白细胞介素6及其启动子基因多态性与儿童1型糖尿病相关性的研究
|
摘要
目的
1型糖尿病是儿童常见的内分泌疾病,它的发病是遗传,环境,免疫因素共同作用的结果。1型糖尿病是多基因疾病,白细胞介素6(IL-6)是近年研究认为可能与1型糖尿病相关的细胞因子。本研究检测1型糖尿病病例组及对照组外周血白细胞介素6的水平,探讨它在1型糖尿病患儿体内的变化,同时应用聚合酶链式反应-限制性片段长度多态性法(PCR-RFLP)对白细胞介素6基因启动子-572位点进行研究,探讨此位点基因多态性是否与1型糖尿病相关,对于不同基因型进一步探讨其是否与外周血IL-6的水平,发病年龄及发病时空腹C肽水平相关。
方法
1应用放射免疫分析法检测1型糖尿病患儿组及对照组外周血IL-6水平。
2应用盐析法提取病例组与对照组外周血的DNA,并在1%琼脂糖凝胶电泳上观察提取结果。
3应用聚合酶链式反应对病例组及对照组包含IL-6基因启动子-572位点的特异片段进行扩增,扩增的目的片段用2.5%琼脂糖凝胶电泳检测。
4将扩增产物用MbiⅠ内切酶进行酶切,酶切产物在3%琼脂糖凝胶电泳上检测,并对其进行定性分析。
5应用放射免疫分析法检测病例组外周血的空腹C肽水平。
6根据Hardy-Weinburg遗传平衡定律检查病例组及对照组所得基因型是否具有群体代表性。
7应用SPSS15.0统计软件对所得数据进行分析,其中病例组与对照组外周血IL-6水平的比较及病例组中首诊病人与复诊病人外周血IL-6水平的比较均采用两组独立样本的t检验。病例组与对照组的IL-6基因启动子-572位点基因型频率的比较采用Fisher精确概率法,等位基因频率的比较采用x~2检验,用相对比值比及95%可信区间表示相对危险度。不同国家IL-6基因启动子-572位点基因型频率的比较采用x~2检验或Fisher精确概率法。病例组不同基因型间IL-6水平,发病年龄及发病时空腹C肽水平的比较均采用两组独立样本的t检验。
结果
1病例组与对照组儿童性别及年龄的差异无统计学意义(P＞0.05),具有可比性。
2病例组与对照组儿童外周血IL-6水平的比较差异无统计学意义,病例组中首诊病人与复诊病人外周血IL-6水平的比较差异仍无统计学意义。(P＞0.05)
3 IL-6基因启动子-572位点经PCR扩增后产物片段为163bp,酶切后分为3种基因型,CC型为1条带(163bp),GC型为3条带(163bp,101bp,62bp),GG型为2条带(101bp,62bp)。
4病例组与对照组基因型频率符合Hardy-Weinburg遗传平衡定律,具有群体代表性。
5对照组IL-6基因启动子-572位点基因型及等位基因频率的分布与中国其他研究结果比较差异无统计学意义(P＞0.05),与日本比较差异无统计学意义(P＞0.05),与法国、美国比较差异有统计学意义(P＜0.05)。
6病例组与对照组IL-6基因启动子-572位点基因型频率及等位基因频率分布的差异均有统计学意义(P＜0.05),等位基因频率的相对风险分析示G等位基因的携带者患1型糖尿病的风险是C等位基因携带者的1.939倍(OR=1.939,95%CI=1.023～3.678)。
7病例组IL-6基因启动子-572位点不同基因型间IL-6水平的差异无统计学意义。(P＞0.05)
8病例组IL-6基因启动子-572位点不同基因型间发病年龄的差异有统计学意义(P＜0.05),其中携带G等位基因的患儿发病年龄早于CC基因型的患儿。
9病例组IL-6基因启动子-572位点不同基因型间空腹C肽水平的差异无统计学意义。(P＞0.05)
结论
11型糖尿病患儿体内IL-6水平无变化,IL-6基因启动子-572位点不同基因型患儿体内的IL-6水平亦无变化。
2不同种族IL-6基因启动子-572位点基因多态性存在差异,亚洲人群可能具有相似的基因型及等位基因分布,欧美国家可能具有相似的基因型及等位基因分布。
3 IL-6基因启动子-572位点基因多态性可能与1型糖尿病的发病存在相关性,其中G等位基因可能是1型糖尿病的易感基因。
4 IL-6基因启动子-572位点不同的基因型可能与患儿患病年龄存在相关性,其中GG+GC基因型的患儿的患病年龄早于CC基因型。
5 IL-6基因启动子-572位点不同的基因型患儿患病时空腹C肽水平无差别。
Objective Type 1 diabetes is a common disease of chinldren,The pathogenesis of type 1 diabetes involve genetically factors,environmental factors and immunological factors.Type 1 diabetes belongs to polygenic disease.IL-6 is considered to play a roal in the pathogenesis of type 1 diabetes,so we detected the level of IL-6 of patients and controls to study the change of IL-6 level in children of type 1 dianbetes,in the same time,we detected the genotype of IL-6-572 of patients and controls by Polymerase Chain Reaction-Restriction Fragment length Polymorphism(PCR-RFLP)to study the relationship between -572G/C polymorphism of IL-6 promoter and type 1 diabetes, we also studied the difference of IL-6 level,the onset year and the C peptide between different genotype of IL-6-572.
