The European respiratory journal · 2024
Genome-wide association study of susceptibility to Pseudomonas aeruginosa infection in cystic fibrosis.
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Lin Boxi, Gong Jiafen, Keenan Katherine, Lin Fan, Lin Yu-Chung, Mésinèle Julie, Calmel Claire, Mohand Oumoussa Badreddine, Boëlle Pierre-Yves, Guillot Loïc, Corvol Harriet, Waters Valerie, Sun Lei, Strug Lisa J
Аннотация
BACKGROUND: Pseudomonas aeruginosa is a common pathogen that contributes to progressive lung disease in cystic fibrosis (CF). Genetic factors other than CF-causing CFTR (CF transmembrane conductance regulator) variations contribute ∼85% of the variation in chronic P. aeruginosa 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 P. aeruginosa infection.
MATERIALS AND METHODS: We conducted a genome-wide association study of chronic P. aeruginosa infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic P. aeruginosa infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bidirectional Mendelian randomisation analysis.
RESULTS: 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 P. aeruginosa 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 P. aeruginosa infection age (p=0.002). Finally, our analysis presented evidence for a causal effect of lung function on chronic P. aeruginosa 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).
CONCLUSIONS: We identified two novel loci that are associated with chronic P. aeruginosa infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between P. aeruginosa 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.
MATERIALS AND METHODS: We conducted a genome-wide association study of chronic P. aeruginosa infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic P. aeruginosa infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bidirectional Mendelian randomisation analysis.
RESULTS: 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 P. aeruginosa 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 P. aeruginosa infection age (p=0.002). Finally, our analysis presented evidence for a causal effect of lung function on chronic P. aeruginosa 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).
CONCLUSIONS: We identified two novel loci that are associated with chronic P. aeruginosa infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between P. aeruginosa 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.