title: Gene variation and premature ovarian failure: a meta-analysis.
abstract: OBJECTIVE
  Premature ovarian failure (POF) is a complex, heterogeneous disorder that is influenced by multiple genetic components. This meta-analysis aimed to investigate the association between gene variants and susceptibility to POF.
  
  
  METHODS
  MEDLINE and CNKI were searched for studies published from inception (1950) to June 2014. Meta-analysis was performed when three or more studies reported genetic data on the same polymorphism or mutation. Additive and dominant models were analyzed using RevMan Version 5.1.
  
  
  RESULTS
  The literature search yielded 575 articles, of which 59 studies on the association between POF and gene variants were identified for meta-analysis. Five genes were selected for analysis, including 10 common gene polymorphisms [BMP15 (-9C>G, 788insTCT and 852C>T), ESR1 (-351A>G and -397C>T), FMR1 CGG repeat, FSHR (919A>G and 2039A>G), INHA (-16C>T and -124A>G)] and two mutations (BMP15 538G>A and INHA 769G>A). BMP15 538G>A was found to be significantly more common in patients with POF compared with controls. No significant associations were found between the other variants of BMP15 and POF. With respect to ESR1, the accumulative results were not significant, although the findings of the individual studies were controversial. The incidence of FMR1 premutation was significantly higher in patients with POF compared with controls [odds ratio (OR) 9.2, 95% confidence interval (CI) 5.42-15.61; p<0.001] in the overall population, as well as in both Caucasian and Asian subgroups. Stratified analysis was applied for INHA 769G>A by ethnicity; a significant association with POF was only found in the Asian subgroup (allelic frequency: OR 8.89, 95% CI 2.1-5.52; p=0.004). No significant associations were found between the other variants of INHA and POF.
  
  
  CONCLUSIONS
  BMP15 538A, FMR1 premutation and INHA 769A (in Asians alone) may indicate susceptibility to POF. Further well-designed studies and larger samples are required to confirm the association between gene variants and POF.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
authors.forename: D
authors.initials: D
authors.lastname: Pu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Obstetrics and Gynaecology, Huai'an First People's Hospital, Huai'an, Jiangsu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Obstetrics and Gynaecology, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China. Electronic address: jie.wuyale@gmail.com.
authors.forename: J
authors.initials: J
authors.lastname: Wu
mesh_terms: D055430:Bone Morphogenetic Protein 15 / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007265:Inhibins / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D044469:Racial Groups / Q000235:genetics; D011962:Receptors, FSH / Q000235:genetics*
chemical_list: D055430:Bone Morphogenetic Protein 15; D047628:Estrogen Receptor alpha; D051860:Fragile X Messenger Ribonucleoprotein 1; D007265:Inhibins; D011962:Receptors, FSH; C525901:BMP15 protein, human; C506487:ESR1 protein, human; C497683:FMR1 protein, human; C094377:inhibin-alpha subunit
keywords: BMP15; ESR1; FMR1; FSHR; INHA; Premature ovarian failure