Haplotype association mapping of acute lung injury in mice implicates activin a receptor, type 1.
ABSTRACT Because acute lung injury is a sporadic disease produced by heterogeneous precipitating factors, previous genetic analyses are mainly limited to candidate gene case-control studies.
To develop a genome-wide strategy in which single nucleotide polymorphism associations are assessed for functional consequences to survival during acute lung injury in mice.
To identify genes associated with acute lung injury, 40 inbred strains were exposed to acrolein and haplotype association mapping, microarray, and DNA-protein binding were assessed.
The mean survival time varied among mouse strains with polar strains differing approximately 2.5-fold. Associations were identified on chromosomes 1, 2, 4, 11, and 12. Seven genes (Acvr1, Cacnb4, Ccdc148, Galnt13, Rfwd2, Rpap2, and Tgfbr3) had single nucleotide polymorphism (SNP) associations within the gene. Because SNP associations may encompass "blocks" of associated variants, functional assessment was performed in 91 genes within ± 1 Mbp of each SNP association. Using 10% or greater allelic frequency and 10% or greater phenotype explained as threshold criteria, 16 genes were assessed by microarray and reverse real-time polymerase chain reaction. Microarray revealed several enriched pathways including transforming growth factor-β signaling. Transcripts for Acvr1, Arhgap15, Cacybp, Rfwd2, and Tgfbr3 differed between the strains with exposure and contained SNPs that could eliminate putative transcriptional factor recognition sites. Ccdc148, Fancl, and Tnn had sequence differences that could produce an amino acid substitution. Mycn and Mgat4a had a promoter SNP or 3'untranslated region SNPs, respectively. Several genes were related and encoded receptors (ACVR1, TGFBR3), transcription factors (MYCN, possibly CCDC148), and ubiquitin-proteasome (RFWD2, FANCL, CACYBP) proteins that can modulate cell signaling. An Acvr1 SNP eliminated a putative ELK1 binding site and diminished DNA-protein binding.
Assessment of genetic associations can be strengthened using a genetic/genomic approach. This approach identified several candidate genes, including Acvr1, associated with increased susceptibility to acute lung injury in mice.
Full-textDOI: · Available from: Peter Di, May 05, 2015
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ABSTRACT: Pulmonary fibrosis is a disease of significant morbidity, with an incompletely defined genetic basis. Herein, we combine linkage and association studies to identify genetic variation associated with pulmonary fibrosis in mice. Mice were treated with bleomycin by osmotic minipump and pulmonary fibrosis was histologically assessed 6 weeks later. Fibrosis was mapped in C57BL6/J (fibrosis susceptible) x A/J (resistant) F2 mice, and the major identified linkage interval evaluated in consomic mice. Genome-wide and linkage interval genes were assessed for association to fibrosis using phenotypic data from 23 inbred strains and the mouse single nucleotide polymorphism map. Pulmonary fibrosis susceptibility mapped to a locus on chromosome 17, which was verified with consomic mice, and to three additional suggestive loci which may interact with alleles on chromosome 17 to affect the trait, in F2 mice. Two of the loci, including the region on chr 17, are homologous to previously mapped loci of human idiopathic fibrosis. Of the 23 phenotyped mouse strains four developed significant fibrosis and the majority presented minimal disease. Genome wide and linkage region specific association studies revealed 11 pulmonary expressed genes (including the autophagy gene Cep55 and Masp2, which is a complement component) to have polymorphisms significantly associated with bleomycin-induced fibrotic lung disease. In conclusion, genomic approaches were used to identify linkage intervals and specific genetic variation associated with pulmonary fibrosis in mice. The common loci and similarity in phenotype suggest these findings to be of relevance to clinical pulmonary fibrosis.American Journal of Respiratory Cell and Molecular Biology 12/2012; DOI:10.1165/rcmb.2012-0078OC · 4.11 Impact Factor
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ABSTRACT: Bioinformatics is the application of omics science, information technology, mathematics and statistics in the field of biomarker detection. Clinical bioinformatics can be applied for identification and validation of new biomarkers to improve current methods of monitoring disease activity and identify new therapeutic targets. Acute lung injurt (ALI)/Acute respiratory distress syndrome (ARDS) affects a large number of patients with a poor prognosis. The present review mainly focused on the progress in understanding disease heterogeneity through the use of evolving biological, genomic, and genetic approaches and the role of clinical bioinformatics in the pathogenesis and treatment of ALI/ARDS. The remarkable advances in clinical bioinformatics can be a new way for understanding disease pathogenesis, diagnosis and treatment.06/2012; 1(1):9. DOI:10.1186/2001-1326-1-9
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ABSTRACT: In this study, a genetically-diverse panel of 43 mouse strains was exposed to phosgene and genome-wide association mapping performed employing a high density SNP assembly. Transcriptomic analysis was also used to improve the genetic resolution in the identification of genetic determinants of phosgene-induced acute lung injury. We prioritized the identified genes based on whether the encoded protein was previously associated with lung injury or contained a nonsynonymous SNP within a functional domain. In addition, candidates were selected that contained a promoter SNP that could alter a putative transcription factor binding site and had variable expression by transcriptomic analyses. The latter 2 criteria also required that ≥10% of mice carried the minor allele and that this allele could account for ≥10% of the phenotypic difference noted between the strains at the phenotypic extremes. This integrative functional approach revealed 14 candidate genes that included Atp1a1, Alox5, Galnt11, Hrh1, Mbd4, Phactr2, Plxnd1, Ptprt, Reln, and Zfand4, which had significant SNP associations, and Itga9, Man1a2, Mapk14, and Vwf, which had suggestive SNP associations. Of the genes with significant SNP associations, Atp1a1, Alox5, Plxnd1, Ptprt, and Zfand4 are particularly noteworthy and could be associated with acute lung injury in several ways. Using a competitive electrophoretic mobility shift analysis, Atp1a1 promoter (rs215053185) oligonucleotide containing the minor G-allele formed a major distinct faster-migrating complex. In addition, a gene with a suggestive SNP association, Itga9, is linked to TGFB1-signaling, which previously has been associated with the susceptibility to acute lung injury in mice.American Journal of Respiratory Cell and Molecular Biology 04/2013; DOI:10.1165/rcmb.2012-0337OC · 4.11 Impact Factor