UMOD as a susceptibility gene for end-stage renal disease

BMC Medical Genetics

Gerjan Navis¹  Marc Seelen¹  Stephan JL Bakker¹  Jan Niesing⁵  Henri GD Leuvenink⁵  Jan-Luuk Hillebrands³  Bouke G Hepkema²  Harry van Goor³  Marcory CRF van Dijk³  Jeffrey Damman⁵  Martin H de Borst¹  Jacob van den Born¹  Harold Snieder⁴  Carsten A Böger⁶  Anna Reznichenko¹ 

[1] Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713AV, the Netherlands;Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;Department of Epidemiology, Unit of Genetic Epidemiology & Bioinformatics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany

关键词: Kidney transplantation;    End-stage renal disease;    SNP;    Polymorphisms;    Uromodulin;    UMOD;   

Others  :  1177806
DOI  :  10.1186/1471-2350-13-78

 received in 2012-05-04, accepted in 2012-08-31,  发布年份 2012

【 摘 要 】

Background

In recent genetic association studies, common variants including rs12917707 in the UMOD locus have shown strong evidence of association with eGFR, prevalent and incident chronic kidney disease and uromodulin urinary concentration in general population cohorts. The association of rs12917707 with end-stage renal disease (ESRD) in a recent case-control study was only nominally significant.

Methods

To investigate whether rs12917707 associates with ESRD, graft failure (GF) and urinary uromodulin levels in an independent cohort, we genotyped 1142 ESRD patients receiving a renal transplantation and 1184 kidney donors as controls. After transplantation, 1066 renal transplant recipients were followed up for GF. Urinary uromodulin concentration was measured at median [IQR] 4.2 [2.2-6.1] yrs after kidney transplantation.

Results

The rs12917707 minor allele showed association with lower risk of ESRD (OR 0.89 [0.76-1.03], p = 0.04) consistent in effect size and direction with the previous report (Böger et al, PLoS Genet 2011). Meta-analysis of these findings showed significant association of rs12917707 with ESRD (OR 0.91 [0.85-98], p = 0.008). In contrast, rs12917707 was not associated with incidence of GF. Urinary uromodulin concentration was lower in recipients-carriers of the donor rs12917707 minor allele as compared to non-carriers, again consistent with previous observations in general population cohorts.

Conclusions

Our study thus corroborates earlier evidence and independently confirms the association between UMOD and ESRD.

【 授权许可】

   
2012 Reznichenko et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Meguid El Nahas A, Bello AK: Chronic kidney disease: The global challenge. Lancet 2005, 365(9456):331-340.
• [2]Levey AS, Atkins R, Coresh J, Cohen EP, Collins AJ, Eckardt KU, et al.: Chronic kidney disease as a global public health problem: Approaches and initiatives - a position statement from kidney disease improving global outcomes. Kidney Int 2007, 72(3):247-259.
• [3]Baumeister SE, Boger CA, Kramer BK, Doring A, Eheberg D, Fischer B, et al.: Effect of chronic kidney disease and comorbid conditions on health care costs: A 10-year observational study in a general population. Am J Nephrol 2010, 31(3):222-229.
• [4]Kottgen A: Genome-wide association studies in nephrology research. Am J Kidney Dis 2010, 56(4):743-758.
• [5]Boger CA, Heid IM: Chronic kidney disease: novel insights from genome-wide association studies. Kidney Blood Press Res 2011, 34(4):225-234.
• [6]O’Seaghdha CM, Fox CS: Genetics of chronic kidney disease. Nephron Clin Pract 2011, 118(1):c55-c63.
• [7]Kottgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, et al.: Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 2009, 41(6):712-717.
• [8]Kottgen A, Pattaro C, Boger CA, Fuchsberger C, Olden M, Glazer NL, et al.: New loci associated with kidney function and chronic kidney disease. Nat Genet 2010, 42(5):376-384.
• [9]Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, et al.: Genetic loci influencing kidney function and chronic kidney disease. Nat Genet 2010, 42(5):373-375.
• [10]Liu CT, Garnaas MK, Tin A, Kottgen A, Franceschini N, Peralta CA, et al.: Genetic association for renal traits among participants of african ancestry reveals new loci for renal function. PLoS Genet 2011, 7(9):e1002264.
• [11]Kottgen A, Hwang SJ, Larson MG, Van Eyk JE, Fu Q, Benjamin EJ, et al.: Uromodulin levels associate with a common UMOD variant and risk for incident CKD. J Am Soc Nephrol 2010, 21(2):337-344.
• [12]Gudbjartsson DF, Holm H, Indridason OS, Thorleifsson G, Edvardsson V, Sulem P, et al.: Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases. PLoS Genet 2010, 6(7):e1001039.
• [13]Shlipak MG, Li Y, Fox C, Coresh J, Grunfeld C, Whooley M: Uromodulin concentrations are not associated with incident CKD among persons with coronary artery disease. BMC Nephrol 2011, 12:2. BioMed Central Full Text
• [14]Boger CA, Gorski M, Li M, Hoffmann MM, Huang C, Yang Q, et al.: Association of eGFR-related loci identified by GWAS with incident CKD and ESRD. PLoS Genet 2011, 7(9):e1002292.
• [15]Padmanabhan S, Melander O, Johnson T, Di Blasio AM, Lee WK, Gentilini D, et al.: Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet 2010, 6(10):e1001177.
• [16]Serafini-Cessi F, Malagolini N, Cavallone D: Tamm-horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis 2003, 42(4):658-676.
• [17]Vyletal P, Bleyer AJ, Kmoch S: Uromodulin biology and pathophysiology - an update. Kidney Blood Press Res 2010, 33(6):456-475.
• [18]Devuyst O, Dahan K, Pirson Y: Tamm-horsfall protein or uromodulin: new ideas about an old molecule. Nephrol Dial Transplant 2005, 20(7):1290-1294.
• [19]Reznichenko A, Snieder H, Van den Born J, de MH B, Damman J, van MCRF D, et al.: CUBN as a novel locus for end-stage renal disease: Insights from renal transplantation. PLoS One 2012, 7:e36512.
• [20]Damman J, Kok JL, Snieder H, Leuvenink HG, van Goor H, Hillebrands JL, et al.: Lectin complement pathway gene profile of the donor and recipient does not influence graft outcome after kidney transplantation. Mol Immunol 2012, 50(1–2):1-8.
• [21]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al.: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007, 81(3):559-575.
• [22]Feldman HI, Appel LJ, Chertow GM, Cifelli D, Cizman B, Daugirdas J, et al.: The chronic renal insufficiency cohort (CRIC) study: Design and methods. J Am Soc Nephrol 2003, 14(7 Suppl 2):S148-S153.
• [23]Konta T, Ikeda A, Ichikawa K, Fujimoto S, Iseki K, Moriyama T, et al.: Blood pressure control in a japanese population with chronic kidney disease: A baseline survey of a nationwide cohort. Am J Hypertens 2012, 25(3):342-347.
• [24]Eckardt KU, Barthlein B, Baid-Agrawal S, Beck A, Busch M, Eitner F, et al.: The german chronic kidney disease (GCKD) study: Design and methods. Nephrol Dial Transplant 2012, 27(4):1454-1460.