功能性外显子 5 多态性和白细胞介素-1 受体相关激酶 1 基因的变异单倍型与中国人群脓毒症易感性和严重程度相关。

Functional polymorphism in exon 5 and variant haplotype of the interleukin-1 receptor-associated kinase 1 gene are associated with susceptibility to and severity of sepsis in the Chinese population.

机构信息

Key Disciplines Laboratory Clinical-Medicine Henan, Department of Emergency and Neurology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, China.

出版信息

Chin Med J (Engl). 2011 Aug;124(15):2248-53.

PMID:21933552

Abstract

BACKGROUND

The interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK1) is believed to play an important role in the pathogenesis of sepsis. Recent studies have suggested that the IRAK1 functional genetic variant could affect the severity of sepsis in Caucasians. In this report, we have investigated whether polymorphisms at the IRAK1 gene are associated with the susceptibility to and severity of sepsis among the Chinese population.

METHODS

Haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from the HapMap database. They were genotyped in 255 patients with sepsis and 260 control subjects by PCR/restriction fragment length polymorphism (RFLP) analysis. The association between the selected htSNPs and the susceptibility to and severity of sepsis were estimated by Logistic regression with adjustments for age, sex, smoking, drinking, chronic disease status, Acute Physiology and Chronic Health Evaluation (APACHE) II score and primary diseases.

RESULTS

rs1059702 was selected to represent the six linked htSNPs for IRAK1. Genotype frequencies of the htSNPs were in Hardy-Weinberg equilibrium for females, as were allele frequencies for both sex groups. Associations were observed in females between the htSNPs C/C genotype and increased susceptibility to sepsis (odds ratio (OR), 5.46; 95% confidence interval (CI), 1.12 - 26.67; P = 0.018), and such associations were also observed between the IRAK1 variant haplotype (CC/C-allele) and increased susceptibility to sepsis (OR, 1.68; 95% CI, 1.05 - 2.70; P = 0.031) when compared with the T/T + T/C genotype and the wild-type haplotype (TC + TT/T-allele). In the multiple organ dysfunction syndrome (MODS) subgroup, the variant haplotype was also associated with increased severity of sepsis (OR, 2.37; 95% CI, 1.13 - 4.94; P = 0.02) when compared with the wild haplotype. This association was not significant in male patients.

CONCLUSIONS

The functional polymorphism in exon 5 and the variant haplotype of IRAK1 gene mediate susceptibility to and severity of sepsis. IRAK1 might be a genetic risk factor for the occurrence and development of sepsis in the Chinese population.

摘要

背景

白细胞介素-1（IL-1）受体相关激酶 1（IRAK1）被认为在脓毒症发病机制中发挥重要作用。最近的研究表明，IRAK1 功能遗传变异可能影响白种人脓毒症的严重程度。在本报告中，我们研究了 IRAK1 基因中的多态性是否与中国人群中脓毒症的易感性和严重程度有关。

方法

从 HapMap 数据库中选择了标签单核苷酸多态性（htSNP）。通过聚合酶链反应/限制性片段长度多态性（PCR/RFLP）分析，对 255 例脓毒症患者和 260 例对照进行了 htSNP 基因分型。通过调整年龄、性别、吸烟、饮酒、慢性疾病状态、急性生理学和慢性健康评估（APACHE）Ⅱ评分和主要疾病，用 Logistic 回归估计所选 htSNP 与脓毒症易感性和严重程度的相关性。

结果

rs1059702 被选为代表 IRAK1 的六个连锁 htSNP 的标记物。女性 htSNP 的基因型频率符合 Hardy-Weinberg 平衡，两性群体的等位基因频率也符合 Hardy-Weinberg 平衡。在女性中，htSNP 的 C/C 基因型与脓毒症易感性增加相关（优势比（OR），5.46；95%置信区间（CI），1.12-26.67；P=0.018），与 IRAK1 变异单倍型（CC/C-等位基因）与脓毒症易感性增加相关（OR，1.68；95%CI，1.05-2.70；P=0.031），与 T/T+T/C 基因型和野生型单倍型（TC+TT/T-等位基因）相比。在多器官功能障碍综合征（MODS）亚组中，与野生型单倍型相比，变异单倍型也与脓毒症严重程度增加相关（OR，2.37；95%CI，1.13-4.94；P=0.02）。在男性患者中，这种相关性不显著。