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)).

Figure 1. An overview of the region around rs4293393.

Shown are the −log₁₀ association P values of SNPs in the region with CKD (black circles), the SNPs' build 36 coordinates, the genes in the region and their exons (in blue), and recombination rates in centimorgans (cM) per megabase (Mb) (pink histogram).

Figure 2. An overview of the effect of age and the number of comorbid conditions on SCr levels, directly and through the rs4293393-T allele count.

(A) The effect of rs4293393-T on SCr stratified on age and sex. (B) The mean SCr stratified by the number of comorbid conditions and sex, compared to the mean SCr in those without any comorbid conditions. (C) The effect of rs4293393-T on SCr stratified by the number of comorbid conditions and sex. (D) The interaction effect between age and rs4293393-T allele count on SCr stratified by the number of comorbid conditions and sex. The circles give the point estimates and the vertical lines show their 95% confidence intervals. Estimates and confidence intervals are given in blue for males and red for females. Sample sizes (N) are given for each strata for males and females, respectively. Effects are given in µmol/L in (A–C) and µmol/L/year in (D).