UMOD Genotype and Determinants of Urinary Uromodulin in African Populations

Abstract

Introduction: Single-nucleotide polymorphisms (SNPs) in the UMOD -PDILT genetic locus are associated with chronic kidney disease (CKD) in European populations, through their effect on urinary uromodulin (uUMOD) levels. The genetic and nongenetic factors associated with uUMOD in African populations remain unknown.

Methods: Clinical parameters, 3 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, 2 cross-sectional, observational studies.

Results: Absolute 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 linkage disequilibrium (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 urine albumin-to-creatinine ratio in Black participants, with a significant interaction of ethnicity on the relationship between all 3 SNPs and uUMOD/creatinine. The multiple regression model explained a greater percentage of the variance of uUMOD/creatinine in White adults compared to Black adults (23% vs. 8%).

Conclusion: We 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 genome-wide association studies (GWAS), and precision medicine recommendations.

Keywords: Africa; GWAS; chronic kidney disease; epidemiology; uromodulin.

Graphical abstract

Figure 1

Distribution of the UMOD/PDILT SNPs in African and European populations from the 1000 Genomes Project, the African-PREDICT and the PURE cohorts. (a) Genotype distribution of rs4293393 (UMOD), rs12917707 (UMOD), and rs12446492 (PDILT) in the African samples from the 1000 Genomes Project, compared to the global and European sample prevalence. (b) Genotype distribution of rs4293393, rs12917707, and rs12446492 in Black and White adults from the African-PREDICT and PURE studies. Blue sections represent the frequencies of “CKD risk” alleles and red sections the frequencies of “CKD protective” alleles. Populations represented in the European ancestry (n = 503) group of the 1000 Genomes Project included: Utah residents from North and West Europe CEU (n = 99), Toscani in Italia TSI (n = 107), Finnish in Finland FIN (n = 99), British in England and Scotland GBR (n = 91), and Iberian population in Spain IBS (n = 107). The African superpopulation is composed of the following populations: African Caribbean in Barbados ACB (n = 96), Gambian in Western Divisions GWD in the Gambia (n = 113), Luhya in Webuye, Kenya LWK (n = 99), Esan in Nigeria ESN (n = 99), Yoruba in Ibadan, Nigeria YRI (n = 108), Mende in Sierra Leone MSL (n = 85), and Americans with African ancestry in Southwest United States ASW (n = 61). The South African population is represented by the North-West Province PURE cohort (n = 1943) and the total of African-PREDICT cohort (n = 1202).

Figure 2

Linkage disequilibrium (LD) and haplotype analysis of the UMOD-PDILT locus. (a) LD map of the UMOD-PDILT locus based on 1000 Genomes Project summary data for African (n = 661) and European (n = 502) populations. D’ values are indicated, and the 3 SNPs of interest highlighted on the graph with their LD statistics (D’ and r²) shown below. Graph generated using Haploview 4.2. (b) LD estimates (D’ and r²) for 3 SNPs of interest in Whites (n = 535) and Blacks (n = 543) from the African-PREDICT cohort. (c) Haplotype frequency estimates in Whites and Blacks from the African-PREDICT cohort. Only the 3 most common haplotypes are shown. The grey star shows a recombination event between rs4293393 and rs12917707 that is frequent in blacks and virtually absent in whites. MAF, minor allele frequencies.

Figure 3

Effects of the UMOD-PDILT genotype on urinary uromodulin levels. Comparison of urinary uromodulin/creatinine levels according to genotypes at rs4293393 (UMOD), rs12917707 (UMOD) and rs12446492 (PDILT) in ● Black and ○ White adults from the African-PREDICT study; and ● Black adults from the PURE study. Data presented as geometric mean and 95th percentile. Bonferroni corrected P values shown for Welch’s analysis of variance comparing uromodulin and uromodulin/creatinine across groups. An interaction term SNP∗ethnicity is reported as p interaction for all 3 SNPs. SNP, single-nucleotide polymorphism.

Figure 4

Determinants of urinary uromodulin in the African-PREDICT study. Multiple regression analyses in the total African-PREDICT study population and split according to ethnicity. Continuous variables were standardized by creating z-variables, which were included into multiple regression models for this forest plot. BMI, body mass index; UACR, urinary albumin-creatinine ratio.