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

目的：研究白介素6(IL-6)、白介素1(IL-1)和肿瘤坏死因子-α(肿瘤坏死因子)相关基因的等位基因频率在IL-6超高危重病患者中的分布频率，并探讨遗传因素对其临床病程的影响。地点：综合重症监护室。用荧光标记的实时定量聚合酶链式反应技术检测IL-6基因-174位和-596位(IL-6-174*G/C和IL-6-596*G/A)、肿瘤坏死因子-308位(IL-308*G/A)和IL-1基因β-511位(IL-1B-511^*C/T)的单核苷酸多态。用凝胶电泳法检测IL-1受体拮抗剂内含子2不同数目串联重复序列多态性(IL1RN^*1-5)。IL-6峰值水平…患者的等位基因频率IL-6峰值水平大于或等于10,000 pg/m L的患者(A组)与IL-6峰值水平为10,000 pg/m L的患者(B组)进行比较。IL-6-174^*C和IL 6-596^*A在所有受试者中均未被识别，但A组与B组相比，TNF-308^*A(p=.054)、IL 1-511^*T(p=.013)和非IL 1^*RN1(p=.008)等位基因频率较B组高，尽管采取了治疗高细胞分裂素血症的措施，A组的IL-308^*A、IL1RN^*2或IL1RN^*3等位基因携带者仍显示出持续的高IL-6水平。结论：TNF-308^*A、IL1RN^*2和IL1RN^*3等位基因与危重病患者超高IL-6水平的发生率、血IL-6动力学失控及预后有关。在肿瘤坏死因子-308^*G/A、IL6-174^*G/C和IL6-596^*G/A中，我国日本人群中的基因分布与已报道的高加索人群中的不同。考虑到这些，我们应该对日本的危重病人应用量身定制的药物。较少

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