AI Article Synopsis

  • Common variants in the UMOD gene can increase the risk of hypertension and chronic kidney disease (CKD) by raising uromodulin levels in the urine, which may lead to salt-sensitive hypertension and kidney damage.
  • A study of various human and primate genomes revealed that the T allele of the UMOD variant rs4293393, linked to CKD risk, is common in modern populations, while ancient genomes like Denisovans and Neanderthals carried a different variant.
  • The frequency of UMOD alleles was found to correlate with pathogen diversity and antibiotic-resistant urinary tract infections (UTIs), suggesting that the ancestral allele helps protect against UTIs, contributing to its higher prevalence today.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042664PMC
http://dx.doi.org/10.1681/ASN.2015070830DOI Listing

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