UMOD Genotype and Determinants of Urinary Uromodulin in African Populations

Abstract

Background and objectivesSingle-nucleotide polymorphisms (SNPs) in the UMOD-PDILT genetic locus are associated with chronic kidney disease (CKD) in European populations, via their effect on urinary uromodulin (uUMOD) levels. The genetic and non-genetic factors associated with uUMOD in African populations remain unknown. MethodsClinical parameters, three selected UMOD-PDILT SNPs and uUMOD levels were obtained in 1202 young Black and White adults from the African-PREDICT study and 1943 middle aged Black adults from the PURE-NWP-SA study, two cross-sectional, observational studies. ResultsAbsolute uUMOD and uUMOD/creatinine levels were lower in Black participants compared to White participants. The prime CKD-risk allele at rs12917707 was more prevalent in Black individuals, with strikingly more risk allele homozygotes compared to White individuals. Haplotype analysis of the UMOD-PDILT locus predicted more recombination events and LD fragmentation in Black individuals. Multivariate testing and sensitivity analysis showed that higher uUMOD/creatinine associated specifically with risk alleles at rs12917707 and rs12446492 in White participants and with higher serum renin and lower uACR in Black participants with a significant interaction of ethnicity on the relationship between all three SNPs and uUMOD/creatinine. The multiple regression model explained a greater percentage of the variance of uUMOD/creatinine in White compared to Black adults (23% vs. 8%). ConclusionsWe evidenced ethnic differences in clinical and genetic determinants of uUMOD levels, in particular an interaction of ethnicity on the relationship between CKD-risk SNPs and uUMOD. These differences should be considered when analyzing the role of uromodulin in kidney function, interpreting GWAS, and precision medicine recommendations.