Finding a needle in the haystack: leveraging bioinformatics to identify a functional genetic risk factor for sepsis death.
Finding a needle in the haystack: leveraging bioinformatics to identify a functional genetic risk factor for sepsis death.
复制标题
大海捞针：利用生物信息学确定脓毒症死亡的功能性遗传风险因素。
DOI：
10.1097/ccm.0000000000000664
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发表时间：
2015
影响因子：
8.8
通讯作者：
Meyer,NualaJ
中科院分区：
文献类型：
--
作者：
Meyer,NualaJ
Among the protein’s many domains, there are domains that might interact with innate immune signaling (pentraxin, tumor necrosis factor), complement, epidermal growth factor, and von Willebrand factor (14). Because the SNP alters the amino acid sequence from glutamine to histidine and is predicted to be deleterious to SVEP1’s function, the authors silenced the gene in endothelial cells and demonstrated that lipopolysaccharide (LPS)-induced interleukin (IL)-8, growth regulated oncogene-α, monocyte chemoattractant protein (MCP)-1, and MCP-3 levels were increased, suggesting that the SNP may influence leukocyte adhesion to endothelium. Another group has demonstrated that SVEP1 was among the most up-regulated genes in human umbilical vein endothelium treated with LPS-primed monocytes and suggested that SVEP1 may regulate whether adhesion molecules are membrane bound or shed (15). The study has numerous strengths, beginning with the elegant design, incorporating bioinformatic resources to amplify the detection of functional SNPs. The use of smallinterfering RNA to model the potential deleterious effects of a nonsynonymous SNP is important. The story would be more complete if patients with sepsis also demonstrated increasing plasma IL-8 with each copy of rs10817033C, although the plasma analysis was relatively underpowered given the rarity of the SNP. The observed effect size between the SNP and sepsis mortality was very large in this original description, which may reflect a strong functional effect as suggested by the in vitro data. Nonetheless, it will be important to replicate this finding in subsequent populations as the initial association is often more extreme than truth (16). Furthermore, with a minor allele frequency of only 11% in European populations, the SNP is unlikely to explain a large proportion of sepsis death. Rather, the strength of the study by Nakada et al (12) is that it focuses attention on leukocyte-endothelial adhesion during sepsis and the possibility that modifying this interaction may influence survival. Finally, with genome-wide genotyping completed on 520 subjects in this population and approximately 1,400 in the Protein C Worldwide Evaluation in Severe Sepsis trial of drotrecogin alpha (activated)(4), a strong case could be made to analyze and report these clinical trial populations as traditional GWAS for sepsis-associated mortality, allowing increased power and the potential for replication as we attempt to understand the heritability of sepsis mortality.
