Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin

Background: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.

Methods: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.

Results: Two genome-wide significant signals were identified for uUMOD: a novel locus ( 1.24E-08) over the gene coding for KRT40, a type 1 keratin expressed in the kidney, and the locus ( 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over and . Two genome-wide significant signals for uUCR were identified at the locus and at the novel locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion.

Conclusions: Common variants in , , , and associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the locus on kidney function.