The bacterium *Pseudomonas aeruginosa* is among the most common respiratory pathogens in people with cystic fibrosis: up to 60% of them eventually become infected, and the establishment of chronic infection is accompanied by a more rapid decline in lung function and reduced survival. Yet the age at which this chronic infection occurs varies considerably between individuals carrying the same pathogenic *CFTR* variants (the gene encoding the cystic fibrosis transmembrane conductance regulator), pointing to the existence of genetic modifying factors. Twin studies estimate that approximately 85% of this variability is explained by such factors, but the loci involved remained unknown. The aim of this work was to shed light on the genetic basis of host susceptibility to *P. aeruginosa*.
To this end, the team conducted a genome-wide association study of the age at onset of chronic infection in 1,037 Canadian individuals with cystic fibrosis. To limit bias, the analysis was restricted to individuals carrying genotypes associated with pancreatic insufficiency and who had not received *CFTR* modulators. Two novel loci reached genome-wide significance: the SNP rs62369766 on chromosome 5p12 (p = 1.98×10⁻⁸) and the SNP rs927553 on chromosome 13q12.12 (p = 1.91×10⁻⁸). The former was confirmed in an independent French cohort of 501 patients. The rs62369766 locus lies near *FGF10*, which is involved in airway morphogenesis, while expression data point to *NNT* as the causal gene, a gene implicated in cellular redox balance and host defense against pathogens.
The authors then explored the genetic overlap between the age of chronic infection and lung function. A polygenic risk score built from SNPs associated with lung function in cystic fibrosis was significantly linked to the age of chronic infection (p = 0.002), indicating a shared polygenic component. A bidirectional Mendelian randomization analysis further revealed a robust causal effect of reduced lung function on earlier chronic infection (β = 0.782 years, p = 4.24×10⁻⁴), as well as a moderate causal effect in the reverse direction (p = 0.012). These findings support the clinical view of a vicious cycle between worsening infection and decline in respiratory function.
The authors highlight several limitations, in particular the sample size and the influence of numerous extrinsic factors — strain virulence, person-to-person transmission, infection control practices, and diagnostic methods — that bear on the age of infection and may limit the detection of host genetic factors. Overall, this work identifies two novel loci and establishes a substantial overlap between the genetic determinants of early *P. aeruginosa* acquisition and those of lung disease. Therapeutic approaches aimed at delaying the establishment of chronic infection therefore appear to be a priority for preserving lung function.