title: Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases.
abstract: 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)).
authors.affiliation: deCODE genetics, Reykjavik, Iceland. daniel.gudbjartsson@decode.is
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: Hilma
authors.initials: H
authors.lastname: Holm
authors.forename: Olafur S
authors.initials: OS
authors.lastname: Indridason
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Vidar
authors.initials: V
authors.lastname: Edvardsson
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Femmie
authors.initials: F
authors.lastname: de Vegt
authors.forename: Frank C H
authors.initials: FC
authors.lastname: d'Ancona
authors.forename: Martin
authors.initials: M
authors.lastname: den Heijer
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
authors.forename: Leifur
authors.initials: L
authors.lastname: Franzson
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.forename: Kristleifur
authors.initials: K
authors.lastname: Kristjansson
authors.forename: Unnur S
authors.initials: US
authors.lastname: Bjornsdottir
authors.forename: Gudmundur I
authors.initials: GI
authors.lastname: Eyjolfsson
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Runolfur
authors.initials: R
authors.lastname: Palsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000367:Age Factors; D016022:Case-Control Studies; D015897:Comorbidity; D003404:Creatinine / Q000097:blood; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006073:Gout; D006801:Humans; D007055:Iceland; D007669:Kidney Calculi / Q000235:genetics*; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D051436:Renal Insufficiency, Chronic / Q000235:genetics*; D012307:Risk Factors; D014508:Urea / Q000097:blood; D014527:Uric Acid / Q000097:blood; D058949:Uromodulin / Q000235:genetics*
chemical_list: C548612:UMOD protein, human; D058949:Uromodulin; D014527:Uric Acid; D014508:Urea; D003404:Creatinine