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

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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