UMOD Genotype and Determinants of Urinary Uromodulin in African Populations

Michél Strauss-Kruger; Eric Olinger; Patrick Hofmann; Ian J Wilson; Carina Mels; Ruan Kruger; Lebo F Gafane-Matemane; John A Sayer; Cristian Ricci; Aletta E Schutte; Olivier Devuyst

doi:10.1016/j.ekir.2024.09.015

UMOD Genotype and Determinants of Urinary Uromodulin in African Populations

Kidney Int Rep. 2024 Sep 21;9(12):3477-3489. doi: 10.1016/j.ekir.2024.09.015. eCollection 2024 Dec.

Authors

Michél Strauss-Kruger^{1

2}, Eric Olinger^{3

4

5}, Patrick Hofmann³, Ian J Wilson⁴, Carina Mels^{1

2}, Ruan Kruger^{1

2}, Lebo F Gafane-Matemane^{1

2}, John A Sayer⁴, Cristian Ricci⁶, Aletta E Schutte^{1

2

7

8

9}, Olivier Devuyst^{3

10}

Affiliations

¹ Hypertension in Africa Research Team, North-West University, Potchefstroom, North-West Province, South Africa.
² MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, North-West Province, South Africa.
³ Institute of Physiology, University of Zurich, Zurich, Switzerland.
⁴ Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
⁵ Center for Human Genetics, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
⁶ African Unit for Transdisciplinary Health Research, North-West University, Potchefstroom, North-West Province, South Africa.
⁷ DSI-NRF Centre of Excellence in Human Development and SAMRC/Wits Developmental Pathways for Health Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
⁸ The George Institute for Global Health, Sydney, New South Wales, Australia.
⁹ School of Population Health, University of New South Wales; Sydney, New South Wales, Australia.
¹⁰ Institute for Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium.

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.