Association of Variants at UMOD with Chronic Kidney Disease and Kidney Stones—Role of Age and Comorbid Diseases

• Published in: PLoS genetics Vol. 6; no. 7; p. e1001039
• Main Authors: Gudbjartsson, Daniel F., Holm, Hilma, Indridason, Olafur S., Thorleifsson, Gudmar, Edvardsson, Vidar, Sulem, Patrick, de Vegt, Femmie, d'Ancona, Frank C. H., den Heijer, Martin, Franzson, Leifur, Rafnar, Thorunn, Kristjansson, Kristleifur, Bjornsdottir, Unnur S., Eyjolfsson, Gudmundur I., Kiemeney, Lambertus A., Kong, Augustine, Palsson, Runolfur, Thorsteinsdottir, Unnur, Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2010; Public Library of Science (PLoS)
• Subjects: Age; Age Factors; Care and treatment; Case-Control Studies; Chronic kidney failure; Comorbidity; Creatinine - blood; Diabetes; Disease; Genetic aspects; Genetic Variation; Genetics and Genomics/Gene Discovery; Genetics and Genomics/Genetics of Disease; Genetics and Genomics/Population Genetics; Genome-Wide Association Study; Genomes; Gout; Health aspects; Humans; Hypotheses; Iceland; Kidney Calculi - genetics; Kidney diseases; Kidney stones; Mortality; Netherlands; Polymorphism, Single Nucleotide; Public health; Renal Insufficiency, Chronic - genetics; Risk Factors; Single nucleotide polymorphisms; Urea - blood; Uric acid; Uric Acid - blood; Uromodulin - genetics; Netherlands; Iceland
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1001039

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)).