title: Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation.
abstract: Innate immunity is involved in the biology of graft versus host disease and common airway diseases. We screened 15 genes in this pathway using a linkage disequilibrium-based approach to identify potential candidate genes that may be involved in the development of airflow obstruction after hematopoietic cell transplantation. Sixty-nine single-nucleotide polymorphisms were selected for assessment in a discovery cohort (n = 363). Significant associations were validated in a validation cohort (n = 209). Expression of the candidate gene was demonstrated by detecting gene transcript and protein in malignant and normal small airway epithelial cells. In the discovery cohort, 133 patients developed significant airflow decline. Four patient and donor bactericidal/permeability-increasing (BPI) haplotypes were associated with a 2-fold to 3-fold increased risk of developing significant airflow decline (P values, .004-.038). This association was confirmed in the validation cohort, which had 66 patients with significant airflow decline, with 9 significant haplotypes (P values, .013-.043). BPI gene transcript and protein were detected in airway epithelial cells. These results suggest mutations in the BPI gene significantly influence the risk of developing rapid airflow decline after hematopoietic cell transplantation and may represent a novel therapeutic target for this form of airway disease.
authors.affiliation: Pulmonary and Critical Care Section, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave North, D5-280, Seattle, WA 98109-1024, USA. jchien@fhcrc.org
authors.forename: Jason W
authors.initials: JW
authors.lastname: Chien
authors.forename: Lue Ping
authors.initials: LP
authors.lastname: Zhao
authors.forename: John A
authors.initials: JA
authors.lastname: Hansen
authors.forename: Wen Hong
authors.initials: WH
authors.lastname: Fan
authors.forename: Tanyalak
authors.initials: T
authors.lastname: Parimon
authors.forename: Joan G
authors.initials: JG
authors.lastname: Clark
mesh_terms: D000328:Adult; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000235:genetics*; D006239:Haplotypes; D019337:Hematologic Neoplasms / Q000150:complications / Q000235:genetics / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012140:Respiratory Tract Diseases / Q000209:etiology / Q000235:genetics*; D012307:Risk Factors; D014184:Transplantation, Homologous
chemical_list: D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D008565:Membrane Proteins; C021623:bactericidal permeability increasing protein