SNP-set analysis replicates acute lung injury genetic risk factors

BMC Medical Genetics

Research Article

Zhongyin John Daye¹  Rui Feng¹  Richard Aplenc²  Nuala J Meyer³  Paul N Lanken³  Michael GS Shashaty⁴  Jason D Christie⁴  Melanie Rushefski⁵ 

[1] Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA;Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA;Division of Hematology – Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;Department of Medicine: Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine University of Pennsylvania, 3600 Spruce Street, 874 Maloney, 19104, Philadelphia, PA, USA;Department of Medicine: Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine University of Pennsylvania, 3600 Spruce Street, 874 Maloney, 19104, Philadelphia, PA, USA;Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA;Division of Hematology – Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;

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

DOI  :  10.1186/1471-2350-13-52

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

来源: Springer

【 摘 要 】

BackgroundWe used a gene – based replication strategy to test the reproducibility of prior acute lung injury (ALI) candidate gene associations.MethodsWe 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).ResultsWe 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.ConclusionsPrior 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】

CC BY   
© Meyer et al.; licensee BioMed Central Ltd. 2012