Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation

• Published in: Blood Vol. 107; no. 5; pp. 2200 - 2207
• Main Authors: Chien, Jason W., Zhao, Lue Ping, Hansen, John A., Fan, Wen Hong, Parimon, Tanyalak, Clark, Joan G.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.03.2006; The Americain Society of Hematology; 2006 by The American Society of Hematology
• Subjects: Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antimicrobial Cationic Peptides; Biological and medical sciences; Blood Proteins - genetics; Blood Proteins - metabolism; Bone marrow, stem cells transplantation. Graft versus host reaction; Cohort Studies; Female; Graft vs Host Disease - etiology; Graft vs Host Disease - genetics; Haplotypes; Hematologic Neoplasms - complications; Hematologic Neoplasms - genetics; Hematologic Neoplasms - therapy; Hematopoietic Stem Cell Transplantation; Humans; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Middle Aged; Polymorphism, Single Nucleotide; Respiratory Tract Diseases - etiology; Respiratory Tract Diseases - genetics; Risk Factors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Transplantation, Homologous; Human; Immunopathology; Genetic variability; Respiratory disease; Stem cell; Hematopoietic cell; Natural immunity; Graft versus host reaction; Epidemiology; Respiratory tract; Risk factor; Bronchus disease; Epithelial cell; Complication; Graft; Genetics; Bronchiolitis obliterans; Mutation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-06-2338

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.