Chronic kidney disease is a progressive and heterogeneous condition that affects 10% of individuals worldwide, and a cause of premature cardiovascular disease and death. Little is known about the mechanisms leading to its development and predisposition. Despite the strong evidence for a role of ancestry in chronic kidney disease susceptibility, few studies have leveraged ancestry for gene discovery. Hispanics are an understudied minority group that is comprised of many overlapping ancestral groups (Amerindian, West African, European). Hispanics have a high prevalence of increased albuminuria and end-stage renal disease, which has been associated with their Amerindian ancestry. We propose to identify ancestry-specific loci, and their corresponding rare and common genetic variants, that explain the higher susceptibility for chronic kidney disease in Hispanics. We will use novel admixture mapping approaches to map genomic segments and variants inherited from the ancestral population with the higher disease variant frequency (Aim 1), followed by fine-mapping and validation of associations in ancestry-specific cohorts (Hispanics, American Indians, European and West Africa ancestries) (Aim 2). We will leverage data from the large population-based Hispanic Community Health Study/Study of Latinos for gene discovery, and propose to fine-map Amerindian loci using a combination of genotyping and targeted sequencing. To gain insights into the functional roles of identified genes, we will prioritize variants for experiments using in vitro and mouse model systems for transgenic and gene targeting studies (Aim 3). This proposal leverages ancestry to identify loci for kidney traits in Hispanics, and uniquely complement large ongoing genome wide association approaches. Our results will provide clues to racial/ethnic disparities in disease risk, and improve understanding of the biological pathways leading to chronic kidney disease. Ultimately this research could inform personalized medicine and improve public health.

Public Health Relevance

This study proposes to identify genetic variants that explain ethnic variation in chronic kidney disease susceptibility in Hispanic/Latinos and American Indians, two understudied populations for genetic risk of chronic kidney disease. Findings from this study may have a broad impact on informing ethnic disparities in disease risk, could inform personalized medicine and improve public health of U.S. minority population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Research Project (R01)
Project #
5R01MD012765-02
Application #
9571128
Study Section
Kidney, Nutrition, Obesity and Diabetes Study Section (KNOD)
Program Officer
Rajapakse, Nishadi
Project Start
2017-09-24
Project End
2022-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hyacinth, Hyacinth I; Carty, Cara L; Seals, Samantha R et al. (2018) Association of Sickle Cell Trait With Ischemic Stroke Among African Americans: A Meta-analysis. JAMA Neurol 75:802-807
Franceschini, Nora; Kopp, Jeffrey B; Barac, Ana et al. (2018) Association of APOL1 With Heart Failure With Preserved Ejection Fraction in Postmenopausal African American Women. JAMA Cardiol 3:712-720
Franceschini, Nora; Frick, Amber; Kopp, Jeffrey B (2018) Genetic Testing in Clinical Settings. Am J Kidney Dis 72:569-581
Sung, Yun J (see original citation for additional authors) (2018) A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. Am J Hum Genet 102:375-400
Franceschini, Nora; Giambartolomei, Claudia; de Vries, Paul S et al. (2018) GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. Nat Commun 9:5141
Sofer, Tamar; Wong, Quenna; Hartwig, Fernando P et al. (2017) Genome-Wide Association Study of Blood Pressure Traits by Hispanic/Latino Background: the Hispanic Community Health Study/Study of Latinos. Sci Rep 7:10348