The uromodulin gene locus shows evidence of pathogen adaptation through human evolution

Silvia Ghirotto, Francesca Tassi, Guido Barbujani, Linda Pattini, Caroline Hayward, Peter Vollenweider, Murielle Bochud, Luca Rampoldi, Olivier Devuyst

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of the American Society of Nephrology
Volume27
Issue number10
DOIs
Publication statusPublished - Oct 1 2016

Fingerprint

Uromodulin
Urinary Tract Infections
Alleles
Genome
Primates
Population
Genes
Salts
Neanderthals
Hypertension
Renal Hypertension
Helminths
Human Genome
Gene Frequency
Anti-Bacterial Agents
Bacteria

ASJC Scopus subject areas

  • Nephrology

Cite this

Ghirotto, S., Tassi, F., Barbujani, G., Pattini, L., Hayward, C., Vollenweider, P., ... Devuyst, O. (2016). The uromodulin gene locus shows evidence of pathogen adaptation through human evolution. Journal of the American Society of Nephrology, 27(10). https://doi.org/10.1681/ASN.2015070830

The uromodulin gene locus shows evidence of pathogen adaptation through human evolution. / Ghirotto, Silvia; Tassi, Francesca; Barbujani, Guido; Pattini, Linda; Hayward, Caroline; Vollenweider, Peter; Bochud, Murielle; Rampoldi, Luca; Devuyst, Olivier.

In: Journal of the American Society of Nephrology, Vol. 27, No. 10, 01.10.2016.

Research output: Contribution to journalArticle

Ghirotto, S, Tassi, F, Barbujani, G, Pattini, L, Hayward, C, Vollenweider, P, Bochud, M, Rampoldi, L & Devuyst, O 2016, 'The uromodulin gene locus shows evidence of pathogen adaptation through human evolution', Journal of the American Society of Nephrology, vol. 27, no. 10. https://doi.org/10.1681/ASN.2015070830
Ghirotto, Silvia ; Tassi, Francesca ; Barbujani, Guido ; Pattini, Linda ; Hayward, Caroline ; Vollenweider, Peter ; Bochud, Murielle ; Rampoldi, Luca ; Devuyst, Olivier. / The uromodulin gene locus shows evidence of pathogen adaptation through human evolution. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 10.
@article{a18fa09f3d51420f9f8843568f147ae4,
title = "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.",
author = "Silvia Ghirotto and Francesca Tassi and Guido Barbujani and Linda Pattini and Caroline Hayward and Peter Vollenweider and Murielle Bochud and Luca Rampoldi and Olivier Devuyst",
year = "2016",
month = "10",
day = "1",
doi = "10.1681/ASN.2015070830",
language = "English",
volume = "27",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "10",

}

TY - JOUR

T1 - The uromodulin gene locus shows evidence of pathogen adaptation through human evolution

AU - Ghirotto, Silvia

AU - Tassi, Francesca

AU - Barbujani, Guido

AU - Pattini, Linda

AU - Hayward, Caroline

AU - Vollenweider, Peter

AU - Bochud, Murielle

AU - Rampoldi, Luca

AU - Devuyst, Olivier

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84992392033&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992392033&partnerID=8YFLogxK

U2 - 10.1681/ASN.2015070830

DO - 10.1681/ASN.2015070830

M3 - Article

AN - SCOPUS:84992392033

VL - 27

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 10

ER -