Location: Obesity and Metabolism ResearchTitle: Dissecting the genetic architecture of cystatin C in diversity outbred mice
|HUDA, NAZMUL - University Of California, Davis|
|VERHAGUE, MELISSA - North Carolina State University|
|ALBRIGHT, JODY - North Carolina State University|
|SMALLWOOD, TANGI - University Of North Carolina|
|BELL, TIM - University Of North Carolina|
|QUE, EXCEL - University Of California, Davis|
|MILLER, DARLA - University Of North Carolina|
|ROSHANRAVAN, BABACK - University Of California, Davis|
|ALLAYEE, HOOMAN - University Of Southern California|
|MANUEL DE VILLENA, FERNANDO PARDO - University Of North Carolina|
Submitted to: Genes, Genomes, and Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/26/2020
Publication Date: 7/7/2020
Citation: Huda, N.M., Verhague, M., Albright, J., Smallwood, T., Bell, T., Que, E., Miller, D., Roshanravan, B., Allayee, H., Manuel De Villena, F., Bennett, B.J. 2020. Dissecting the genetic architecture of cystatin C in diversity outbred mice. Genes, Genomes, and Genomics. 10(7):2529-2541. https://doi.org/10.1534/g3.120.401275.
Interpretive Summary: Reduced kidney function is a major public health problem and can lead to higher morbidity and mortality as it is a risk factor for many diseases including cardiovascular diseases, infection, and cancer. Genetic predisposition can increase the risk of kidney disease susceptibility. In this study, by utilizing Diversity Outbred (DO) female elderly mice, we identified genetic loci and potential candidate genes associated with elevated kidney biomarkers in blood and urine namely cystatin C, urinary total protein, and Na+ excretion rate. The identification of the genes and pathways involved in kidney function may help us to understand the pathophysiology and susceptibility of kidney diseases and help us to improve or refine current therapies.
Technical Abstract: Impaired renal function is a major but at times underappreciated determinant of morbidity and mortality. In particular, reduced renal function is a risk factor for many chronic diseases including cardiovascular disease. Thus identification of genes and pathways involved in regulating renal function may improve or refine current therapies. In this study, we utilized 120 DO female mice, 56 weeks of age, to perform Quantitative Trait Loci (QTL) analysis of renal function in blood and urine. We prioritize candidate genes using renal gene expression to identify positional candidate genes with expression under similar genetic regulation. We found plasma concentration of cystatin C is influenced by a QTL on Chromosome 2 which is further supported by the cis-eQTL of Cst3 gene at the same locus, and correlation between mRNA levels in kidney and plasma concentration of cystatin C. We also found two other loci is associated with urinary total protein and Na+ excretion rate. Additionally, using DO mice we were able to map one trans-eQTL's hotspot in kidney which affects more than a quarter of the total trans-gene expression. Overall, our study clearly demonstrates the utility of the DO mice in renal studies to find out the genetic susceptibility of kidney diseases. Our findings of the kidney biomarker's associated gene loci indicate that decreased renal function may be influenced by the genetic architecture of the individual, at least partly. The candidate genes found in this study may help us to understand the underlying mechanism of pathophysiology and susceptibility of renal disease.