title: Polymorphisms associated with expression of BPIFA1/BPIFB1 and lung disease severity in cystic fibrosis.
abstract: BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are putative innate immune molecules expressed in the upper airways. Because of their hypothesized roles in airway defense, these molecules may contribute to lung disease severity in cystic fibrosis (CF). We interrogated BPIFA1/BPIFB1 single-nucleotide polymorphisms in data from an association study of CF modifier genes and found an association of the G allele of rs1078761 with increased lung disease severity (P = 2.71 × 10(-4)). We hypothesized that the G allele of rs1078761 is associated with decreased expression of BPIFA1 and/or BPIFB1. Genome-wide lung gene expression and genotyping data from 1,111 individuals with lung disease, including 51 patients with CF, were tested for associations between genotype and BPIFA1 and BPIFB1 gene expression levels. Findings were validated by quantitative PCR in a subset of 77 individuals. Western blotting was used to measure BPIFA1 and BPIFB1 protein levels in 93 lung and 101 saliva samples. The G allele of rs1078761 was significantly associated with decreased mRNA levels of BPIFA1 (P = 4.08 × 10(-15)) and BPIFB1 (P = 0.0314). These findings were confirmed with quantitative PCR and Western blotting. We conclude that the G allele of rs1078761 may be detrimental to lung function in CF owing to decreased levels of BPIFA1 and BPIFB1.
authors.affiliation: 1 Centre for Heart Lung Innovation, UBC and St. Paul's Hospital, Vancouver, British Columbia.
authors.forename: Aabida
authors.initials: A
authors.lastname: Saferali
authors.affiliation: 1 Centre for Heart Lung Innovation, UBC and St. Paul's Hospital, Vancouver, British Columbia.
authors.forename: Ma'en
authors.initials: M
authors.lastname: Obeidat
authors.affiliation: 2 Institut Universitaire de Cardiologie et de Pneumologie de Québec and.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bérubé
authors.affiliation: 2 Institut Universitaire de Cardiologie et de Pneumologie de Québec and.
authors.forename: Maxime
authors.initials: M
authors.lastname: Lamontagne
authors.affiliation: 2 Institut Universitaire de Cardiologie et de Pneumologie de Québec and.|3 Department of Molecular Medicine, Laval University, Québec, Quebec.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: 2 Institut Universitaire de Cardiologie et de Pneumologie de Québec and.
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
authors.affiliation: 4 Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: 5 Merck Research Laboratories, Boston, Massachusetts.|6 Merck, Rahway, New Jersey.|7 Genetics, Rosetta Inpharmatics, Merck, Seattle, Washington.
authors.forename: David C
authors.initials: DC
authors.lastname: Nickle
authors.affiliation: Departments of 8 Pathology and Medical Biology and.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: 1 Centre for Heart Lung Innovation, UBC and St. Paul's Hospital, Vancouver, British Columbia.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: 9 Pulmonary Medicine and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: 10 Program in Genetics and Genome Biology, The Hospital For Sick Children, and Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
authors.affiliation: 11 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gallins
authors.affiliation: 1 Centre for Heart Lung Innovation, UBC and St. Paul's Hospital, Vancouver, British Columbia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.affiliation: 12 Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Bingle
authors.affiliation: 1 Centre for Heart Lung Innovation, UBC and St. Paul's Hospital, Vancouver, British Columbia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sandford
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D003550:Cystic Fibrosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D050556:Fatty Acid-Binding Proteins; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006023:Glycoproteins / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010750:Phosphoproteins / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics* / Q000276:immunology; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D012463:Saliva / Q000737:chemistry; D012720:Severity of Illness Index; D015398:Signal Transduction
chemical_list: D001324:Autoantigens; C485599:BPIFA1 protein, human; C568077:BPIFB1 protein, human; D050556:Fatty Acid-Binding Proteins; D006023:Glycoproteins; D010750:Phosphoproteins; D011506:Proteins; D012333:RNA, Messenger
keywords: BPIFA1; BPIFB1; PLUNCs; cystic fibrosis; gene modifiers