Mapping Genetic Susceptibility to Urinary Tract Infection from Kidney Papilla to Bladder

Area of Science:

• Genetics
• Immunology
• Urology

Background:

• Urinary tract infections (UTIs) are common bacterial infections, but the genetic basis of susceptibility is not well understood.
• Understanding genetic factors is crucial for developing new therapeutic strategies.

Purpose of the Study:

• To identify genetic loci associated with recurrent UTI susceptibility.
• To elucidate the functional roles of identified genes in host defense mechanisms.
• To explore the relationship between UTI susceptibility genes and other diseases.

Main Methods:

• Genome-wide association study (GWAS) of over 1.8 million individuals.
• Integrative functional annotation, expression quantitative trait loci (eQTL) colocalization, and single-cell multi-omic analyses.
• In vitro experiments to assess the function of candidate genes like PSCA.

Main Results:

• Identified 36 independent genome-wide significant loci associated with UTI susceptibility, many with sex-specific effects.
• UTI risk alleles modulate gene expression in kidney, ureter, and bladder epithelia, impacting pathways like epithelial barrier defense and innate immunity.
• PSCA identified as a strong candidate causal gene, acting as a secreted epithelial defense factor against uropathogenic E. coli, but associated with increased cancer risk.

Conclusions:

• The polygenic architecture of UTI susceptibility involves epithelial defense, immune regulation, and nutritional immunity.
• PSCA plays a dual role, protecting against infections while potentially increasing cancer risk (antagonistic pleiotropy).
• Findings provide a framework for developing host-directed, non-antibiotic UTI interventions.