title: DAZ duplications confer the predisposition of Y chromosome haplogroup K* to non-obstructive azoospermia in Han Chinese populations.
abstract: OBJECTIVE
  What are the genetic causes for the predisposition of certain Y chromosome haplogroups (Y-hgs) to spermatogenic impairment?
  
  
  CONCLUSIONS
  The AZFc(azoospermia factor c)/DAZ (deleted in azoospermia) duplications might underlie the susceptibility of Y-hg K* to spermatogenic impairment.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  A total of 2444 individuals with azoospermia or oligozoospermia and 2456 healthy controls were recruited to this study from March 2004 and January 2011.
  
  
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Toxicology, Nanjing Medical University, Nanjing, China.
authors.forename: Chuncheng
authors.initials: C
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Lu
authors.forename: Miaofei
authors.initials: M
authors.lastname: Xu
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Qin
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Shilin
authors.initials: S
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Shuping
authors.initials: S
authors.lastname: Yang
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.forename: Jiahao
authors.initials: J
authors.lastname: Sha
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
mesh_terms: D000328:Adult; D044466:Asian People; D053713:Azoospermia / Q000209:etiology; D016022:Case-Control Studies; D002681:China; D041322:Chromosomes, Human, Y; D000075364:Deleted in Azoospermia 1 Protein; D018628:Gene Dosage; D020440:Gene Duplication; D056726:Genetic Association Studies; D050174:Genetic Diseases, Y-Linked / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009845:Oligospermia / Q000209:etiology; D010802:Phylogeny; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C095668:DAZ1 protein, human; D000075364:Deleted in Azoospermia 1 Protein; D016601:RNA-Binding Proteins
keywords: DAZ gene; Y chromosome haplogroup; chromosomal rearrangement; copy number; spermatogenic impairment