P-698 Genetics and reproductive health outcomes: An Asian perspective
Authors: Huang Z , Long C , Benny P , Yap J , Lee J 
Published: June 2023

Abstract

Study question
Does genetics play a role in the reproductive outcomes in women undergoing assisted reproductive technology (ART)?

Summary answer
We describe a trend towards poorer reproductive outcomes associated with Asian women and ART. Subsequently, we posit a potential biological mechanism.

What is known already
In the last four decades, advances in assisted reproductive technology (ART) have afforded the possibility of conceiving a child to individuals who encounter fertility complications. However, a closer examination of the clinical outcomes of ART shows a stark contrast in Asian women compared to Caucasians, with the majority of studies reporting lower reproductive success among Asian women. In this study, a systematic review was performed to elucidate the genes associated with ART clinical outcomes, with a focus on Asian ethnicities. Concomitantly, we highlight the need for personalized medicine to bridge the gaps in female reproductive health.

Study design, size, duration
We performed a Pubmed and Embase database search, from inception to December 2022, to identify all studies which investigated the differential reproductive outcomes in Asian women compared to their Caucasian counterparts, genetic mutations contributing to fertility in Asian women and personalized medicine. Following the PRISMA workflow, the preliminary search yielded a total of 2,145 papers to be reviewed.

Participants/materials, setting, methods
Following the inclusion/exclusion criteria screening, 128 studies were analyzed (ART outcomes in Asians, n=75; Genetics on women’s reproductive health, n=38; Personalized medicine in Asians, n=15). As each research paper identified one or more genes/SNPs involved in female fertility and reproductive health, we took a step further and performed a pathway analysis of gene-sets using STRING in Cytoscape v3.4.0. Network analysis and biological process associations were performed using GSEA and MSigDB. Significant gene-sets were annotated if FDR&lt;0.05.

Main results and the role of chance
We observed that age at menarche(AAM) was found to be correlated with the timing of the first pregnancy, with Hawaiians having the lowest age(22.2yrs) and Japanese women having the highest age(25.0yrs). LIN28 mutations were highly associated with AAM and prevalent in both Chinese and American populations. FMR1 was most associated with ovarian reserve, with BMP15, ESR1, INHA, PRIM, TMEM150B to a lesser extent. Finally, FSHR polymorphisms were found to affect IVF outcomes most significantly. Network analysis highlighted a close association between 5 genes; FMR1, FSHR, ESR1, BMP15 and INHA, through biological functions of ovarian follicle development, menstrual cycle and hyperpituitarism. Network analysis revealed 4 major biological pathways (ovarian follicle development, oocyte maturation, ovulation, steroidogenesis), as well as key proteins which are involved in female fertility and reproductive health outcomes. PI3K/Akt are critical regulators of ovarian function through primordial follicle maturation and granulosa cell proliferation. MAPK signaling is involved with gonadotrophin-releasing hormone which controls FSH and LH secretion while Gq/11 signaling is activated through LH receptor. Therefore, PI3K/Akt, MAPK and Gq/11 protein signaling pathway appear to be key components to a broad range of reproductive outcomes and represent potential pathways to target in future studies investigating ovarian, follicular and steroidogenesis dysfunction.

Limitations, reasons for caution
A large majority of the papers reviewed relied on the self-reporting of ethnicities, which can vary considerably in accordance to how an individual defines his or her own ethnicity. Hence, we could not exclude the possibility of reporting bias in the studies.

Wider implications of the findings
Leveraging these findings,we propose the development of a biomarker panel which would enhance patient stratification,moving towards personalized medicine to address every woman’s unique reproductive potential.With several countries reporting low fertility rates due to shifts in socio-economic and life priorities, this has strong implications for those who wish to delay childbearing.

Trial registration number
Not applicable