ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio

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-Vasserman, Michael F. Beers, Carolyn S. Calfee, Mitchell J. Cohen, Jean Francois Pittet, David C. Christiani, Grant E. O'Keefe, Lorraine B. WareAddison K. May, Mark M. Wurfel, Hakon Hakonarson, Jason D. Christie

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Abstract

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

Original languageEnglish
Pages (from-to)1344-1353
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume183
Issue number10
DOIs
Publication statusPublished - 15 May 2011
Externally publishedYes

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Keywords

  • Acute lung injury
  • Acute respiratory distress syndrome
  • Functional genetic polymorphism
  • Genetic association study

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Meyer, N. J., Li, M., Feng, R., Bradfield, J., Gallop, R., Bellamy, S., Fuchs, B. D., Lanken, P. N., Albelda, S. M., Rushefski, M., Aplenc, R., Abramova, H., Atochina-Vasserman, E. N., Beers, M. F., Calfee, C. S., Cohen, M. J., Pittet, J. F., Christiani, D. C., O'Keefe, G. E., ... Christie, J. D. (2011). ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio. American Journal of Respiratory and Critical Care Medicine, 183(10), 1344-1353. https://doi.org/10.1164/rccm.201005-0701OC