Bone morphogenetic protein 15 (BMP15) alleles predict over-response to recombinant follicle stimulation hormone and iatrogenic ovarian hyperstimulation syndrome (OHSS)
Bone morphogenetic protein 15 (BMP15) alleles predict over-response to recombinant follicle stimulation hormone and iatrogenic ovarian hyperstimulation syndrome (OHSS)
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DOI：
10.1097/01.fpc.0000215073.44589.96
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发表时间：
2006-07-01
影响因子：
2.6
通讯作者：
Ruiz, Agustin
中科院分区：
文献类型：
--
作者：
Moron, Francisco J.;de Castro, Francisco;Ruiz, Agustin
目的：重组卵泡刺激素（rFSH）控制性促排卵（COS）是辅助生殖的主要治疗方法。我们在COS中使用单核苷酸多态性（SNPs）对骨形态发生蛋白15（BMP 15）基因进行了药物遗传学分析。我们还研究了BMP 15基因在卵巢过度刺激综合征（OHSS）中的作用。方法：我们分析了307例接受rFSH治疗的妇女的BMP 15基因内的不同基因内SNP，评估其与COS结局的关系。首先，我们分析了两种多态性，通过应用不同的遗传关联测试，我们发现在两种BMP 15基因多态性中，COS中产生>= 12个卵泡的患者（高反应者）的P值最小。使用双向DNA测序，我们鉴定了另外两种单核苷酸DNA变体。其次，我们对所有多态性进行了关联研究，并注意到它们似乎都不能完全解释BMP 15基因与rFSH过度反应的关联。然而，N103 S错义突变被预测为破坏人BMP 15蛋白的二级结构，并且与OHSS弱相关。BMP 15基因的这种编码突变可能部分解释了我们研究期间获得的结果。使用Thesias软件，我们用四个基因内变异体重建单倍型，并计算它们在正常和对rFSH过度反应者中的频率。单倍型TGGA在高应答者中的比例高于其他患者。此外，这种关联更高的OHSS患者，与一个显着的全球单倍型效应的BMP 15 gene.Conclusion：我们的研究结果表明，在COS和BMP 15等位基因在人类rFSH的反应，卵泡产量增加之间的直接关系。使用BMP 15标记物来预防OHSS也是一种需要彻底评估的可能性。药理遗传学和基因组学16：485-495（c）2006 Lippincott威廉姆斯和威尔金斯。
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 >= 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.Conclusion: 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. Pharmacogenetics and Genomics 16:485-495 (c) 2006 Lippincott Williams & Wilkins.