ANGPT2 Genetic Variant Is Associated with Trauma-associated Acute Lung Injury and Altered Plasma Angiopoietin-2 Isoform Ratio

• DOI: 10.1164/rccm.201005-0701oc
• Publication Date: 2011-01-22T04:59:19Z
• Authors: Nuala J. Meyer; Mingyao Li; Rui Feng; Jonathan Bradfield; Robert Gallop; Scarlett Bellamy; Barry D. Fuchs; Paul N. Lanken; Steven M. Albelda; Melanie Rushefski; Richard Aplenc; Helen Abramova; Elena N. Atochina...; Michael F. Beers; Carolyn S. Calfee; Mitchell J. Cohen; Jean-Francois Pittet; David C. Christiani; Grant E. O'Keefe; Lorraine B. Ware; Addison K. May; Mark M. Wurfel; Hakon Hakonarson; Jason D. Christie
• Keywords: Linkage Disequilibrium; SNP; Genome-wide Association Study

Acute lung injury (ALI) acts as a complex genetic trait, yet its risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI.To identify ALI variants after major trauma using large-scale candidate gene approach.We performed two-stage association study. We derived findings in an African American cohort (n = 222) cardiopulmonary disease-centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with without ALI, adjustment clinical factors. Top performing SNPs (P < 10(-4)) tested multicenter European trauma-associated case-control population 600 ALI; n 2,266 population-based control subjects) replication. The ALI-associated genomic region was sequenced, analyzed silico prediction of function, plasma assayed by ELISA immunoblot.Five demonstrated significant covariates Stage I. Two ANGPT2 (rs1868554 rs2442598) replicated their II. rs1868554 robust to multiple comparison correction: odds ratio 1.22 (1.06-1.40), P 0.0047. Resequencing identified predicted novel splice sites linkage disequilibrium rs1868554, immunoblots showed higher proportion variant angiopoietin-2 (ANG2) isoform associated rs1868554T (0.81 vs. 0.48; 0.038).An is both variation isoforms. Characterization the regulation may yield important insights about pathogenesis susceptibility.