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.
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ghirotto
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tassi
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Barbujani
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Pattini
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Department of Internal Medicine, Institute of Social and Preventive Medicine, Lausanne University Hospital Center, Lausanne, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.affiliation: Department of Internal Medicine, Institute of Social and Preventive Medicine, Lausanne University Hospital Center, Lausanne, Switzerland.
authors.forename: Murielle
authors.initials: M
authors.lastname: Bochud
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; and rampoldi.luca@hsr.it olivier.devuyst@uzh.ch.
authors.forename: Luca
authors.initials: L
authors.lastname: Rampoldi
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland rampoldi.luca@hsr.it olivier.devuyst@uzh.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D056426:Genetic Loci; D005819:Genetic Markers; D014644:Genetic Variation; D006801:Humans; D014552:Urinary Tract Infections / Q000235:genetics; D058949:Uromodulin / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D058949:Uromodulin
keywords: Urinary tract infection; chronic kidney disease; genetic renal disease; kidney tubule; tubular epithelium