title: Annexin A5 Promoter Haplotype M2 Is Not a Risk Factor for Recurrent Pregnancy Loss in Northern Europe.
abstract: BACKGROUND
  Annexin A5 is an essential component of placental integrity that may potentially mediate susceptibility to phenotypes of compromised pregnancy. A promoter haplotype termed M2 of the coding gene ANXA5 has been implicated in various pregnancy complications such as preeclampsia and recurrent pregnancy loss (RPL), however with inconclusive results.
  
  
  METHODS
  A retrospective case-control study combining resequencing and restriction fragment length polymorphism (RFLP) analysis was undertaken in 313 women with unexplained RPL and 214 fertile women from Estonia and Denmark to estimate the RPL disease risk of the M2 haplotype in Northern Europe. Comparative prevalence of the studied ANXA5 genetic variants in human populations was estimated based on the 1000 Genomes Project (n = 675, whole-genome sequencing data) and the KORA S3 500K dataset of South German samples (n = 1644, genome-wide genotyping data).
  
  
  RESULTS
  Minor allele frequency of common polymorphisms in ANXA5 promoter was up to two-fold lower among Estonian RPL subjects than fertile controls. The M2 haplotype was not associated with RPL and a trend for decreased prevalence was observed among RPL patients compared to controls both in Estonia (8.1% vs 15.2%, respectively) and Denmark (9.7% vs 12.6%). The high M2 prevalence in fertile controls was consistent with estimations for European and East Asian populations (9.6%-16.0%).
  
  
  CONCLUSIONS
  This study cautions to consider the M2 haplotype as a deterministic factor in early pregnancy success because: i) no RPL disease risk was associated with the haplotype in two clinically well-characterized RPL case-control study samples, ii) high prevalence of the haplotype among fertile controls and world-wide populations is inconsistent with the previously proposed severe impact on early pregnancy success, iii) weak impact of M2 haplotype on the production of ANXA5 protein has been established by others.
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Liina
authors.initials: L
authors.lastname: Nagirnaja
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Diana
authors.initials: D
authors.lastname: Nõmmemees
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Department of Obstetrics and Gynaecology, University of Tartu, Tartu, Estonia.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rull
authors.affiliation: The Fertility Clinics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Obstetrics and Gynaecology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Ole B
authors.initials: OB
authors.lastname: Christiansen
authors.affiliation: The Fertility Clinics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Henriette S
authors.initials: HS
authors.lastname: Nielsen
authors.affiliation: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Maris
authors.initials: M
authors.lastname: Laan
mesh_terms: D000026:Abortion, Habitual / Q000235:genetics*; D000328:Adult; D000483:Alleles; D017304:Annexin A5 / Q000235:genetics*; D016022:Case-Control Studies; D003718:Denmark; D004957:Estonia; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D010920:Placenta / Q000473:pathology; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011225:Pre-Eclampsia / Q000235:genetics; D011247:Pregnancy; D015995:Prevalence; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D017304:Annexin A5