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Open Access Research article

SNP-set analysis replicates acute lung injury genetic risk factors

Nuala J Meyer1*, Zhongyin John Daye2, Melanie Rushefski3, Richard Aplenc23, Paul N Lanken1, Michael GS Shashaty12, Jason D Christie12 and Rui Feng2

Author Affiliations

1 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

2 Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA

3 Division of Hematology – Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

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BMC Medical Genetics 2012, 13:52  doi:10.1186/1471-2350-13-52

Published: 28 June 2012

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.

Keywords:
Genetic association study; Acute respiratory distress syndrome; Kernel machine regression