FSHB −211 G&gt;T is a major genetic modulator of reproductive physiology and health in childbearing age women

Rull, Kristiina; Grigorova, Marina; Ehrenberg, Aivar; Vaas, Pille; Sekavin, Aire; Nõmmemees, Diana; Adler, Mart; Hanson, Ele; Juhanson, Peeter; Laan, Maris

doi:10.1093/humrep/dey057

Cited by 27 publications

(27 citation statements)

References 38 publications

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“…The carriers of AA genotype showed a lower number of oocytes retrieved and a higher consumption of exogenous gonadotropin than GG carriers. As for the FSH β chain polymorphism (rs10835638), a study involving 169 healthy women, and 186 infertile women suggested that this polymorphism is associated with significantly higher FSH and LH levels in both healthy and female infertility patients (33). In this report, the T-allele carriers were found more frequently among idiopathic infertility cases, a fact that could be explained by the influence of this particular polymorphism on FSHR function (26, 34, 35).…”

Section: Unexpected Suboptimal or Low Oocyte Number And Its Associatimentioning

confidence: 99%

Management of Women With an Unexpected Low Ovarian Response to Gonadotropin

et al. 2019

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POSEIDON groups 1 and 2 patients respond poorly (<4 oocytes retrieved) or sub-optimally (4–9 oocytes retrieved) to gonadotropin stimulation despite the presence of adequate ovarian parameters, which negatively affect their cumulative chances of delivering a baby using Assisted Reproductive Technology. A polygenic trait involving gonadotropins and/or their receptors seems to be the primary pathophysiology mechanism explaining this phenomenon. The clinical management is mainly focused on maximizing oocyte yield as to increase the likelihood of having at least one euploid embryo for transfer. Indices such as FORT (follicle output rate) and FOI (follicle-to-oocyte index) may be used to determine if the ovarian reserve was properly explored during a previous ovarian stimulation. Testing for the presence of common polymorphisms affecting gonadotropins and/or their receptors can also be considered to identify patients at risk of hypo-response. An individualized estimation of the minimum number of oocytes needed to obtain at least one euploid embryo can assist counseling and treatment planning. Among currently existing pharmacological interventions, use of recombinant FSH in preference over urinary gonadotropin preparations, FSH dosage increase, and use of rLH supplementation may be considered -alone or combined- for optimally managing POSEIDON's groups 1 and 2 patients. However, given the recent introduction of the POSEIDON criteria, there is still a lack of studies examining the role of interventions specifically to patients classified as groups 1 and 2, thus making it an area for open research.

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Section: Unexpected Suboptimal or Low Oocyte Number And Its Associatimentioning

confidence: 99%

Management of Women With an Unexpected Low Ovarian Response to Gonadotropin

et al. 2019

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“…It is important to note that the significant association observed for the FSHB gene reconfirms the important role it plays in both male and female fertility. Recently, Rull and colleagues [24] proposed that FSHB -211 G>T variant (association p-value in this study = 2.02 × 10 −5 ) represents a key genetic modulator of circulating gonadotropin, leading to various possible downstream effects on reproductive physiology. The novel genome-wide hit on chromosome 15 identified in this study, rs428022, is an intergenic SNP flanked by PIAS1 and SKOR1, and was additionally mapped to CALML4 in all three mapping strategies.…”

Section: Discussionmentioning

confidence: 51%

Biological insights into multiple birth: genetic findings from UK Biobank

et al. 2019

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The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. We performed a genome-wide association study (GWAS) in 8962 participants with Caucasian ancestry from UK Biobank who reported being part of a multiple birth, and 409,591 singleton controls. We replicated the association between FSHB, SMAD3 and twinning in the gene-based (but not SNP-based) test, which had been established in previous genome-wide association analyses in mothers with dizygotic twin offspring. Additionally, we report a novel genetic variant associated with multiple birth, rs428022 at 15q23 (p = 2.84 × 10 −8) close to two genes: PIAS1 and SKOR1. Finally, we identified meaningful genetic correlations between being part of a multiple birth and other phenotypes (anthropometric traits, health-related traits, and fertility-related measures). The outcomes of this study provide important new insights into the genetic aetiology of multiple births and fertility, and open up novel directions for fertility and reproduction research.

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“…In females, the T allele decreases the risk of developing endometriosis, delayed age of menopause, and longer menstrual cycles than the G allele 191 . At the same time, other studies found an association between the T allele and the FSH and LH levels, idiopathic infertility, and worst clinical assisted reproduction outcome 192 , 193 . These data indicate a lower transcriptional activity of the T allele of the FSHB promoter SNP 194 , which would modulate the circulating levels of the hormone, thus impacting ovarian response.…”

Section: Recent Advancesmentioning

confidence: 82%

Recent advances in understanding gonadotropin signaling

Casarini¹,

Simoni²

2021

Fac Rev

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Gonadotropins are glycoprotein sex hormones regulating development and reproduction and bind to specific G protein–coupled receptors expressed in the gonads. Their effects on multiple signaling cascades and intracellular events have recently been characterized using novel technological and scientific tools. The impact of allosteric modulators on gonadotropin signaling, the role of sugars linked to the hormone backbone, the detection of endosomal compartments supporting signaling modules, and the dissection of different effects mediated by these molecules are areas that have advanced significantly in the last decade. The classic view providing the exclusive activation of the cAMP/protein kinase A (PKA) and the steroidogenic pathway by these hormones has been expanded with the addition of novel signaling cascades as determined by high-resolution imaging techniques. These new findings provided new potential therapeutic applications. Despite these improvements, unanswered issues of gonadotropin physiology, such as the intrinsic pro-apoptotic potential to these hormones, the existence of receptors assembled as heteromers, and their expression in extragonadal tissues, remain to be studied. Elucidating these issues is a challenge for future research.

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FSHB −211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women

Abstract: Not applicable.

Cited by 27 publications

References 38 publications

Management of Women With an Unexpected Low Ovarian Response to Gonadotropin

Management of Women With an Unexpected Low Ovarian Response to Gonadotropin

Biological insights into multiple birth: genetic findings from UK Biobank

Recent advances in understanding gonadotropin signaling

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