title: Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion.
abstract: 1) To perform the first comprehensive systematic review of genetic association studies (GASs) in idiopathic recurrent spontaneous abortion (IRSA); 2) to analyze studies according to recurrent spontaneous abortion (RSA) definition and selection criteria for patients and control subjects; and 3) to perform meta-analyses for the association of candidate genes with IRSA.
  
  
  
  Systematic review and meta-analysis.
  
  
  
  Not applicable.
  
  
  
  Couples with IRSA and their spontaneously aborted embryos.
  
  
  
  Summary odds ratios (ORs) were calculated by means of fixed- or random-effects models.
  
  
  
  Association of genetic variants with IRSA.
  
  
  
  The systematic review included 428 case-control studies (1990-2015), which differed substantially regarding RSA definition, clinical evaluation of patients, and selection of control subjects. In women, 472 variants in 187 genes were investigated. Meta-analyses were performed for 36 variants in 16 genes. Association with IRSA defined as three or more spontaneous abortions (SAs) was detected for 21 variants in genes involved in immune response (IFNG, IL10, KIR2DS2, KIR2DS3, KIR2DS4, MBL, TNF), coagulation (F2, F5, PAI-1, PROZ), metabolism (GSTT1, MTHFR), and angiogenesis (NOS3, VEGFA). However, ORs were modest (0.51-2.37), with moderate or weak epidemiologic credibility. Minor differences in summary ORs were detected between IRSA defined as two or more and as three or more SAs. Male partners were included in 12.1% of studies, and one study included spontaneously aborted embryos.
  
  
  
  Candidate gene studies show moderate associations with IRSA. Owing to large differences in RSA definition and selection criteria for participants, consensus is needed. Future GASs should include both partners and spontaneously aborted embryos. Genome-wide association studies and large-scale replications of identified associations are recommended.
authors.affiliation: Department of Biology and Medical Genetics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia. Electronic address: nina.pereza@medri.uniri.hr.
authors.forename: Nina
authors.initials: N
authors.lastname: Pereza
authors.affiliation: Department of Biology and Medical Genetics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
authors.forename: Saša
authors.initials: S
authors.lastname: Ostojić
authors.affiliation: Department of Biology and Medical Genetics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
authors.forename: Miljenko
authors.initials: M
authors.lastname: Kapović
authors.affiliation: Clinical Institute of Medical Genetics, Department of Gynecology and Obstetrics, University Medical Center, Ljubljana, Slovenia.
authors.forename: Borut
authors.initials: B
authors.lastname: Peterlin
mesh_terms: D000026:Abortion, Habitual / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D010641:Phenotype; D011247:Pregnancy; D018570:Risk Assessment; D012307:Risk Factors
keywords: Candidate gene; evidence-based medicine; genetic polymorphism; meta-analysis; miscarriage