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.

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.

Two novel genome-wide significant loci with lead single nucleotide polymorphisms (SNPs) rs62369766 (chr5p12; p=1.98x10^–8) and rs927553 (chr13q12.12; p=1.91x10^–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=4.24x10^–4). In the reverse direction, we observed a moderate effect (β=0.002, p=0.012).

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.

铜绿假单胞菌是一种常见的病原体，可导致囊性纤维化 （CF） 患者患上进行性肺病。根据双胞胎研究，除 CF 导致 CFTR （CF 跨膜电导调节剂） 变异外，其他遗传因素贡献了 CF 慢性铜绿假单胞菌感染年龄的 ~85% 的变异，但易感基因位点仍然未知。我们的目标是促进对宿主对铜绿假单胞菌感染易感性的遗传基础的理解。

我们对 1037 名加拿大 CF 患者的慢性铜绿假单胞菌感染年龄进行了全基因组关联研究。随后，我们通过多基因风险评分 （PRS） 分析评估了慢性铜绿假单胞菌感染年龄与肺功能之间的遗传相关性，并通过双向孟德尔随机化分析推断了它们的因果关系。

两个具有先导单核苷酸多态性 （SNP） 的新全基因组显著基因座 rs62369766 （chr5p12;p=1.98x ^10-8） 和 rs927553 （chr13q12.12;p=1.91x ^10-8） 与慢性铜绿假单胞菌感染年龄相关。rs62369766 位点使用独立的法国队列 （n=501） 进行验证。此外，由 CF 肺功能相关 SNP 构建的 PRS 与慢性铜绿假单胞菌感染年龄显著相关 （p=0.002）。最后，我们的分析提供了肺功能对慢性铜绿假单胞菌感染年龄 （β=0.782 岁，p=4.24x ^10-4） 的因果影响的证据。相反，我们观察到中等效果 （β=0.002，p=0.012）。

我们确定了两个与 CF 个体慢性铜绿假单胞菌感染年龄相关的新基因座。此外，我们还提供了常见遗传因素的证据以及铜绿假单胞菌感染易感性与 CF 肺功能之间的潜在因果关系。针对这些遗传因素的治疗可能会延迟慢性感染的发生，这解释了 CF 中显着的剩余发病率。