Xiangfei Wang, Ruolin Mao, Rui Long, Limin Gao, Meng Wang, Juepu Zhou, Kun Qian, Lixia Zhu, Lei Jin
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引用次数: 0
Abstract
Purpose: To screen drug targets of ovarian aging from a genetic perspective.
Methods: Systematic analyses were conducted with cis-expression quantitative trait loci data of druggable genes extracted as instrument variables. Summary statistics were from large genome-wide association studies for age at menopause. The following colocalization analysis was utilized to examine whether identified genes and ovarian aging shared causal variants. Furthermore, clinical validation was conducted by comparing expression of identified genes in granulosa cells from women with normal or diminished ovarian reserve (DOR) who went through in vitro fertilization (IVF) and by evaluating correlation of targeted gene expression with ovarian function and IVF outcomes. Moreover, single-nuclear RNA (snRNA) seq and drug database were analyzed to find target cells within the ovary and potential drugs targeting identified genes.
Results: Systematic analyses identified five therapeutic targets of ovarian aging, including four protective factors (BRCA1, KLHL18, PNP, SRPK1) and one risk factor (PDIA3). The change in expression level of four protective factors has been verified in clinical validation. Particularly, both BRCA1 and SRPK1 have been downregulated among advanced-aged women with DOR and were positively correlated with anti-Müllerian hormone and antral follicle count. Specific target cells and potential small molecule targeted drugs of these genes were identified through snRNA analysis and searching in the drug database.
Conclusions: By systematic genetic analyses combined with clinical validation, we identified five potential druggable genes for ovarian aging, providing theoretical basis and promising direction of therapeutic genetic targets for ovarian aging in the future.
期刊介绍：
The Journal of Assisted Reproduction and Genetics publishes cellular, molecular, genetic, and epigenetic discoveries advancing our understanding of the biology and underlying mechanisms from gametogenesis to offspring health. Special emphasis is placed on the practice and evolution of assisted reproduction technologies (ARTs) with reference to the diagnosis and management of diseases affecting fertility. Our goal is to educate our readership in the translation of basic and clinical discoveries made from human or relevant animal models to the safe and efficacious practice of human ARTs. The scientific rigor and ethical standards embraced by the JARG editorial team ensures a broad international base of expertise guiding the marriage of contemporary clinical research paradigms with basic science discovery. JARG publishes original papers, minireviews, case reports, and opinion pieces often combined into special topic issues that will educate clinicians and scientists with interests in the mechanisms of human development that bear on the treatment of infertility and emerging innovations in human ARTs. The guiding principles of male and female reproductive health impacting pre- and post-conceptional viability and developmental potential are emphasized within the purview of human reproductive health in current and future generations of our species.
The journal is published in cooperation with the American Society for Reproductive Medicine, an organization of more than 8,000 physicians, researchers, nurses, technicians and other professionals dedicated to advancing knowledge and expertise in reproductive biology.
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