Bone morphogenetic protein 15 (BMP15) alleles predict over-response to recombinant follicle stimulation hormone and iatrogenic ovarian hyperstimulation syndrome (OHSS).
OBJECTIVE
Controlled ovarian stimulation (COS) using recombinant follicle-stimulating hormone (rFSH) is the main treatment in assisted reproduction. We performed a pharmacogenetic analysis of bone morphogenetic protein 15 (BMP15) gene using single nucleotide polymorphisms (SNPs) in COS. We also investigated the role of the BMP15 gene in ovarian hyperstimulation syndrome (OHSS).


METHODS
We analysed different intragenic SNPs located within the BMP15 gene in 307 women treated with rFSH, evaluating its involvement in COS outcome.


RESULTS
First, we analysed two polymorphisms, by applying different tests for genetic association, and we found a minimum P-value in patients producing > or =12 follicles in COS (high responders) in both polymorphisms of the BMP15 gene. Using bi-directional DNA sequencing, we identified two additional single nucleotide DNA variants. Second, we conducted association studies with all polymorphisms together, and noticed that none of them seemed to fully explain the association of the BMP15 gene with over-response to rFSH. However, N103S missense mutation is predicted to disrupt the secondary structure of human BMP15 protein and is weakly associated with OHSS. This coding mutation of the BMP15 gene may partially explain the results obtained during our research. Using Thesias software, we reconstructed haplotypes with the four intragenic variants and calculated their frequencies in normal and over-responders to rFSH. The haplotype TGGA was over-represented in high responders when compared with the rest of patients. Moreover, this association was higher in patients with OHSS, with a significant global haplotypic effect of the BMP15 gene.


CONCLUSIONS
Our results suggest a direct relationship between increased follicle production during COS and BMP15 alleles in response to rFSH in humans. The use of BMP15 markers to prevent OHSS is also a possibility that requires thorough evaluation.
Morón
Francisco J
FJ
Departamento de Genómica Estructural, Neocodex, Avda. Charles Darwin s/n, Parque Tecnológico Isla de la Cartuja, 41092 Seville, Spain.
de Castro
Francisco
F
Royo
Jose L
JL
Montoro
Luis
L
Mira
Emilia
E
Sáez
María E
ME
Real
Luis M
LM
González
Alejandro
A
Mañes
Santos
S
Ruiz
Agustín
A
D000328:Adult; D000483:Alleles; D055430:Bone Morphogenetic Protein 15; D005260:Female; D005307:Fertilization in Vitro; D005640:Follicle Stimulating Hormone / Q000009:adverse effects* / Q000627:therapeutic use; D055429:Growth Differentiation Factor 9; D006801:Humans; D007049:Iatrogenic Disease; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D016471:Ovarian Hyperstimulation Syndrome / Q000139:chemically induced / Q000209:etiology / Q000235:genetics*; D010062:Ovulation Induction / Q000009:adverse effects / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011994:Recombinant Proteins; D012189:Retrospective Studies
C525901:BMP15 protein, human; D055430:Bone Morphogenetic Protein 15; C525897:GDF9 protein, human; D055429:Growth Differentiation Factor 9; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D005640:Follicle Stimulating Hormone