TAILOR-MADE MEDICINE AGAINST PATHOPHYSIOLOGICAL RESPONSE TO STRESS BASED ON THE GENOME ANALYSIS

目的：确定白细胞介素（IL）-6、IL-1和肿瘤坏死因子-α（TNF）相关基因多态性在IL-6血水平极高的危重患者中的等位基因频率，并检测遗传对其临床病程的影响。150名连续的危重患者在进入ICU时被招募，无论诊断如何。测量和主要结果：每天测量IL-6血液水平。采用荧光探针实时定量PCR技术检测IL-6基因-174和-596位点（IL-6 - 174 ^* G/C和IL-6 - 596 ^* G/A）、TNF基因-308位点（TNF-308 ^* G/A）和IL-1 β基因-511位点（IL-1B-511 ^* C/T）的单核苷酸多态性。采用PCR和凝胶电泳技术检测IL-1受体拮抗剂内含子2不同数目串联重复序列多态性（IL 1RN ^* 1 - 5）。具有IL-6峰值水平的患者的等位基因频率 ...更多信息 [大于或等于] 10，000 pg/mL的患者（A组）与IL-6峰值水平<10，000 pg/mL的患者（B组）进行比较。在所有受试者中均未识别出IL 6 - 174 ^* C或IL 6 - 596 ^* A，然而与组B相比，组A显示出更高的TNF-308 ^* A（p = 0.054）、IL 1 - 511 ^* T（p = 0.013）和非IL 1 ^* RN 1（p = 0.008）等位基因频率。A组TNF-308 ^* A、IL 1RN ^* 2或IL 1RN ^* 3等位基因携带者尽管采取了高细胞因子血症的治疗措施，但仍显示出持续的高IL-6水平（如PMMA-CHDF），其生存率低于非高危等位基因携带者（p =.025）.结论：TNF-308 ^* A、IL-1RN ^* 2和IL-1RN ^* 3等位基因与危重病患者IL-6血水平极高的患病率、其血IL-6动力学失控、和结果。在TNF-308 ^* G/A、IL6 - 174 ^* G/C和IL6 - 596 ^* G/A中，我们的日本人群的基因型分布与已报道的高加索人群的基因型分布不同。考虑到这些因素，我们应该对日本的重症患者使用量身定制的药物。少

Objective : To determine the allelic frequencies of interleukin(IL) -6, IL-1 and tumor necrosis factor-α(TNF)-related gene polymorphisms in critically ill patients with extremely high IL-6 blood level and to examine the genetic effects on their clinical courses.Setting : A general intensive care unit(ICU).Patients : One hundred and fifty consecutive critically ill patients recruited on admission to the ICU, regardless of diagnosis.Measurements and Main Results : IL-6 blood levels were measured daily. Single nucleotide polymorphism at position -174 and -596 sites of the IL-6(IL6-174^*G/C and IL6-596^*G/A), -308 site of the TNF(TNF-308^*G/A) and -511 site of the IL-1β(IL1B-511^*C/T) were identified with real-time polymerase chain reaction(PCR) assay using specific fluorescence-labeled probe. IL-1 receptor antagonist intron 2 various number of tandem repeat polymorphism (IL1RN^*1-5) was identified after PCR with gel electrophoresis. Allelic frequencies of patients with IL-6 peak levels of … More 【greater than or equal】10,000 pg/mL (Group A) were compared with those of patients with IL-6 peak levels of <10,000 pg/mL (Group B). Neither IL6-174^*C nor IL6-596^* A were recognized in all the subjects, however Group A showed higher frequency of TNF-308^*A (p=.054), IL1-511^*T (p=.013) and non-IL1^*RN1(p=.008) allele compared with Group B. TNF-308^*A, IL1RN^*2 or IL1RN^*3 allele carriers of Group A showed sustained high IL-6 levels despite countermeasures against hypercytokinemia (ex.PMMA-CHDF), and their survival rate was lower than that of the non-carriers of those high-risk alleles (p=.025).Conclusions : TNF-308^*A, IL1RN^*2 and IL1RN^*3 allele were associated with the prevalence of the extremely high IL-6 blood level in the critically ill, their uncontrollable blood IL-6 kinetics, and outcome. In TNF-308^*G/A, IL6-174^*G/C and IL6-596^*G/A, genotypic distributions in our Japanese populations were diverted from those in already reported Caucasian populations. Taking those into consideration, we should apply tailor-made medicine on the Japanese critically ill patients. Less