title: Effect of pregnancy-associated plasma protein-A (PAPP-A) single-nucleotide polymorphisms on the level and activity of PAPP-A and the hormone profile in fluid from normal human small antral follicles.
abstract: OBJECTIVE
  To reveal a possible relationship between two single nucleotide polymorphisms (SNPs) in PAPP-A-1224 (rs7020782) and 327 (rs12375498)-and the level and activity of PAPP-A in follicular fluid (FF) of human small antral follicles, and to analyze the intrafollicular hormone levels.
  
  
  METHODS
  Laboratory investigation.
  
  
  METHODS
  University hospital.
  
  
  METHODS
  Fifty volunteer women who contributed a total of 210 samples of FF from normal small antral follicles.
  
  
  METHODS
  Genotyping and measurement of antigen levels of steroids, PAPP-A, stanniocalcin-2 (STC2), and antimüllerian hormone (AMH) plus activity of PAPP-A toward insulin-like growth factor binding protein 4 (IGFBP-4).
  
  
  METHODS
  Measurement of PAPP-A levels and hormones with enzyme-linked immunosorbent assay (ELISA) and PAPP-A activity toward radiolabeled IGFBP-4.
  
  
  RESULTS
  Women homozygous for the minor C allele of the 1224 SNP showed a statistically significantly lower level of PAPP-A protein and activity in FF compared with women carrying the major A allele. These women also displayed nonsignificant reduced levels of estradiol and increased levels of AMH and androgen. A statistically significant correlation between FF levels of PAPP-A activity and the molar ratio of PAPP-A/STC2 was obtained. The 327 SNP did not show statistically significant associations.
  
  
  CONCLUSIONS
  This study presents a statistically significant effect of the 1224 SNP on the level and activity of PAPP-A in human follicles, suggesting that the FF level of bioactive insulin-like growth factor depends on the genotype. We observed STC2 to be an important regulator of PAPP-A in human FF. The 1224 SNP has previously been associated with recurrent pregnancy loss, so further evaluation of an underlying mechanism including aberrant control of insulin-like growth factor activity is warranted.
authors: Laboratory of Reproductive Biology, Juliane Marie Centre for Women, Children and Reproduction, Copenhagen University Hospital, Copenhagen University, Copenhagen, Denmark. Electronic address: jane.alroe.boetkjaer@regionh.dk.
authors: Jane Alrø
authors: JA
authors: Bøtkjær
authors: Laboratory of Reproductive Biology, Juliane Marie Centre for Women, Children and Reproduction, Copenhagen University Hospital, Copenhagen University, Copenhagen, Denmark.
authors: Tanni
authors: T
authors: Borgbo
authors: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Søren
authors: S
authors: Kløverpris
authors: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Pernille Rimmer
authors: PR
authors: Noer
authors: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors: Claus
authors: C
authors: Oxvig
authors: Laboratory of Reproductive Biology, Juliane Marie Centre for Women, Children and Reproduction, Copenhagen University Hospital, Copenhagen University, Copenhagen, Denmark.
authors: Claus Yding
authors: CY
authors: Andersen
mesh_terms: D000328:Adult; D054304:Anti-Mullerian Hormone / Q000032:analysis; D005260:Female; D015571:Follicular Fluid / Q000737:chemistry*; D005787:Gene Frequency; D006023:Glycoproteins / Q000032:analysis; D012739:Gonadal Steroid Hormones / Q000032:analysis; D006579:Heterozygote; D006720:Homozygote; D006785:Hospitals, University; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000032:analysis; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D015810:Linkage Disequilibrium; D006080:Ovarian Follicle / Q000737:chemistry* / Q000166:cytology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011266:Pregnancy-Associated Plasma Protein-A / Q000032:analysis* / Q000235:genetics*; D055815:Young Adult
chemical_list: D006023:Glycoproteins; D012739:Gonadal Steroid Hormones; D018974:Insulin-Like Growth Factor Binding Protein 4; D036341:Intercellular Signaling Peptides and Proteins; C114997:STC2 protein, human; D054304:Anti-Mullerian Hormone; D011266:Pregnancy-Associated Plasma Protein-A; C579283:PAPPA protein, human
keywords: Human follicles; IGF signaling; PAPP-A; human ovarian steroidogenesis; single-nucleotide polymorphisms