The Genetics of Female Reproductive Aging

女性生殖衰老的遗传学

• 批准号: 7256606
• 负责人: TARA C. MATISE
• 金额: $ 7.72万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256606
• 关键词: Activins; Age; Aging; Aneuploidy; Applications Grants; BMP15 gene; Biological Assay; Biological Factors; Biological Markers; Blood specimen; Budgets; Cancer Patient; Candidate Disease Gene; Code; Collection; Complex; Condition; DNA; Enrollment; Epigenetic Process; Evaluation; FOXO3A gene; Family Planning; Family member; Female; Follicle Stimulating Hormone; Follicular Atresia; Future; GDF9 gene; Genes; Genetic; Genotype; Goals; Growth Differentiation Factor 9; Hormones; Incidence; Individual; Infertility; Inherited; Knowledge; Lead; Light; Measures; Medical Records; Menopause; Mothers; Mullerian duct inhibiting substance; Mutation; Ovarian; Pathway interactions; Patient currently pregnant; Perimenopause; Phase; Physiological; Pituitary Hormones; Play; Population; Population Control; Primordial Follicle; Process; Proxy; Rate; Reproduction; Reproductive system; Research; Research Project Grants; Role; Sampling; Screening procedure; Single Nucleotide Polymorphism; Spontaneous abortion; Staging; Stratification; System; Technology; Testing; Time; Woman; age related; base; cancer therapy; density; falls; female reproductive system; genetic analysis; genetic variant; genome wide association study; human female; improved; inhibin; inhibin B; interest; programs; reproductive; senescence; size; trait

DESCRIPTION (provided by applicant): Aging of the reproductive system is unique in that human females reach a reproductively nonfunctional state at a time when they are otherwise healthy. Age at menopause is an inherited trait, and the ages at earlier reproductive stages (subfertility, infertility, and perimenopause) are strongly correlated with age at menopause. The age at naturally-occurring menopause is largely determined by the size of the initial primordial follicle pool and the rate of follicular atresia. Many biological factors are known to play a role in determining the size and quality of the follicle pool and the rate of decline of the ovarian reserve, and hence age at menopause. However, these factors interact through complex pathways, and very little is currently understood about the underlying genes and genetic variants that control these factors. We plan to identify genes that contribute to the control of female reproductive aging (see PA-06-347 Reproductive Genetics and Epigenetics). The long-term goals of our research are to: a) ascertain a very large population-based sample suitable for association studies of the quantitative trait ovarian reserve; b) screen a set of likely candidate genes for association with this trait; c) conduct high-density genome-wide association analysis; d) search for causative mutations in any genes with which association is detected. The short-term goals of this R03 Small Research Grant application are to begin the process of sample ascertainment and to begin screening candidate genes for association. For the pilot phase of this project we will enroll at least 150 subjects, and to improve power for future analyses, we plan to also enroll immediate family members. We will genotype single nucleotide polymorphisms (SNPs) from 9-10 candidate genes including AMH [anti-M¿llerian hormone], INHa, INH¿A, INH¿B, FOXL2, GDF9, BMP15, FOXO3A, and POF1B. SNPs from these genes will then be evaluated for association with biomarkers for ovarian reserve. The association testing will be based on Zhang's semiparametric test for association (SPTA) which uses a sample of 100-200 neutral markers to control for population stratification. Improved understanding of the role of genes in controlling female reproductive aging will increase our general knowledge of a critical physiological system and may shed light on general mechanisms of aging. We anticipate it will lead to the ability to predict at an early age whether a woman's ovarian reserve will decline faster or slower than average and whether she should anticipate early menopause. This will facilitate better family planning, which could reduce the need for age-related infertility treatment and reduce the incidence of miscarriage and aneuploidy among older mothers. Individualized evaluation of rate of reproductive aging will also be of considerable interest to female cancer patients, since cancer treatments often lead to reduction of ovarian reserve. Finally, enhancing our understanding of reproductive senescence may facilitate improvements in technologies used for assisted reproduction.

描述(申请人提供)：生殖系统的老化是独一无二的，因为人类女性在其他方面是健康的时候，却达到了生殖不能的状态。绝经年龄是一种遗传特征，早期生殖阶段(不孕、不孕和围绝经期)的年龄与绝经年龄密切相关。自然绝经的年龄在很大程度上取决于原始卵泡池的大小和卵泡闭锁率。众所周知，许多生物因素在决定卵泡池的大小和质量以及卵巢储备的下降速度，从而决定绝经年龄方面发挥着重要作用。然而，这些因素通过复杂的途径相互作用，目前对控制这些因素的潜在基因和遗传变异了解很少。 我们计划识别有助于控制女性生殖衰老的基因(参见PA-06-347《生殖遗传学和表观遗传学》)。我们研究的长期目标是：a)确定一个非常大的基于群体的样本，适合于数量性状卵巢储备的关联研究；b)筛选一组可能与该性状相关的候选基因；c)进行高密度全基因组关联分析；d)在任何检测到关联的基因中寻找致病突变。这个R03小型研究资助申请的短期目标是开始样本确定的过程，并开始筛选候选基因以进行关联。在这个项目的试验阶段，我们将招收至少150名受试者，为了提高未来分析的能力，我们还计划招收直系亲属。我们将对9-10个候选基因的单核苷酸多态(SNPs)进行分型，这些候选基因包括AMH、INHA、INH？A、INH？B、FOXL2、GDF9、BMP15、FOXO3a和POF1B。然后将评估来自这些基因的SNPs与卵巢储备生物标记物的关联。关联性检验将基于张的半参数关联性检验(SPTA)，该方法使用100-200个中性标记的样本来控制种群分层。更好地了解基因在控制女性生殖衰老中的作用将增加我们对关键生理系统的一般知识，并可能有助于阐明衰老的一般机制。我们预计，这将导致能够在早期预测女性卵巢储备下降的速度是快于平均水平还是慢于平均水平，以及她是否应该提前绝经。这将促进更好的计划生育，从而减少与年龄有关的不孕不育治疗的需要，并减少老年母亲流产和非整倍体的发生率。女性癌症患者对生殖老年率的个体化评估也会相当感兴趣，因为癌症治疗往往会导致卵巢储备的减少。最后，加强我们对生殖衰老的理解可能会促进辅助生殖技术的改进。