RAGE基因标签单核甘酸多态性(-429T/C)与严重创伤并发症的临床关联及功能研究
批准号:
81201462
项目类别:
青年科学基金项目
资助金额:
23.0 万元
负责人:
曾灵
依托单位:
学科分类:
H1701.创伤
结题年份:
2015
批准年份:
2012
项目状态:
已结题
项目参与者:
姚波、段朝霞、王永堂、陈客宏、张安强、王海燕、岳彩黎
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中文摘要
脓毒症和多器官功能衰竭(MODS)是创伤后的严重并发症,对它们的机制研究对大幅降低危重患者并发症有重要意义。糖基化终末产物受体(RAGE)是近年来发现的具有重要警报素受体分子,已发现其单核基因多态性(SNP)与多种感染性疾病密切相关,但与脓毒症易感性关系尚无研究。基于RAGE与严重创伤后并发症的密切关系,我们对RAGE基因进行了连锁不平衡分析,并在此基础上筛选出其整个基因的标签SNP-63bp ins/del,rs1800625,rs1800624和rs2070600。我们采用232名严重创伤患者DNA样本,对这4个标签SNP进行了基因分型和临床关联分析,发现rs1800625(-429 T/C)是一个与脓毒症和MODS密切相关的位点。因此,我们推测-429T/C是一个有功能意义的,可能影响了RAGE基因启动子活性的SNP,并拟扩大在全国多中心收集的样本中对其进行关联和功能研究。
英文摘要
Sepsis and multiple organ dysfunction syndrome (MODS) are shown to be common and severe complications in trauma patients. Therefore, preventing sepsis and MODS is crucial in the treatment of surviving patients with major trauma. Increasing evidence suggests that genetic variants, particularly single nucleotide polymorphisms (SNPs), are critical determinants for inter-individual differences in both inflammatory responses and clinical outcome in trauma patients. Delineating the variation in genes and associated differences in response to trauma might contribute to the development of new genetically tailored diagnostic and therapeutic interventions that will improve outcome in the patients with major trauma.The receptor for advanced glycation end products (RAGE), has been recognized as a multiligand receptor, specially playing a pivotal roles in innate immune responses as a pattern-recognition receptor (PRR) in sensing both "pathogen-associated molecular patterns" (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). RAGE gene polymorphism have been associated with a variety of inflammation-related dieases, but the impact of RAGE gene polymorphism on the outcome of critical ill patients remains to be unidentified. Among the four tag SNPs of the RAGE gene(63bp ins/del,rs1800625,rs1800624 and rs2070600), only the rs1800625(-429T/C)is significantly associated with sepsis morbidity rate and MOD scores in 232 patients with major trauma(P = 0.016 and P = 0.042 for sepsis morbidity rates and MOD scores). In this study, we hypothesized that -429T/C are significantly associated with sepsis and MODS in multiple cohorts in China populations. We plan to investigate the clinical relevance of -429T/C in multiple cohorts'samples we collected in China and to further determine the functionality of -429T/C.
脓毒症和多器官功能衰竭(MODS)是创伤后的严重并发症,对它们的机制研究对大幅降低危重患者并发症有重要意义。糖基化终末产物受体(RAGE)是近年来发现的具有重要警报素受体分子,已发现其单核基因多态性(SNP)与多种感染性疾病密切相关,但与脓毒症易感性关系尚无研究。基于RAGE与严重创伤后并发症的密切关系,我们对RAGE基因进行了连锁不平衡分析,并在此基础上筛选出其整个基因的四个标签单核苷酸多态性位点-63bp ins/del,rs1800625,rs1800624和rs2070600。我们预实验采用了232名重庆严重创伤患者DNA样本,对这4个标签SNP进行了基因分型和临床关联分析,发现rs1800625(-429 T/C)是一个与脓毒症和MODS密切相关的位点。因此,我们推测-429T/C是一个有功能意义的,可能影响了RAGE基因启动子活性的SNP,并拟扩大在全国多中心收集的样本中对其进行关联和功能研究。我们在通过扩大样本,对837例重庆严重创伤人群的基因分型和关联研究发现,-429T/C是一个与脓毒症和MODS密切相关的位点,T等位基因携带者创伤后患脓毒症的几率显著大于C等位基因携带者(P=0.002)。同时,T等位基因携带者MODs评分也显著高于C等位基因携带者(P=0.001)。进一步,我们的结果在340例浙江地区和367例云南地区的严重创伤人群中得到了验证。功能研究方面,我们分析了分泌型和膜型RAGE蛋白的表达,发现分泌型RAGE蛋白的表达无差异,而rs1800625TT基因型携带者的白细胞表面,膜RAGE表达显著高于TC和CC基因型,RAGE蛋白表达升高会抑制白细胞粘附和白细胞聚集,这可能是TT基因型的携带者脓毒症发病率和MODS评分升高的原因。我们首次揭示了RAGE基因标签启动子位点-429T/C与创伤后严重并发症的相关性,并证明其通过影响启动子活性和蛋白表达进而影响创伤后严重并发症发病率,该研究可能为创伤后严重并发症的预警诊断提供了一个有效诊断标记分子。
期刊论文列表
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DOI:10.1016/j.mimet.2013.07.008
发表时间:2013-09
期刊:Journal of microbiological methods
影响因子:2.2
作者:L. Zeng;Jing Yu;W. Gu;Anqiang Zhang;Cai-li Yue;Ke-hong Chen;Jian-xin Jiang
通讯作者:L. Zeng;Jing Yu;W. Gu;Anqiang Zhang;Cai-li Yue;Ke-hong Chen;Jian-xin Jiang
Rs1800625 in the receptor for advanced glycation end products gene predisposes to sepsis and multiple organ dysfunction syndrome in patients with major trauma.
晚期糖基化终末产物基因受体中的Rs1800625易导致重大创伤患者败血症和多器官功能障碍综合征
DOI:10.1186/s13054-014-0727-2
发表时间:2015-01-09
期刊:Critical care (London, England)
影响因子:--
作者:Zeng L;Du J;Gu W;Zhang AQ;Wang HY;Wen DL;Qiu L;Yang XT;Sun JH;Zhang M;Hao J;Jiang JX
通讯作者:Jiang JX
DOI:10.1097/sla.0000000000000687
发表时间:2015
期刊:Annals of Surgery
影响因子:9
作者:Anqiang Zhang;W. Gu;L. Zeng;lianyang zhang;D. Du;Mao Zhang;J. Hao;Cai-li Yue;Jian-xin Jiang
通讯作者:Anqiang Zhang;W. Gu;L. Zeng;lianyang zhang;D. Du;Mao Zhang;J. Hao;Cai-li Yue;Jian-xin Jiang
CXC趋化因子家族错义突变I123T和A181V与创伤并发症易感性的临床关联和功能研究
- 批准号:81571892
- 项目类别:面上项目
- 资助金额:58.0万元
- 批准年份:2015
- 负责人:曾灵
- 依托单位:
国内基金
海外基金















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