Investigation of known estimated glomerular filtration rate loci in patients with type 2 diabetes

H A Deshmukh, C N A Palmer, A D Morris, H M Colhoun, H A Deshmukh, C N A Palmer, A D Morris, H M Colhoun

Abstract

Aims: To replicate the association of genetic variants with estimated glomerular filtration rate (GFR) and albuminuria, which has been found in recent genome-wide studies in patients with Type 2 diabetes.

Methods: We evaluated 16 candidate single nucleotide polymorphisms for estimated GFR in 3028 patients with Type 2 diabetes sampled from clinics across Tayside, Scotland, UK, who were included in the Genetics of Diabetes Audit and Research Tayside (GoDARTs) study. These single nucleotide polymorphisms were tested for their association with estimated GFR at entry to the study, with albuminuria, and with time to stage 3B chronic kidney disease (estimated GFR<45 ml/min/1.73 m(2)). We also stratified the effects on estimated GFR in patients with (n = 2096) and without albuminuria (n = 613).

Results: rs1260326 in GCKR (β=1.30, P = 3.23E-03), rs17319721 in SHROOM3 (β = -1.28, P-value = 3.18E-03) and rs12917707 in UMOD (β = 2.0, P-value = 8.84E-04) were significantly associated with baseline estimated GFR. Analysis of effects on estimated GFR, stratified by albuminuria status, showed that in those without albuminuria (normoalbuminura; n = 613), UMOD had a significantly stronger effect on estimated GFR (β(normo) = 4.03 ± 1.23 vs β(albuminuria) = 1.72 ± 0.76, P = 0.002) compared with those with albuminuria, while GCKR (β(normo) = 0.45 ± 0.89 vs β(albuminuria) = 1.12 ± 0.55, P = 0.08) and SHROOM3 (β(normo) = -0.07 ± 0.89 vs β(albuminuria) = -1.43 ± 0.53, P = 0.003) had a stronger effect on estimated GFR in those with albuminuria. UMOD was also associated with a lower rate of transition to stage 3B chronic kidney disease (hazard ratio = 0.83[0.70, 0.99], P = 0.03).

Conclusion: The genetic variants that regulate estimated GFR in the general population tend to have similar effects in patients with Type 2 diabetes and in this latter population, it is important to adjust for albuminuria status while investigating the genetic determinants of renal function.

© 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

References

    1. Böger 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:e1002292.
    1. O’Seaghdha CM, Fox CS. Genome-wide association studies of chronic kidney disease: what have we learned? Nat Rev Nephrol. 2012;8:89–99.
    1. Köttgen 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;41:712–717.
    1. Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Glazer NL, et al. New loci associated with kidney function and chronic kidney disease. Nat Genet. 2010;42:376–384.
    1. Shriner D, Herbert A, Doumatey AP, Zhou J, Huang H, Erdos MR, et al. Multiple loci associated with renal function in African Americans. PloS One. 2012;7:e45112.
    1. MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ, Jerums G. Nonalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care. 2004;27:195–200.
    1. MacIsaac RJ, Panagiotopoulos S, McNeil KJ, Smith TJ, Tsalamandris C, Hao H. Is nonalbuminuric renal insufficiency in type 2 diabetes related to an increase in intrarenal vascular disease? Diabetes Care. 2006;29:1560–1566.
    1. Ellis JW, Chen MH, Foster MC, Liu CT, Larson MG, de Boer I, et al. Validated SNPs for eGFR and their associations with albuminuria. Hum Mol Genet. 2012;21:3293–3298.
    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. 1999;130:461–70.
    1. 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;81:559–575.
    1. Bellenguez C, Strange A, Freeman C Wellcome Trust Case Control Consortium. Donnelly P, Spencer CC. A robust clustering algorithm for identifying problematic samples in genome-wide association studies. Bioinformatics. 2012;28:134–135.
    1. Reznichenko A, Böger CA, Snieder H, van den Born J, de Borst MH, Damman J, et al. UMOD as a susceptibility gene for end-stage renal disease. BMC Med Genet. 2012;13:78.
    1. Köttgen A, Yang Q, Shimmin LC, Tin A, Schaeffer C, Coresh J, et al. Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. PloS One. 2012;7:e38311.
    1. Ahluwalia TS, Lindholm E, Groop L, Melander O. Uromodulin gene variant is associated with type 2 diabetic nephropathy. J Hypertens. 2011;29:1731–1734.
    1. 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:e1001039.
    1. 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:e1002264.
    1. Bonetti S, Trombetta M, Boselli ML, Turrini F, Malerba G, Trabetti E. Variants of GCKR affect both beta-cell and kidney function in patients with newly diagnosed type 2 diabetes: the Verona newly diagnosed type 2 diabetes study 2. Diabetes Care. 2011;34:1205–1210.
    1. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1–12.
    1. Ritz E, Zeng XX, Rychlík I. Clinical manifestation and natural history of diabetic nephropathy. Contrib Nephrol. 2011;170:19–27.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj