The Locus: Insights into the Pathogenesis and Prognosis of Kidney Disease

Overview

Journal J Am Soc Nephrol

Specialty Nephrology

Date 2017 Nov 29

PMID 29180396

Citations 38

Authors

Olivier Devuyst

Cristian Pattaro

Affiliations

Soon will be listed here.

Abstract

The identification of genetic factors associated with kidney disease has the potential to provide critical insights into disease mechanisms. Genome-wide association studies have uncovered genomic regions associated with renal function metrics and risk of CKD. is among the most outstanding loci associated with CKD in the general population, because it has a large effect on eGFR and CKD risk that is consistent across different ethnic groups. The relevance of for CKD is clear, because the encoded protein, uromodulin (Tamm-Horsfall protein), is exclusively produced by the kidney tubule and has specific biochemical properties that mediate important functions in the kidney and urine. Rare mutations in are the major cause of autosomal dominant tubulointerstitial kidney disease, a condition that leads to CKD and ESRD. In this brief review, we use the paradigm to describe how population genetic studies can yield insight into the pathogenesis and prognosis of kidney diseases.

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References

Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M . Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet. 2014; 46(11):1187-96. PMC: 4213311. DOI: 10.1038/ng.3118. View

Han J, Liu Y, Rao F, Nievergelt C, OConnor D, Wang X . Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels. Kidney Int. 2013; 83(4):733-40. PMC: 3687544. DOI: 10.1038/ki.2012.449. View

Boger C, Chen M, Tin A, Olden M, Kottgen A, de Boer I . CUBN is a gene locus for albuminuria. J Am Soc Nephrol. 2011; 22(3):555-70. PMC: 3060449. DOI: 10.1681/ASN.2010060598. View

Przeworski M, Coop G, Wall J . The signature of positive selection on standing genetic variation. Evolution. 2006; 59(11):2312-23. View

Ghirotto S, Tassi F, Barbujani G, Pattini L, Hayward C, Vollenweider P . The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution. J Am Soc Nephrol. 2016; 27(10):2983-2996. PMC: 5042664. DOI: 10.1681/ASN.2015070830. View

Vinkhuyzen A, Wray N, Yang J, Goddard M, Visscher P . Estimation and partition of heritability in human populations using whole-genome analysis methods. Annu Rev Genet. 2013; 47:75-95. PMC: 4037293. DOI: 10.1146/annurev-genet-111212-133258. View

Liu C, Garnaas M, Tin A, Kottgen A, Franceschini N, Peralta C . Genetic association for renal traits among participants of African ancestry reveals new loci for renal function. PLoS Genet. 2011; 7(9):e1002264. PMC: 3169523. DOI: 10.1371/journal.pgen.1002264. View

Ying W, Allen C, Curtis L, Aaron K, Sanders P . Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model. J Clin Invest. 2012; 122(5):1777-85. PMC: 3336971. DOI: 10.1172/JCI46490. View

Sanna S, Li B, Mulas A, Sidore C, Kang H, Jackson A . Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet. 2011; 7(7):e1002198. PMC: 3145627. DOI: 10.1371/journal.pgen.1002198. View

10.

Bernascone I, Vavassori S, Di Pentima A, Santambrogio S, Lamorte G, Amoroso A . Defective intracellular trafficking of uromodulin mutant isoforms. Traffic. 2006; 7(11):1567-79. DOI: 10.1111/j.1600-0854.2006.00481.x. View

11.

Davis E, Zhang Q, Liu Q, Diplas B, Davey L, Hartley J . TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011; 43(3):189-96. PMC: 3071301. DOI: 10.1038/ng.756. View

12.

Genovese G, Friedman D, Ross M, Lecordier L, Uzureau P, Freedman B . Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010; 329(5993):841-5. PMC: 2980843. DOI: 10.1126/science.1193032. View

13.

Graham L, Padmanabhan S, Fraser N, Kumar S, Bates J, Raffi H . Validation of uromodulin as a candidate gene for human essential hypertension. Hypertension. 2013; 63(3):551-8. DOI: 10.1161/HYPERTENSIONAHA.113.01423. View

14.

Gorski M, van der Most P, Teumer A, Chu A, Li M, Mijatovic V . 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function. Sci Rep. 2017; 7:45040. PMC: 5408227. DOI: 10.1038/srep45040. View

15.

Kottgen A, Hwang S, Larson M, Van Eyk J, Fu Q, Benjamin E . Uromodulin levels associate with a common UMOD variant and risk for incident CKD. J Am Soc Nephrol. 2009; 21(2):337-44. PMC: 2834540. DOI: 10.1681/ASN.2009070725. View

16.

Nasr S, Lucia J, Galgano S, Markowitz G, DAgati V . Uromodulin storage disease. Kidney Int. 2007; 73(8):971-6. DOI: 10.1038/sj.ki.5002679. View

17.

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood A, Teumer A . A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016; 48(10):1279-83. PMC: 5388176. DOI: 10.1038/ng.3643. View

18.

Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux J . A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. J Am Soc Nephrol. 2003; 14(11):2883-93. DOI: 10.1097/01.asn.0000092147.83480.b5. View

19.

Mahajan A, Rodan A, Le T, Gaulton K, Haessler J, Stilp A . Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity. Am J Hum Genet. 2016; 99(3):636-646. PMC: 5011075. DOI: 10.1016/j.ajhg.2016.07.012. View

20.

Naik R, Derebail V, Grams M, Franceschini N, Auer P, Peloso G . Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. JAMA. 2014; 312(20):2115-25. PMC: 4356116. DOI: 10.1001/jama.2014.15063. View