Uromodulin levels associate with a common UMOD variant and risk for incident CKD

Anna Köttgen, Shih-Jen Hwang, Martin G Larson, Jennifer E Van Eyk, Qin Fu, Emelia J Benjamin, Abbas Dehghan, Nicole L Glazer, W H Linda Kao, Tamara B Harris, Vilmundur Gudnason, Michael G Shlipak, Qiong Yang, Josef Coresh, Daniel Levy, Caroline S Fox, Anna Köttgen, Shih-Jen Hwang, Martin G Larson, Jennifer E Van Eyk, Qin Fu, Emelia J Benjamin, Abbas Dehghan, Nicole L Glazer, W H Linda Kao, Tamara B Harris, Vilmundur Gudnason, Michael G Shlipak, Qiong Yang, Josef Coresh, Daniel Levy, Caroline S Fox

Abstract

Common variants in the region of the UMOD gene, which encodes uromodulin (Tamm-Horsfall protein), associate with chronic kidney disease (CKD) and estimated GFR (eGFR). Whether uromodulin levels associate with UMOD variants or with the risk for developing CKD is unknown. We conducted an age- and gender-matched case-control study (n = 200) of incident CKD (eGFR <60 ml/min per 1.73 m(2)) within the Framingham Heart Study (FHS). Baseline urinary uromodulin concentrations were related to case-control status 9.9 yr later and to genotype at rs4293393. As a replication set, we tested the genotype association with uromodulin concentration in the Atherosclerosis Risk in Communities (ARIC) Study (n = 42). Geometric means of uromodulin concentrations were 51% higher in case than in control subjects (P = 0.016). The adjusted odds ratio of CKD per 1-SD higher concentration of uromodulin was 1.72 (95% confidence interval 1.07 to 2.77; P = 0.03) after accounting for CKD risk factors and baseline eGFR. We observed lower urinary uromodulin concentrations per each copy of the C allele at rs4293393 in both cohorts. In summary, elevated uromodulin concentrations precede the onset of CKD and associate with a common polymorphism in the UMOD region.

Figures

Figure 1.
Figure 1.
Geometric mean uromodulin concentrations in the case patients and control subjects at baseline are shown. Error bars represent SEs.
Figure 2.
Figure 2.
Distribution of uromodulin concentrations and kidney function measures in the FHS and ARIC samples by number of copies of the C allele at rs4293393 is shown. (A) Geometric mean uromodulin concentrations in FHS. (B) Geometric mean uromodulin concentrations in ARIC. (C) Proportion with CKD at FHS follow-up. (D) Mean eGFR at FHS follow-up. Genotype and phenotype information was available for 169 FHS participants: 121 had zero copies of the C allele at rs4293393, 42 had one copy, and six had two copies. Error bars represent SEs. P values in A, C, and D were obtained from regression models accounting for the matched design.

