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

Fertil Steril. 2016 Dec;106(7):1778-1786.e8. doi: 10.1016/j.fertnstert.2016.09.008. Epub 2016 Oct 25.

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.

Design: Laboratory investigation.

Setting: University hospital.

Patient(s): Fifty volunteer women who contributed a total of 210 samples of FF from normal small antral follicles.

Intervention(s): 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).

Main outcome measure(s): Measurement of PAPP-A levels and hormones with enzyme-linked immunosorbent assay (ELISA) and PAPP-A activity toward radiolabeled IGFBP-4.

Result(s): 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.

Conclusion(s): 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.

Keywords: Human follicles; IGF signaling; PAPP-A; human ovarian steroidogenesis; single-nucleotide polymorphisms.

MeSH terms

  • Adult
  • Anti-Mullerian Hormone / analysis
  • Female
  • Follicular Fluid / chemistry*
  • Gene Frequency
  • Glycoproteins / analysis
  • Gonadal Steroid Hormones / analysis
  • Heterozygote
  • Homozygote
  • Hospitals, University
  • Humans
  • Insulin-Like Growth Factor Binding Protein 4 / analysis
  • Intercellular Signaling Peptides and Proteins / analysis
  • Linkage Disequilibrium
  • Ovarian Follicle / chemistry*
  • Ovarian Follicle / cytology
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Pregnancy-Associated Plasma Protein-A / analysis*
  • Pregnancy-Associated Plasma Protein-A / genetics*
  • Young Adult

Substances

  • Glycoproteins
  • Gonadal Steroid Hormones
  • Insulin-Like Growth Factor Binding Protein 4
  • Intercellular Signaling Peptides and Proteins
  • STC2 protein, human
  • Anti-Mullerian Hormone
  • Pregnancy-Associated Plasma Protein-A
  • PAPPA protein, human