Kidney Week

Abstract: SA-PO590

The Minor rs4293393 SNP Variant Is Associated with a Delayed Age of ESRD in Uromodulin Kidney Disease

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Bleyer, Anthony J., Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Anthony J. Bleyer,

• Kidd, Kendrah O., Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Kendrah O. Kidd,

• Vyletal, Petr, First Faculty of Medicine, Institute of Inherited Metabolic Disordes, Charles University, Prague, Czechia

Petr Vyletal,

• Reis Almeida, Jorge, Vanderbilt University, Nashville, Tennessee, United States

Jorge Reis Almeida,

• Calado, Joaquim T., Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Joaquim T. Calado,

• Torres, Rosa J, La Paz University Hospital, IdiPaz, Madrid, Spain

Rosa J Torres,

• Jorge, Sofia C.a., Portuguese Society of Nepghrology, Lisbon, Portugal

Sofia C.a. Jorge,

• Silveira, Catarina Sofia Urbano, GenoMed, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

Catarina Sofia Urbano Silveira,

• Olinger, Eric Gregory, University of Zürich, Zürich, Switzerland

Eric Gregory Olinger,

• Devuyst, Olivier, University of Zurich, Zurich, Switzerland

Olivier Devuyst,

• Kmoch, Stanislav, Institute of Inherited Metabolic Disorders, Prague, Czechia

Stanislav Kmoch,

Background

Uromodulin kidney disease (UKD) is a form of autosomal dominant tubulo-interstitial kidney disease (ADTKD) caused by mutations in the UMOD gene encoding uromodulin. UKD is characterized by slowly progressive kidney failure. The minor variant of rs4293393 in the UMOD promoter is associated with 50% decreased uromodulin production. We hypothesized that if this minor variant is found in the mutated UMOD gene promoter in individuals with UKD, there will be decreased mutant UMOD production and a later ESRD onset.

Methods

Genotyping of the rs4293393 snp was performed in 365 individuals from 149 families. Association with the mutated UMOD gene was determined. Age of ESRD was determined.

Results

Hardy Weinberg equilibrium was not met, with only 8/149 (5%) families linked to the minor variant vs. 15% expected (p-value < 0.0001). The mean age of end stage renal disease (ESRD) for individuals linked to the minor variant was 59.5+/-11.1 (n=6) vs. 45.3+/- 10.5 years for individuals linked to the major variant (n=139) (p=0.0008). No individual linked to the minor variant reached ESRD before age 45 as opposed to 71 individuals (51%) linked to the major variant (Figure 1).

Conclusion

The rs4299393 minor variant, previously linked to decreased uromodulin production has a significant protective effect on age of ESRD if it is found in the promoter of the mutant UMOD gene in individuals with UKD. The deviation from expected allele and genotype frequencies could be due to the preservation of kidney function such that families linked to the minor variant are not being diagnosed at the same rate as other UKD families. These findings identify a prognostic factor in age of ESRD in UKD and suggest that decreasing mutant uromodulin production will improve renal survival.

Figure 1: Association of CKD with rs4293393 linkage. The rs4293393 minor variant is C and the ancestral variant is T. CKD stages are based upon NKF KDOQI guidelines.

Funding

• NIDDK Support