References

    1. Zhang QL, Rothenbacher D: Prevalence of chronic kidney disease in population-based studies: systematic review. BMC Public Health 8: 117, 2008
    1. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS: Prevalence of chronic kidney disease in the United States. JAMA 298: 2038–2047, 2007
    1. de Lusignan S, Chan T, Stevens P, O'Donoghue D, Hague N, Dzregah B, Van Vlymen J, Walker M, Hilton S: Identifying patients with chronic kidney disease from general practice computer records. Fam Pract 22: 234–241, 2005
    1. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW; American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention: Kidney disease as a risk factor for development of cardiovascular disease: A statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension 42: 1050–1065, 2003
    1. Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, Salem DN, Levey AS, Sarnak MJ: Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: A pooled analysis of community-based studies. J Am Soc Nephrol 15: 1307–1315, 2004
    1. Satko SG, Sedor JR, Iyengar SK, Freedman BI: Familial clustering of chronic kidney disease. Semin Dial 20: 229–236, 2007
    1. Köttgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, Yang Q, Gudnason V, Launer LJ, Harris TB, Smith AV, Arking DE, Astor BC, Boerwinkle E, Ehret GB, Ruczinski I, Scharpf RB, Ida Chen YD, de Boer IH, Haritunians T, Lumley T, Sarnak M, Siscovick D, Benjamin EJ, Levy D, Upadhyay A, Aulchenko YS, Hofman A, Rivadeneira F, Uitterlinden AG, van Duijn CM, Chasman DI, Paré G, Ridker PM, Kao WH, Witteman JC, Coresh J, Shlipak MG, Fox CS: Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 41: 712–717, 2009
    1. Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ: Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 39: 882–892, 2002
    1. Serafini-Cessi F, Malagolini N, Cavallone D: Tamm-Horsfall glycoprotein: Biology and clinical relevance. Am J Kidney Dis 42: 658–676, 2003
    1. Tamm I, Horsfall FL, Jr: Characterization and separation of an inhibitor of viral hemagglutination present in urine. Proc Soc Exp Biol Med 74: 106–108, 1950
    1. Muchmore AV, Decker JM: Uromodulin: A unique 85-kilodalton immunosuppressive glycoprotein isolated from urine of pregnant women. Science 229: 479–481, 1985
    1. Rampoldi L, Caridi G, Santon D, Boaretto F, Bernascone I, Lamorte G, Tardanico R, Dagnino M, Colussi G, Scolari F, Ghiggeri GM, Amoroso A, Casari G: Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Hum Mol Genet 12: 3369–3384, 2003
    1. Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux JM, Viron B, Jacquot C, Gagnadoux MF, Chauveau D, Büchler M, Cochat P, Cosyns JP, Mougenot B, Rider MH, Antignac C, Verellen-Dumoulin C, Pirson Y: A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. J Am Soc Nephrol 14: 2883–2893, 2003
    1. Bleyer AJ, Hart TC, Shihabi Z, Robins V, Hoyer JR: Mutations in the uromodulin gene decrease urinary excretion of Tamm-Horsfall protein. Kidney Int 66: 974–977, 2004
    1. Thornley C, Dawnay A, Cattell WR: Human Tamm-Horsfall glycoprotein: Urinary and plasma levels in normal subjects and patients with renal disease determined by a fully validated radioimmunoassay. Clin Sci (Lond) 68: 529–535, 1985
    1. Bernascone I, Vavassori S, Di Pentima A, Santambrogio S, Lamorte G, Amoroso A, Scolari F, Ghiggeri GM, Casari G, Polishchuk R, Rampoldi L: Defective intracellular trafficking of uromodulin mutant isoforms. Traffic 7: 1567–1579, 2006
    1. Vylet'al P, Kublová M, Kalbácová M, Hodanová K, Baresová V, Stibůrková B, Sikora J, Hůlková H, Zivný J, Majewski J, Simmonds A, Fryns JP, Venkat-Raman G, Elleder M, Kmoch S: Alterations of uromodulin biology: A common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int 70: 1155–1169, 2006
    1. Williams SE, Reed AA, Galvanovskis J, Antignac C, Goodship T, Karet FE, Kotanko P, Lhotta K, Morinière V, Williams P, Wong W, Rorsman P, Thakker RV: Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum. Hum Mol Genet 18: 2963–2974, 2009
    1. Su SJ, Chang KL, Lin TM, Huang YH, Yeh TM: Uromodulin and Tamm-Horsfall protein induce human monocytes to secrete TNF and express tissue factor. J Immunol 158: 3449–3456, 1997
    1. Kobayashi K, Fukuoka S: Conditions for solubilization of Tamm-Horsfall protein/uromodulin in human urine and establishment of a sensitive and accurate enzyme-linked immunosorbent assay (ELISA) method. Arch Biochem Biophys 388: 113–120, 2001
    1. Lynn KL, Shenkin A, Marshall RD: Factors affecting excretion of human urinary Tamm-Horsfall glycoprotein. Clin Sci (Lond) 62: 21–26, 1982
    1. Dawnay AB, Thornley C, Cattell WR: An improved radioimmunoassay for urinary Tamm-Horsfall glycoprotein: Investigation and resolution of factors affecting its quantification. Biochem J 206: 461–465, 1982
    1. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP: An investigation of coronary heart disease in families. The Framingham Offspring Study. Am J Epidemiol 110: 281–290, 1979
    1. National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 39: S1–S266, 2002
    1. The Atherosclerosis Risk in Communities (ARIC) Study: Design and objectives. The ARIC investigators. Am J Epidemiol 129: 687–702, 1989
    1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130: 461–470, 1999
    1. Fox CS, Larson MG, Leip EP, Culleton B, Wilson PW, Levy D: Predictors of new-onset kidney disease in a community-based population. JAMA 291: 844–850, 2004
    1. Coresh J, Astor BC, McQuillan G, Kusek J, Greene T, Van Lente F, Levey AS: Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 39: 920–929, 2002
    1. Fu Q, Garnham CP, Elliott ST, Bovenkamp DE, Van Eyk JE: A robust, streamlined, and reproducible method for proteomic analysis of serum by delipidation, albumin and IgG depletion, and two-dimensional gel electrophoresis. Proteomics 5: 2656–2664, 2005
    1. Matt P, Fu Z, Carrel T, Huso DL, Dirnhofer S, Lefkovits I, Zerkowski HR, Van Eyk JE: Proteomic alterations in heat shock protein 27 and identification of phosphoproteins in ascending aortic aneurysm associated with bicuspid and tricuspid aortic valve. J Mol Cell Cardiol 43: 792–801, 2007

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