The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution.

Abstract

Common variants in the UMOD gene encoding uromodulin, associated with risk of hypertension and CKD in the general population, increase UMOD expression and urinary excretion of uromodulin, causing salt-sensitive hypertension and renal lesions. To determine the effect of selective pressure on variant frequency, we investigated the allelic frequency of the lead UMOD variant rs4293393 in 156 human populations, in eight ancient human genomes, and in primate genomes. The T allele of rs4293393, associated with CKD risk, has high frequency in most modern populations and was the one detected in primate genomes. In contrast, we identified only the derived, C allele in Denisovan and Neanderthal genomes. The distribution of the UMOD ancestral allele did not follow the ancestral susceptibility model observed for variants associated with salt-sensitive hypertension. Instead, the global frequencies of the UMOD alleles significantly correlated with pathogen diversity (bacteria, helminths) and prevalence of antibiotic-resistant urinary tract infections (UTIs). The inverse correlation found between urinary levels of uromodulin and markers of UTIs in the general population substantiates the link between UMOD variants and protection against UTIs. These data strongly suggest that the UMOD ancestral allele, driving higher urinary excretion of uromodulin, has been kept at a high frequency because of its protective effect against UTIs.

• Authors: Silvia Ghirotto, Francesca Tassi, Guido Barbujani, Linda Pattini, Caroline Hayward, Peter Vollenweider, Murielle Bochud, Luca Rampoldi, Olivier Devuyst
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 27 Issue 10 Pg. 2983-2996 (Oct 2016) ISSN: 1533-3450 [Electronic] United States
• PMID: 26966016 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 by the American Society of Nephrology.

Chemical References

• Genetic Markers
• Uromodulin

Topics

• Animals
• Evolution, Molecular
• Genetic Loci
• Genetic Markers
• Genetic Variation
• Humans
• Urinary Tract Infections (genetics)
• Uromodulin (genetics)