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

Autor: 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
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Zdroj: PLoS Genetics, Vol 6, Iss 7, p e1001039 (2010)
Druh dokumentu: article
ISSN: 1553-7390
1553-7404
DOI: 10.1371/journal.pgen.1001039
Popis: 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)).
Databáze: Directory of Open Access Journals
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