Genetics of kidney disease in diverse populations

点击翻译按钮获取中文摘要

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.