Haplotype Association Mapping of Acute Lung Injury in Mice Implicates Activin A Receptor, Type 1
Haplotype Association Mapping of Acute Lung Injury in Mice Implicates Activin A Receptor, Type 1
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DOI：
10.1164/rccm.201006-0912oc
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发表时间：
2011-06-01
影响因子：
24.7
通讯作者：
Prows, Daniel R.
中科院分区：
文献类型：
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作者：
Leikauf, George D.;Concel, Vincent J.;Prows, Daniel R.
理论基础：由于急性肺损伤是一种由异质性诱发因素引起的散发性疾病，以往的遗传分析主要局限于候选基因病例对照研究。目的：建立一种全基因组策略，评估单核苷酸多态关联对小鼠急性肺损伤存活的功能影响。方法：为了确定与急性肺损伤相关的基因，对40个近交系菌株进行了丙烯醛暴露、单倍型关联作图、基因芯片和DNA-蛋白质结合分析。测量和主要结果：不同品系的小鼠平均存活时间不同，极性品系的平均存活时间相差约2.5倍。有7个基因(ACVR1、Cacnb4、Ccdc148、Galnt13、Rfwd2、RPap2和Tgfbr3)在该基因内存在单核苷酸多态(SNP)关联。由于SNP关联可能包含相关变异的“区块”，因此对每个SNP关联的+/-1 MBP内的91个基因进行了功能评估。以等位基因频率大于或等于10%和表型大于或等于10%为阈值标准，用基因芯片和反向实时定量聚合酶链式反应对16个基因进行评估。微阵列揭示了几个丰富的途径，包括转化生长因子-β信号转导。ACVR1、Arhgap15、CacyBP、Rfwd2和Tgfbr3的转录产物在暴露于不同的菌株之间存在差异，并且包含可以消除假定的转录因子识别位点的SNPs。Ccdc148、Fanc1和Tnn具有序列差异，可产生氨基酸替换。MYCN和Mgat4a分别含有启动子SNP和3‘非翻译区SNPs。一些相关的基因编码受体(ACVR1、TGFBR3)、转录因子(MYCN，可能是CCDC148)和泛素蛋白酶体(RFWD2、FANCL、CACYBP)蛋白，这些蛋白可以调节细胞信号。ACVR1SNP消除了推测的ELK1结合位点，减少了DNA与蛋白质的结合。结论：使用遗传/基因组方法可以加强对遗传相关性的评估。这种方法确定了几个候选基因，包括ACVR1，与小鼠对急性肺损伤的易感性增加有关。
Rationale: 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.Objectives: 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.Methods: 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.Measurements and Main Results: 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-beta 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.Conclusions: 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.