DAZ duplications confer the predisposition of Y chromosome haplogroup K to non-obstructive azoospermia in Han Chinese populations
DAZ duplications confer the predisposition of Y chromosome haplogroup K to non-obstructive azoospermia in Han Chinese populations
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DAZ重复导致中国汉族人群中Y染色体单倍群K易患非梗阻性无精症
DOI：
10.1093/humrep/det234
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发表时间：
2013-09-01
影响因子：
6.1
通讯作者：
Wang, Xinru
中科院分区：
文献类型：
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作者：
Lu, Chuncheng;Wang, Ying;Wang, Xinru
某些Y染色体单倍群（Y-hgs）易患生精障碍的遗传原因是什么？AZFc（无精子症因子c）/DAZ（在无精子症中缺失）重复可能是Y-hg - K对生精障碍的易感性的基础。Y染色体遗传背景在精子发生中的作用是有争议的，并且在人群中有所不同。易感Y-hgs的个体可能携带一些遗传因子，这些遗传因子可能是Y-hgs特异性对生精障碍易感性的潜在遗传修饰因子。2004年3月至2011年1月，共招募了2444名无精子症或少精子症患者和2456名健康对照者。我们进行了一项两阶段的关联研究，以调查Y-hgs对生精障碍的风险和/或保护性。此外，还研究了某些Y-hg易致生精障碍的遗传原因。对易感Y-hgs个体进行缺失分型和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具有显著差异。综合分析发现，Y-hg - K有显著的非阻塞性无精子症倾向[比值比（OR） 8.58；95可信区间（CI） 3.3122.28；P 1.40 10(5)]，但Y-hg O3e有保护作用（OR 0.64; 95 CI 0.530.78; P 4.20 10(5)）。基于Y染色体的动态特性，我们假设Y-hgs - K和O3e可能伴随着改变的遗传因素，从而在精子发生中起到易感或保护作用。因此，我们量化了DAZ基因的多拷贝数，该基因在个体之间具有可变的拷贝数，在精子发生中起重要作用。综合分析，我们发现Y-hg K患者DAZ过量的发生率明显高于O3e患者（OR 4.79; 95 CI 1.6713.70; P 6.10(3)）。由于遗传背景的不一致性，从汉族人群中得出的结果是否适用于其他民族仍有待确定。本研究的发现可以推进致精功能障碍的病因学研究，也为人类Y染色体的进化提供了新的思路。y -hg特异性遗传因子修饰生精表型值得在更大和更多样化的人群中进一步研究。国家973计划（2009|CB941703, 2011CB944304和2012CB944600），国家自然科学基金（30930079,81100461和31000552），江苏省自然科学基金（BK2011774），中国高等学校博士点研究基金（RFDP）（20113234120001）。江苏省高校自然科学研究项目（11KJB330001）和江苏省高等学校发展重点学科项目（公共卫生与预防医学）。没有相互竞争的利益。
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.A total of 2444 individuals with azoospermia or oligozoospermia and 2456 healthy controls were recruited to this study from March 2004 and January 2011.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) 3.3122.28; P 1.40 10(5)], but a protecting effect in Y-hg O3e (OR 0.64; 95 CI 0.530.78; 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 1.6713.70; P 6 10(3)).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.Funding was provided by grants from National 973 Program (2009|CB941703, 2011CB944304 and 2012CB944600), National Natural Science Foundation of China (30930079, 81100461 and 31000552), Jiangsu Natural Science Foundation (BK2011774), Research Fund for the Doctoral Program of Higher Education of China (RFDP) (20113234120001), University Natural Science Research Project in Jiangsu Province (11KJB330001) and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). There were no competing interests.