Mining for the genetic determinants of septic shock: when is it really gold?
Mining for the genetic determinants of septic shock: when is it really gold?
复制标题
挖掘感染性休克的遗传决定因素：什么时候才是真正的黄金？
DOI：
10.1097/00003246-200205000-00037
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发表时间：
2002
影响因子：
8.8
通讯作者：
Randolph,AdrienneG
中科院分区：
文献类型：
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作者：
Randolph,AdrienneG
了解一个人的基因构成如何影响对感染性休克和急性呼吸窘迫综合征等复杂人类炎症综合征的易感性，可能会深入了解这些疾病的发病机制，从而改进预防，诊断和治疗策略。Gibot博士及其同事（1）在这期《重症监护医学》杂志上发表了一项病例对照关联研究，研究了CD 14启动子基因多态性（从转录起始位点的-159碱基对处的C到T转变）与感染性休克的发生和严重程度之间的关系。在感染性休克组中，死亡者携带T等位基因和T等位基因纯合子的可能性更大。感染性休克组的死亡率从26.3%（C/C基因型）增加到58.1%（C/T基因型）再增加到71.4%（T/T基因型），这些差异具有高度统计学意义（p<0.05）。0001）。在得出结论对感染性休克患者进行CD 14基因多态性的基因分型可能是有益的之前，了解病例对照研究设计的局限性对于确定脓毒症易感性和预后的遗传决定因素是很重要的。多态性是已知的DNA序列变异，发生在≥ 1%的人群中（2）。这些多态性中只有一些具有功能意义。通过使用病例对照关联研究设计，研究者发现脓毒症与许多先天免疫基因的多态性之间存在正相关性，如白细胞介素-1受体拮抗剂基因（3）、肿瘤坏死因子-α基因（4，5）、脂多糖结合蛋白基因（6）和纤溶酶原激活因子-1基因（7）。尽管这种设计很受欢迎，但它的使用产生了相当大的争议，因为许多主要疾病和各种遗传标记之间高度显着相关性的初步发现在随后的研究中通常不会重复（8，9）。事实上，Hubacek et al. (10)先前报道，在204例严重脓毒症患者和247例对照中，相同的CD 14（C-159 T）多态性与脓毒症发展或死亡率之间没有关联。由于病例对照研究设计的固有问题，先天免疫基因多态性与脓毒症之间相关性的相互矛盾的报道可能会变得更常见。Silverman和Palmer（11）已经制定了评估候选基因病例对照关联研究的标准。在Gibot博士及其同事的研究中，我使用这些标准来评估CD 14（C-159 T）多态性与脓毒性休克之间关联的有效性（1）。
Understanding how a person’s genetic makeup influences susceptibility to complex human inflammatory syndromes like septic shock and acute respiratory distress syndrome may give insight into the pathogenesis of these disorders, leading to improved strategies for their prevention, diagnosis, and treatment. In this issue of Critical Care Medicine, Dr. Gibot and colleagues (1) present a case-control association study examining the relationship between a polymorphism in the CD14 promoter gene (a C to T transition at a base pair− 159 from the transcription start site) and the occurrence and severity of septic shock. Within the septic shock group, nonsurvivors were significantly more likely to carry the T allele and to be homozygous for the T allele. The observed mortality rate in the septic shock group increased from 26.3%(C/C genotype) to 58.1%(C/T genotype) to 71.4%(T/T genotype), and these differences were highly statistically significant (p<. 0001). Before concluding that it might be beneficial to genotype septic shock patients for this CD14 polymorphism, it is important to understand the limitations of the case-control study design for identifying the genetic determinants of sepsis susceptibility and outcome.Polymorphisms are known variations in the sequence of DNA occurring in≥ 1% of the population (2). Only some of these polymorphisms have functional significance. By using the case-control association study design, investigators have found positive associations between sepsis and polymorphisms in many innate immunity genes such as the interleukin-1 receptor antagonist gene (3), the tumor necrosis factor-α gene (4, 5), the lipopolysaccharide binding protein gene (6), and the plasminogen activating factor-1 gene (7). Despite the popularity of this design, its use has generated considerable controversy because initial findings of highly significant associations between many major disorders and various genetic markers are frequently not replicated in subsequent studies (8, 9). In fact, Hubacek et al.(10) previously reported no association between this same CD14 (C− 159T) polymorphism and sepsis development or mortality rate in 204 patients with severe sepsis and 247 controls. Because of inherent problems with the case-control study design, conflicting reports of associations between polymorphisms in innate immunity genes and sepsis are likely to become a more common occurrence. Silverman and Palmer (11) have developed criteria to evaluate candidate gene case-control association studies. I use these criteria to evaluate the validity of the association between the CD14 (C− 159T) polymorphism and septic shock in the study reported herein by Dr. Gibot and colleagues (1).