(369) - Candidate Gene Association Study in BOS

Abstract

Bronchiolitis obliterans syndrome (BOS), a form of chronic lung allograft dysfunction, is the primary factor limiting long-term survival for lung transplant recipients. We sought to identify genetic variants in lung transplant recipients associated with increased risk of BOS. We performed a large-scale candidate gene association study utilizing recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between 2002-2011. The primary outcome was defined as time from transplant to BOS grade 1, conditional on surviving 180 days after transplant. Genotyping was performed using the Illumina HumanCVD BeadChip v2, containing SNPs from cardiovascular, metabolic and inflammatory gene loci. Cox proportional hazards models were used to test the association between each locus and time to BOS, in an additive mode, adjusting for recipient age, predisposing diagnosis, transplant type, and population admixture. A significance threshold of p<1x10-4 was utilized based on the candidate gene design of the chip. 695 subjects were included in the analysis, 159 of whom developed BOS. Median follow-up time was 914 days (IQR 526, 1495) with median time to BOS=696 days (IQR 376, 1175). Four single nucleotide polymorphisms (SNPs) were significantly associated with time to BOS. The minor allele at rs34926152 in activated leukocyte cell adhesion molecule (ALCAM; HR=2.9, p=2.2x10-6), a gene associated with tumor aggressiveness, is a coding non-synonomous variant. One 5’ UTR SNP in the gene encoding resistin like beta (RETNLB), a gene significantly associated with asthma and airway remodeling, was significantly associated with a lower risk of BOS (HR=0.5, p=4.0x10-5). SNPs in 4 genes were significantly associated with time to BOS in a multicenter cohort study. Variants in 2 genes, RETNLB and C3, are known to be related to airways disease and asthma. Important future directions will involve validating these findings and investigating the functional implications of these variants in lung transplant recipients.