title: SNP-set analysis replicates acute lung injury genetic risk factors.
abstract: BACKGROUND
  We used a gene - based replication strategy to test the reproducibility of prior acute lung injury (ALI) candidate gene associations.
  
  
  METHODS
  We phenotyped 474 patients from a prospective severe trauma cohort study for ALI. Genomic DNA from subjects' blood was genotyped using the IBC chip, a multiplex single nucleotide polymorphism (SNP) array. Results were filtered for 25 candidate genes selected using prespecified literature search criteria and present on the IBC platform. For each gene, we grouped SNPs according to haplotype blocks and tested the joint effect of all SNPs on susceptibility to ALI using the SNP-set kernel association test. Results were compared to single SNP analysis of the candidate SNPs. Analyses were separate for genetically determined ancestry (African or European).
  
  
  RESULTS
  We identified 4 genes in African ancestry and 2 in European ancestry trauma subjects which replicated their associations with ALI. Ours is the first replication of IL6, IL10, IRAK3, and VEGFA associations in non-European populations with ALI. Only one gene - VEGFA - demonstrated association with ALI in both ancestries, with distinct haplotype blocks in each ancestry driving the association. We also report the association between trauma-associated ALI and NFKBIA in European ancestry subjects.
  
  
  CONCLUSIONS
  Prior ALI genetic associations are reproducible and replicate in a trauma cohort. Kernel - based SNP-set analysis is a more powerful method to detect ALI association than single SNP analysis, and thus may be more useful for replication testing. Further, gene-based replication can extend candidate gene associations to diverse ethnicities.
authors: Department of Medicine: Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine University of Pennsylvania, 3600 Spruce Street, 874 Maloney, Philadelphia, PA 19104, USA. nuala.meyer@uphs.upenn.edu
authors: Nuala J
authors: NJ
authors: Meyer
authors: Zhongyin John
authors: ZJ
authors: Daye
authors: Melanie
authors: M
authors: Rushefski
authors: Richard
authors: R
authors: Aplenc
authors: Paul N
authors: PN
authors: Lanken
authors: Michael G S
authors: MG
authors: Shashaty
authors: Jason D
authors: JD
authors: Christie
authors: Rui
authors: R
authors: Feng
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics*; D000328:Adult; D044383:Black People / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D020411:Oligonucleotide Array Sequence Analysis / Q000295:instrumentation / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D044465:White People / Q000235:genetics; D014947:Wounds and Injuries / Q000235:genetics; D055815:Young Adult
chemical_list: D020672:I-kappa B Proteins; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; C000606204:NFKBIA protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D000072000:NF-KappaB Inhibitor alpha; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases