PLoS Genetics (Jul 2010)

Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases.

  • Daniel F Gudbjartsson,
  • Hilma Holm,
  • Olafur S Indridason,
  • Gudmar Thorleifsson,
  • Vidar Edvardsson,
  • Patrick Sulem,
  • Femmie de Vegt,
  • Frank C H d'Ancona,
  • Martin den Heijer,
  • Jack F M Wetzels,
  • Leifur Franzson,
  • Thorunn Rafnar,
  • Kristleifur Kristjansson,
  • Unnur S Bjornsdottir,
  • Gudmundur I Eyjolfsson,
  • Lambertus A Kiemeney,
  • Augustine Kong,
  • Runolfur Palsson,
  • Unnur Thorsteinsdottir,
  • Kari Stefansson

DOI
https://doi.org/10.1371/journal.pgen.1001039
Journal volume & issue
Vol. 6, no. 7
p. e1001039

Abstract

Read online

Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1x10(-10)). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3 x 10(-23)) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0 x 10(-17)) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0 x 10(-6)), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7 x 10(-5)).