Wading into the genomic pool to unravel acute lung injury genetics.
Wading into the genomic pool to unravel acute lung injury genetics.
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DOI：
10.1513/pats.200609-157jg
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
N. Meyer;Joe G. N. Garcia
中科院分区：
文献类型：
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作者：
N. Meyer;Joe G. N. Garcia
急性肺损伤(ALI)是一种常见且往往是毁灭性的疾病，其特征是急性低氧血症、肺泡积水以及令人无法接受的高发病率和死亡率。由于暴露在ALI刺激事件中的患者中只有一小部分发展为ALI综合征，因此识别可能导致ALI易感性或预后的遗传因素具有重要意义。用于阐明ALI遗传学的两种互补策略形成了“候选基因方法”，即通过在人类或ALI动物模型中的全球基因表达谱识别基因，通常产生跨多个物种的高度保守的候选基因，或通过相关文献搜索来识别基因。检测这些ALI候选基因的相关变异或单核苷酸多态(单碱基替换)在ALI易感性和预后方面的等位基因频率在ALI患者和对照ALI高危患者之间的差异。这种方法已经在许多与ALI表型有关的基因(血管紧张素转换酶、表面活性蛋白B、热休克蛋白70、前B细胞集落增强因子、肌球蛋白轻链激酶和巨噬细胞移动抑制因子)产生了重要的变异。一种尚未用于ALI遗传学研究的替代策略包括全基因组分析，以定位含有数百个基因的“热门”基因组片段，这些片段中嵌入了潜在的ALI候选基因。总体而言，对ALI相关特定基因多态性的详细研究将继续为理解ALI的发病机制提供新的见解，揭示新的分子靶点，并促进个性化治疗的发展，以降低这种毁灭性疾病的发病率和死亡率。
Acute lung injury (ALI) is a common and often devastating illness characterized by acute hypoxemia, alveolar flooding, and an unacceptably high morbidity and mortality. Because only a fraction of the patients exposed to ALI-inciting events progress to development of the syndrome, there is significant interest in the identification of genetic factors potentially contributing to ALI susceptibility or prognosis. Two complementary strategies used to elucidate ALI genetics formulate the "candidate gene approach," whereby genes are identified by either global gene expression profiling in humans or animal models of ALI, often yielding highly conserved candidates across multiple species, or by related literature searches. Relevant variants or single nucleotide polymorphisms (single base pair substitutions) in these ALI candidate genes are tested for differences in allelic frequency for both ALI susceptibility and outcome between ALI cases and control patients at risk for ALI. This approach has yielded important variants in a number of genes (angiotensin converting enzyme, surfactant protein B, heat shock protein 70, pre-B-cell colony enhancing factor, myosin light chain kinase, and macrophage migration inhibitory factor) contributing toward an ALI phenotype. An alternative strategy not yet used in ALI genetic studies includes genomewide analyses to locate "hot" genomic segments harboring several hundred genes, with potential ALI candidate genes embedded within these segments. Overall, the detailing of specific ALI-associated polymorphisms will continue to provide new insights in the understanding of ALI pathogenesis, reveal novel molecular targets, and promote the development of individualized therapies to reduce morbidity and mortality from this devastating disease.