Searching for candidate genes in acute lung injury: SNPs, Chips and PBEF.
Acute lung injury (ALI) is a devastating illness, occurring in the setting of sepsis, with genetic variations contributing to ALI susceptibility and severity. We utilized the "candidate gene approach" with extensive expression profiling in animal and human ALI models to identify novel candidate genes. We noted significant expression of pre-B-cell colony enhancing factor (PBEF), a gene not previously associated with lung pathophysiology. This finding was validated by molecular, biochemical and immunohistochemical approaches with increased levels of PBEF also detected in human BAL and serum. DNA sequencing identified two single nucleotide polymorphisms (SNPs) in the PBEF promoter (T-1001G, C-1543T), which were genotyped in a Caucasian cohort of sepsis-associated ALI patients. Carriers of the GC haplotype exhibited a 5.7-fold relative ALI risk compared to controls associated with increased PBEF promoter activity. These studies demonstrate the successful application of genomic technologies in the identification of novel candidate genes in complex lung disease.
Center for Translational Respiratory Medicine, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, 4B.77, Baltimore, MD 21224-6801, USA. drgarcia@jhmi.edu
Joe G N
JG
Garcia
D000483:Alleles; D000818:Animals; D016207:Cytokines / Q000235:genetics*; D004195:Disease Models, Animal; D004285:Dogs; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D054409:Nicotinamide Phosphoribosyltransferase; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012128:Respiratory Distress Syndrome / Q000235:genetics*; D014162:Transfection
D016207:Cytokines; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human