Genetics of kidney disease in diverse populations

摘要 慢性肾脏疾病影响全球十分之一的人，它导致过早发病和 死亡。其发生和易感的潜在机制尚不清楚，限制了在 预后生物标志物的识别或治疗干预措施的发展。有一些已知的 慢性肾脏疾病风险的种族差异，但在不同(非欧洲)地区进行的研究很少 人口。研究已经确定了几个祖先的变异(例如，APOL1，镰状细胞)会增加罹患 非洲血统的人，包括拉美裔/拉丁裔混血的慢性肾脏疾病。为了更好地 为了了解不同人群慢性肾脏疾病的遗传风险，我们最近建立了 大陆起源和遗传流行病学网络肾脏(CONTER-KIDNNEY)联盟，该联盟包括 来自四个主要祖传群体(非洲、西班牙裔/拉丁裔、欧洲和东亚)的71,638名参与者。 使用新的跨种族荟萃分析方法，我们确定了20个影响肾功能的基因座，并显示 在使用不同群体发现基因座内的功能变异方面的重要收获。目前的提案 寻求提供重要的所需信息，以解决特定于祖先的变体对 未充分研究的拉美裔/拉美裔美国人慢性肾脏疾病表型的自然病史(目标1)，通过利用 西班牙裔社区健康研究/研究12000多名参与者的综合纵向数据 拉丁裔的。为了识别与所有祖先相关的新的遗传基因座和潜在的机制，我们 建议为令人信服的肾脏联盟招募更多的研究人员，进行前所未有的跨种族研究 肾脏特征的Meta分析，包括来自不同人群(东部和东部)的总共622,000名参与者 南亚人、西班牙裔/拉丁裔、非洲人和非裔美国人、美国印第安人和白人)(目标2)。我们会 优先选择基因，以测试它们在体外实验和小鼠肾脏损伤模型中的功能作用(目标3)。 我们的结果可以为慢性肾脏的种族差异的遗传贡献提供重要的见解。 介绍肾脏疾病的风险，并介绍与慢性肾脏疾病发展有关的分子机制。 最终，这项研究将为个性化医疗提供信息，提高对个性化医疗的理解和管理 肾脏的健康和疾病。

ABSTRACT Chronic kidney disease affects one in 10 people worldwide, and it contributes to premature morbidity and death. The underlying mechanisms for its development and predisposition are unknown, limiting progress in the identification of prognostic biomarkers or the development of treatment interventions. There are known ethnic disparities in chronic kidney disease risk, yet little research has been done in diverse (non-European) populations. Studies have identified several ancestral variants (e.g., APOL1, sickle cell) conferring risk of chronic kidney disease in persons of African ancestry including admixed Hispanics/Latinos. To better understand the genetic risk for chronic kidney disease across diverse populations, we recently established the Continental Origins and Genetic Epidemiology Network Kidney (COGENT-Kidney) Consortium, which includes 71,638 participants from four major ancestral groups (African, Hispanic/Latino, European and East Asian). Using novel trans-ethnic meta-analysis approaches, we identified 20 loci for kidney function and showed important gains in uncovering functional variants within loci using diverse populations. The current proposal seeks to provide important needed information to address the contribution of ancestry-specific variants to the natural history of chronic kidney disease phenotypes in under-studied Hispanics/Latinos (Aim 1), by leveraging the comprehensive longitudinal data in over 12,000 participants of the Hispanic Community Health Study/Study of Latino. To identify novel genetic loci and underlying mechanisms that are relevant to all ancestries, we propose to recruit additional studies to the COGENT-Kidney Consortium for an unprecedented trans-ethnic meta-analysis of kidney traits, including a total of over 622,000 participants from diverse populations (East and South Asian, Hispanic/Latino, African and African American, American Indian, and white) (Aim 2). We will prioritize genes to test their functional role in in vitro experiments and mouse models of kidney injury (Aim 3). Our results can provide important insight into genetic contributions to ethnic disparities in chronic kidney disease risk and to inform on molecular mechanisms related to chronic kidney disease development. Ultimately, this research could inform personalized medicine and improve the understanding and management of kidney health and disease.