MO048: Genome-wide studies reveal factors associated with circulating uromodulin and its relations with complex diseases

BACKGROUND AND AIMS UMOD is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is the most abundant protein in urine and related to chronic kidney disease, hypertension and pathogen defense. Through basolateral release from kidney epithelial cells, uromodulin also reaches the blood, where its function is largely unknown. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin in seven cohorts using two complementary assays. METHOD Separate genome-wide association study meta-analyses for circulating uromodulin were conducted for the antibody-based assay (five cohorts, N = 13 985) and the aptamer-based SOMAscan assay (two cohorts, N = 18 070). Genome-wide significant loci were placed into their functional genomic context using RNA-seq, ATAC-seq and Hi-C data generated from primary human kidney tissue. An array of downstream genetic analyses was then performed for significant loci, including fine-mapping, colocalization analyses and gene-by-gene interaction analyses. The B4GALNT2 p.Cys466Arg allele was expressed in MDCK cells and studied by immunofluorescence and Western blotting analyses. RESULTS We detected and replicated 13 genome-wide significant loci (P CONCLUSION This study provides human genetic evidence of new pathway members of uromodulin and delivers novel insights into its determinants and systemic role in the circulation.