Variation in the bactericidal/permeability increasing protein gene influences the risk of developing rapid airflow decline after hematopoietic cell transplantation

Abstract

Significant airflow decline affects up to 26% of patients who receive a hematopoietic cell transplant. Since innate immunity is involved in the biology of graft versus host disease and common airways diseases, we screened 15 genes in this pathway using a haplotype approach to identify genes that are critical to the development of this syndrome. The presence or absence of significant airflow decline, defined as a >5% annualized rate of one second forced expiratory volume decrease after transplant, was determined in discovery (n = 363) and validation (n = 209) cohorts. Sixty-nine haplotype tagging single nucleotide polymorphisms were selected for the initial screen. 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 significantly associated with a 2 to 3-fold increased risk for developing significant airflow decline (P = .004 to .038). This association was confirmed in the validation cohort, which had 66 patients with significant airflow decline, with 9 significant haplotypes (P = .013 to .043). Patient haplotypes on the lipopolysaccharide binding protein (LBP) gene, located directly adjacent to the BPI gene on chromosome 20, were also associated with the phenotype. Fine-mapping studies of the 1-mb region surrounding the BPI gene indicated there was no evidence of extended haplotype blocks and the genomic region of highest association was confirmed to be within the BPI gene. BPI gene transcript and protein was detected for the first time in airway epithelial cells. These results indicate that genetic variation affecting the BPI gene significantly influences the risk for developing rapid airflow decline after hematopoietic cell transplantation and may represent a novel therapeutic target for this form of airways disease. Significant airflow decline affects up to 26% of patients who receive a hematopoietic cell transplant. Since innate immunity is involved in the biology of graft versus host disease and common airways diseases, we screened 15 genes in this pathway using a haplotype approach to identify genes that are critical to the development of this syndrome. The presence or absence of significant airflow decline, defined as a >5% annualized rate of one second forced expiratory volume decrease after transplant, was determined in discovery (n = 363) and validation (n = 209) cohorts. Sixty-nine haplotype tagging single nucleotide polymorphisms were selected for the initial screen. 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 significantly associated with a 2 to 3-fold increased risk for developing significant airflow decline (P = .004 to .038). This association was confirmed in the validation cohort, which had 66 patients with significant airflow decline, with 9 significant haplotypes (P = .013 to .043). Patient haplotypes on the lipopolysaccharide binding protein (LBP) gene, located directly adjacent to the BPI gene on chromosome 20, were also associated with the phenotype. Fine-mapping studies of the 1-mb region surrounding the BPI gene indicated there was no evidence of extended haplotype blocks and the genomic region of highest association was confirmed to be within the BPI gene. BPI gene transcript and protein was detected for the first time in airway epithelial cells. These results indicate that genetic variation affecting the BPI gene significantly influences the risk for developing rapid airflow decline after hematopoietic cell transplantation and may represent a novel therapeutic target for this form of airways disease.