Modifies Chronic Airway Infection Risk in Cystic Fibrosis.

Rationale: Chronic () 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 among PwCF include cystic fibrosis transmembrane conductance regulator genotype, genetic modifiers, and environmental factors. Intensive antibiotic therapy and highly effective modulators do not eradicate in most adolescents and adults with cystic fibrosis.

Objective: To identify new genetic modifiers contributing to the pathophysiology of chronic infection in PwCF.

Methods: 4,945 participants in the CF Genome Project with whole genome sequencing linked to longitudinal clinical data from the 2017 CF Foundation Patient Registry were used to conduct a time-to-event genome-wide association study using two definitions of chronic infection.

Main Results: We identified a genome-wide significant association (p=2.2E-8) between delayed onset of chronic infection and rs194810, a common variant near the gene 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 to G allele homozygotes.

Conclusion: Variants near are associated with a significant delay in the age of chronic infection in PwCF.