biostudies-literatureLin BNatural Sciences and Engineering Research Council of CanadaCanada Research Chairs ProgramGovernment of OntarioCystic Fibrosis FoundationCystic Fibrosis CanadaGenome CanadaCanadian Institutes of Health Research2400062https://www.ebi.ac.uk/biostudies/studies/S-EPMC11540985biostudies-literatureUnknown64(5)<h4>Background</h4><i>Pseudomonas aeruginosa</i> is a common pathogen that contributes to progressive lung disease in cystic fibrosis (CF). Genetic factors other than CF-causing <i>CFTR</i> (CF transmembrane conductance regulator) variations contribute ∼85% of the variation in chronic <i>P. aeruginosa</i> infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to <i>P. aeruginosa</i> infection.<h4>Materials and methods</h4>We conducted a genome-wide association study of chronic <i>P. aeruginosa</i> infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic <i>P. aeruginosa</i> infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bidirectional Mendelian randomisation analysis.<h4>Results</h4>Two novel genome-wide significant loci with lead single nucleotide polymorphisms (SNPs) rs62369766 (chr5p12; p=1.98×10^-8) and rs927553 (chr13q12.12; p=1.91×10^-8) were associated with chronic <i>P. aeruginosa</i> infection age. The rs62369766 locus was validated using an independent French cohort (n=501). Furthermore, the PRS constructed from CF lung function-associated SNPs was significantly associated with chronic <i>P. aeruginosa</i> infection age (p=0.002). Finally, our analysis presented evidence for a causal effect of lung function on chronic <i>P. aeruginosa</i> infection age (β=0.782 years, p=4.24×10^-4). In the reverse direction, we observed a moderate effect (β=0.002, p=0.012).<h4>Conclusions</h4>We identified two novel loci that are associated with chronic <i>P. aeruginosa</i> infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between <i>P. aeruginosa</i> infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections, which account for significant remaining morbidity in CF.The European respiratory journalGenome-wide association study of susceptibility to <i>Pseudomonas aeruginosa</i> infection in cystic fibrosis.PMC11540985FRN-167282STRUG17POOGI-148FRN-310732RGPIN-04934RGPIN-2015-037422626Mohand Oumoussa BStrug LJGuillot LCorvol HMesinele JWaters VCalmel CSun LLin BLin YCBoelle PYLin FKeenan KGong JfalseGenome-wide association study of susceptibility to <i>Pseudomonas aeruginosa</i> infection in cystic fibrosis.<h4>Background</h4><i>Pseudomonas aeruginosa</i> is a common pathogen that contributes to progressive lung disease in cystic fibrosis (CF). Genetic factors other than CF-causing <i>CFTR</i> (CF transmembrane conductance regulator) variations contribute ∼85% of the variation in chronic <i>P. aeruginosa</i> infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to <i>P. aeruginosa</i> infection.<h4>Materials and methods</h4>We conducted a genome-wide association study of chronic <i>P. aeruginosa</i> infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic <i>P. aeruginosa</i> infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bidirectional Mendelian randomisation analysis.<h4>Results</h4>Two novel genome-wide significant loci with lead single nucleotide polymorphisms (SNPs) rs62369766 (chr5p12; p=1.98×10^-8) and rs927553 (chr13q12.12; p=1.91×10^-8) were associated with chronic <i>P. aeruginosa</i> infection age. The rs62369766 locus was validated using an independent French cohort (n=501). Furthermore, the PRS constructed from CF lung function-associated SNPs was significantly associated with chronic <i>P. aeruginosa</i> infection age (p=0.002). Finally, our analysis presented evidence for a causal effect of lung function on chronic <i>P. aeruginosa</i> infection age (β=0.782 years, p=4.24×10^-4). In the reverse direction, we observed a moderate effect (β=0.002, p=0.012).<h4>Conclusions</h4>We identified two novel loci that are associated with chronic <i>P. aeruginosa</i> infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between <i>P. aeruginosa</i> infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections, which account for significant remaining morbidity in CF.2024-01-01T00:00:00Z2024 Nov2026-06-08T06:28:23.485Z2026-06-08T03:14:26.891ZS-EPMC115409853911743010.1183/13993003.00062-2024