SNP-set analysis replicates acute lung injury genetic risk factors

BMC Medical Genetics

Rui Feng²  Jason D Christie²  Michael GS Shashaty²  Paul N Lanken³  Richard Aplenc¹  Melanie Rushefski¹  Zhongyin John Daye²  Nuala J Meyer³ 

[1] Division of Hematology – Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA;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

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

Others  :  1177840
DOI  :  10.1186/1471-2350-13-52

 received in 2012-01-31, accepted in 2012-06-18,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Meyer et al.; licensee BioMed Central Ltd.

【 图 表 】

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