Immunomodulatory function of the cystic fibrosis modifier gene BPIFA1

Autoři: Aabida Saferali aff001;  Anthony C. Tang aff002;  Lisa J. Strug aff005;  Bradley S. Quon aff001;  James Zlosnik aff002;  Andrew J. Sandford aff001;  Stuart E. Turvey aff002
Působiště autorů: Centre for Heart Lung Innovation, University of British Columbia and St Paul’s Hospital, Vancouver, British Columbia, Canada aff001;  Department of Pediatrics, University of British Columbia and BC Children’s Hospital, Vancouver, British Columbia, Canada aff002;  Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America aff003;  Harvard Medical School, Boston, Massachusetts, United States of America aff004;  Program in Genetics and Genome Biology, The Hospital for Sick Children, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada aff005
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article



Cystic fibrosis (CF) is characterized by a progressive decline in lung function due to airway obstruction, infection, and inflammation. CF patients are particularly susceptible to respiratory infection by a variety of pathogens, and the inflammatory response in CF is dysregulated and prolonged. BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are proteins expressed in the upper airways that may have innate immune activity. We previously identified polymorphisms in the BPIFA1/BPIFB1 region associated with CF lung disease severity.


We evaluated whether the BPIFA1/BPIFB1 associations with lung disease severity replicated in individuals with CF participating in the International CF Gene Modifier Consortium (n = 6,365). Furthermore, we investigated mechanisms by which the BPIFA1 and BPIFB1 proteins may modify lung disease in CF.


The association of the G allele of rs1078761 with reduced lung function was replicated in an independent cohort of CF patients (p = 0.001, n = 2,921) and in a meta-analysis of the full consortium (p = 2.39x10-5, n = 6,365). Furthermore, we found that rs1078761G which is associated with reduced lung function was also associated with reduced BPIFA1, but not BPIFB1, protein levels in saliva from CF patients. Functional assays indicated that BPIFA1 and BPIFB1 do not have an anti-bacterial role against P. aeruginosa but may have an immunomodulatory function in CF airway epithelial cells. Gene expression profiling using RNAseq identified Rho GTPase signaling pathways to be altered in CF airway epithelial cells in response to treatment with recombinant BPIFA1 and BPIFB1 proteins.


BPIFA1 and BPIFB1 have immunomodulatory activity and genetic variation associated with low levels of these proteins may increase CF lung disease severity.

Klíčová slova:

Cystic fibrosis – Epithelial cells – Gene expression – Genetics of disease – Inflammation – Pseudomonas aeruginosa – Recombinant proteins – Saliva


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