Uromodulin levels associate with a common UMOD variant and risk for incident CKD

Abstract

Common variants in the region of the UMOD gene, which encodes uromodulin (Tamm-Horsfall protein), associate with chronic kidney disease (CKD) and estimated GFR (eGFR). Whether uromodulin levels associate with UMOD variants or with the risk for developing CKD is unknown. We conducted an age- and gender-matched case-control study (n = 200) of incident CKD (eGFR <60 ml/min per 1.73 m(2)) within the Framingham Heart Study (FHS). Baseline urinary uromodulin concentrations were related to case-control status 9.9 yr later and to genotype at rs4293393. As a replication set, we tested the genotype association with uromodulin concentration in the Atherosclerosis Risk in Communities (ARIC) Study (n = 42). Geometric means of uromodulin concentrations were 51% higher in case than in control subjects (P = 0.016). The adjusted odds ratio of CKD per 1-SD higher concentration of uromodulin was 1.72 (95% confidence interval 1.07 to 2.77; P = 0.03) after accounting for CKD risk factors and baseline eGFR. We observed lower urinary uromodulin concentrations per each copy of the C allele at rs4293393 in both cohorts. In summary, elevated uromodulin concentrations precede the onset of CKD and associate with a common polymorphism in the UMOD region.

Figure 1.

Geometric mean uromodulin concentrations in the case patients and control subjects at baseline are shown. Error bars represent SEs.

Figure 2.

Distribution of uromodulin concentrations and kidney function measures in the FHS and ARIC samples by number of copies of the C allele at rs4293393 is shown. (A) Geometric mean uromodulin concentrations in FHS. (B) Geometric mean uromodulin concentrations in ARIC. (C) Proportion with CKD at FHS follow-up. (D) Mean eGFR at FHS follow-up. Genotype and phenotype information was available for 169 FHS participants: 121 had zero copies of the C allele at rs4293393, 42 had one copy, and six had two copies. Error bars represent SEs. P values in A, C, and D were obtained from regression models accounting for the matched design.