Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases.
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)).
Gudbjartsson
Daniel F
DF
deCODE genetics, Reykjavik, Iceland. daniel.gudbjartsson@decode.is
Holm
Hilma
H
Indridason
Olafur S
OS
Thorleifsson
Gudmar
G
Edvardsson
Vidar
V
Sulem
Patrick
P
de Vegt
Femmie
F
d'Ancona
Frank C H
FC
den Heijer
Martin
M
Wetzels
Jack F M
JF
Franzson
Leifur
L
Rafnar
Thorunn
T
Kristjansson
Kristleifur
K
Bjornsdottir
Unnur S
US
Eyjolfsson
Gudmundur I
GI
Kiemeney
Lambertus A
LA
Kong
Augustine
A
Palsson
Runolfur
R
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
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*
C548612:UMOD protein, human; D058949:Uromodulin; D014527:Uric Acid; D014508:Urea; D003404:Creatinine