome, we hypothesized that Y-hgs K* and O3e* may be accompanied by modifying genetic factors for their predisposing or protecting effects in spermatogenesis. Accordingly, we quantified the multi-copy DAZ gene, which has variable copy numbers between individuals and plays an important role in spermatogenesis. In combined analysis, we found that the over-dosage of DAZ was significantly more frequent in Y-hg K* than in O3e* (OR 4.79; 95% CI 1.67-13.70; P = 6 × 10⁻³).
LIMITATIONS, REASONS FOR CAUTION: Owing to the inconsistency of genetic background, it remains to be determined whether the results derived from Han Chinese populations are applicable to other ethnic groups.
The findings of this study can advance the etiology of spermatogenic impairment, and also shed new light on Y chromosome evolution in human populations. Y-hg-specific genetic factors of modifying spermatogenic phenotypes deserve further investigation in larger and diverse populations.
哪些遗传因素导致某些 Y 染色体单倍群（Y-hgs）易发生精子发生障碍？
AZFc（无精子因子 c）/DAZ（缺失型无精子症）重复可能是 Y-hg K*易发生精子发生障碍的基础。
Y 染色体遗传背景在精子发生中的作用存在争议，并且在不同人群中存在差异。处于易感性 Y-hgs 的个体可能携带一些遗传因素，这些因素可能是 Y-hg 特异性精子发生障碍易感性的潜在遗传修饰因子。
研究设计、大小、持续时间：本研究共招募了 2444 名无精子症或严重少精子症患者和 2456 名健康对照者，时间为 2004 年 3 月至 2011 年 1 月。
参与者/材料、地点、方法：我们进行了两阶段关联研究，以调查精子发生障碍的风险和/或保护性 Y-hgs。此外，还研究了某些 Y-hg 易发生精子发生障碍的遗传原因。对处于易感性 Y-hgs 的个体进行缺失型检测和 DAZ 基因拷贝数定量。
在两阶段研究中，Y-hgs K和 O3e在病例和对照组之间的分布始终存在显著差异。综合分析表明，Y-hg K* 易发生非梗阻性无精子症（比值比[OR]8.58；95%置信区间[CI]3.31-22.28；P=1.40×10⁻⁵），但 Y-hg O3e* 具有保护作用（OR 0.64；95%CI 0.53-0.78；P=4.20×10⁻⁵）。基于 Y 染色体的动态性质，我们假设 Y-hgs K和 O3e可能伴随着修饰性遗传因素，从而导致其在精子发生中具有易感性或保护性作用。因此，我们对多拷贝 DAZ 基因进行了定量分析，该基因在个体之间具有可变的拷贝数，在精子发生中起着重要作用。在综合分析中，我们发现 Y-hg K* 的 DAZ 基因超量表达明显多于 O3e*（OR 4.79；95%CI 1.67-13.70；P=6×10⁻³）。
局限性、谨慎的原因：由于遗传背景不一致，汉族人群的研究结果是否适用于其他种族仍有待确定。
本研究的结果可以推进精子发生障碍的病因学研究，并为人类群体中 Y 染色体进化提供新的线索。修饰精子发生表型的 Y-hg 特异性遗传因素值得在更大、更多样化的人群中进一步研究。
