Abstract
Rationale: Chronic Pseudomonas aeruginosa (Pa) airway infection is common and a key contributor to diminished lung function and early mortality in persons with cystic fibrosis (PwCF). Risk factors for chronic Pa among PwCF include CFTR (cystic fibrosis transmembrane conductance regulator) genotype, genetic modifiers, and environmental factors. Intensive antibiotic therapy and highly effective modulators do not eradicate Pa in most adolescents and adults with cystic fibrosis. Objectives: To identify new genetic modifiers contributing to the pathophysiology of chronic Pa infection in PwCF. Methods: A total of 4,945 participants in the CF Genome Project with whole-genome sequencing linked to longitudinal clinical data from the 2017 Cystic Fibrosis Foundation Patient Registry were used to conduct a time-to-event genome-wide association study using two definitions of chronic Pa infection. Results: We identified a genome-wide significant association (P = 2.2 × 10(-8)) between delayed onset of chronic Pa infection and rs194810, a common variant near the gene CHP2, which encodes calcineurin B homolog protein 2 (minor A allele frequency 43%). Survival curves by rs198410 allele dosage show that PwCF homozygous for the A allele are an average of 3 years older when achieving chronic Pa infection compared with G allele homozygotes. Conclusions: Variants near CHP2 are associated with a significant delay in the age of chronic Pa infection among PwCF.