title: Chorionic gonadotropin beta-gene variants are associated with recurrent miscarriage in two European populations.
abstract: BACKGROUND
  The incidence of recurrent miscarriage (RM) (>or=3 consecutive pregnancy losses) is estimated as 1-2% in fertile couples. Familial clustering of RM has suggested the contribution of a genetic component.
  
  
  OBJECTIVE
  A low level of human chorionic gonadotropin (HCG) in maternal serum during the first trimester of the pregnancy is a clinically accepted risk factor for miscarriage. We sought to study whether variation in chorionic gonadotropin beta-subunit genes (CGBs) expressed in placenta may contribute to the risk of RM.
  
  
  METHODS
  Resequencing of CGB5 and CGB8, the two most actively transcribed loci of the four HCG beta-duplicate genes, was performed.
  
  
  METHODS
  A case-control study involving two sample sets, from Estonia (n = 194) and Finland (n = 185), was performed.
  
  
  METHODS
  RM patients (n = 184) and fertile controls (n = 195) participated in the study.
  
  
  RESULTS
  From 71 identified variants in CGB5 and CGB8, 48 polymorphisms were novel. Significant protective effect was associated with two single nucleotide polymorphisms located at identical positions in intron 2 in both CGB5 [P = 0.007; odds ratio (OR) = 0.53] and CGB8 (P = 0.042; OR = 0.15), and with four CGB5 promoter variants (P < 0.03; OR = 0.54-0.58). The carriers of minor alleles had a reduced risk of RM. The haplotype structure of the CGB8 promoter was consistent with balancing selection; a rare mutation in CGB8 initiator element was detected only among patients (n = 3). In addition, three rare nonsynonymous substitutions were identified among RM cases as possible variants increasing the risk of recurrent pregnancy loss.
  
  
  CONCLUSIONS
  The findings encourage studying the functional effect of the identified variants on CGB expression and HCG hormone activity to elucidate further the role of CGB variation in RM.
authors.affiliation: Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rull
authors.forename: Liina
authors.initials: L
authors.lastname: Nagirnaja
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Ulander
authors.forename: Piret
authors.initials: P
authors.lastname: Kelgo
authors.forename: Tõnu
authors.initials: T
authors.lastname: Margus
authors.forename: Milja
authors.initials: M
authors.lastname: Kaare
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Maris
authors.initials: M
authors.lastname: Laan
mesh_terms: D000026:Abortion, Habitual / Q000453:epidemiology* / Q000235:genetics*; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000235:genetics*; D016000:Cluster Analysis; D004957:Estonia / Q000453:epidemiology; D005060:Europe / Q000453:epidemiology; D005260:Female; D005387:Finland / Q000453:epidemiology; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000097:blood; D012307:Risk Factors; D055815:Young Adult
chemical_list: D018997:Chorionic Gonadotropin, beta Subunit, Human
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