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.

Keywords: Urinary tract infection; chronic kidney disease; genetic renal disease; kidney tubule; tubular epithelium.

Figure 1.

Genomic sequence variation at UMOD variant rs4293393. Schematic representation of the UMOD locus showing the localization of the top variant rs4293393 in the gene promoter. The alignment shows the genetic variation in the genomic region surrounding the variant. Phylogenetic relationship among the considered species is also shown. Only the major, T allele is detected in all ancient genomes that are collectively indicated as “Anatomically Modern Humans”. By contrast, only the minor, C allele is detected in the archaic genomes of Denisova and Neanderthal. The characteristics of the analyzed genomes are listed in Supplemental Table 1.

Figure 2.

The allelic frequency distribution of the rs4293393 UMOD variant does not fit the ancestral susceptibility model. Distribution of ancestral (blue) and derived (red) allele frequencies in 156 worldwide populations at the following variants: rs4293393 of the UMOD gene (top), rs699 of the AGT gene (central), and rs776746 of the CYP3A5 gene (bottom).

Figure 3.

Allelic frequencies of the rs4293393 UMOD variant do not show significant variation between African and European populations. Comparison between the F_ST values estimated between African and European populations for 2000 random noncoding regions (histogram), rs4293393 of the UMOD gene, rs699 of the AGT gene, and rs776746 of the CYP3A5 gene.

Figure 4.

The frequencies of the UMOD ancestral allele correlate with bacteria and helminth diversity. Correlation between the frequency of the UMOD ancestral T allele for rs4293393 in different populations (data from the Human Genome Diversity Panel, HGDP-CEPH) and diversity of (A) bacteria, (B) helminths, (C) viruses, and (D) protozoa. The trend was estimated using the Theil–Sen method. Populations from different continents are represented by different symbols: Africa (○), Asia (x), America (□), Oceania (◊), Europe (△).

Figure 5.

The frequencies of the UMOD ancestral allele correlate with the prevalence of antibiotic resistance in Gram-negative pathogens. Correlation between the frequency of the ancestral T allele for UMOD variant rs4293393 in different populations and prevalence (%) of antibiotic-resistant Gram-negative pathogens of the urinary tract, as available in Zowawi et al. The trend was estimated using the Theil–Sen method. The complete list of population and prevalence data are reported in Supplemental Table 4.

Figure 6.

Inverse relationship between urinary levels of uromodulin and urinary leukocyte counts in CoLaus. N represents sample sizes in each tertile (total n=2497). Bars represent median uromodulin/creatinine ratio in spot urine in each sex-specific tertile of urinary leukocytes. Data are uromodulin-to-creatinine medians (Umod P50) and whiskers interquartile range (Umod P25 and Umod P75). P values for trend are from a nonparametric test for trend across sex-specific leukocyte tertiles. *P<0.001 for median test comparing men and women. Leuco P50: median leukocyte counts in each tertile.