Methods
1 The level of IL-6 of patients and controls was detected by Radioimmunologic method.
2 The DNA of patients and controls was extracted by salt fractionation and the purity of DNA was detected by 1.0%agarose gel electrophoresis.
3 The promoter of IL-6-572 was amplificated by PCR and the amplification was detected by 2.5%agarose gel electrophoresis.
4 The amplification was cut by incision enzyme MbiⅠand the genotype was detected by 3.0%agarose gel electrophoresis to undertake qualitative analysis.
5 The C peptide of patients and controls was detected by Radioimmunologic method.
6 The representation of genotype of patients and controls was detected accorrding to Hardy-Weinberg equilibrium.
7 The data was analyzed by sofeware of spss15.0,The IL-6 level of patients and controls and the IL-6 level of preliminary diagnosed patients and re-examination diagnosed patients were all compared by two indepentent t test.The -572 genotype frequencies of IL-6 promoter of patients and controls were compared by Fisher exact probability test,the IL-6-572 allele frequencies were compared byχ~2 test and the relative risk was expressed by OR and 95%CI.The IL-6-572 disposition of different countries were compared byχ~2 test or Fisher exact probability test.The IL-6 level,the onset year,the C peptide of different genotype were also compared by two indepentent t test.
Results
1 There was no difference between patients and controls in spite of sex and age.
2 The level of IL-6 was not different between patients and controls,and the level of IL-6 was also not different between the preliminary diagnosed patients and re-examined diagnosd patients.
3 The amplification of IL-6 -572 was 163bp and there were three genotypes after cuting by incision enzyme,CC genotype was one bright bar(163bp)on the electropherogram,CG genotype was three bright bar(163bp,101bp,62bp)and GG genotype was two bright bar(101bp,62bp)on the electropherogram.
4 The genotype and allele frequencies of IL-6-572 were all in Hardy-Weinburg equilibrium,so the patients and controls were representative.
5 The IL-6-572 genotype and allele frequencies were not different between the controls and other Chinese people and Japanese,but which were different between the controls and France and American.
6 The IL-6-572 genotype and allele frequencies were different between the patients and the controls(P＜0.05),the relative risk of allele of type 1 diabetes indicated G allele was 1.939 times to the G allele,odds ratio is 1.939,95%confidence interval is 1.023～3.678.(OR=1.939,95%CI=1.023～3.678)
7 The comparison of the level of IL-6 between GG+GC genotype and CC genotype had no statistical significance.(P＞0.05)
8 The comparison of the onset year between GG+GC genotype and CC genotype had statistical significance(P＜0.05),the onset year of child who take along G allele was earlier than the C allele.
9 The comparison of C peptide between GG+GC genotype and CC genotype had no statistical significance.(P＞0.05)
Conelusion
(1)The level of IL-6 is not different between patients and controls,the IL-6 level is also not different between different genotypes of IL-6-572.
(2)Different race has different frequency of IL-6-572 genotype and allele,The Asian have resemble frequency of IL-6-572 genotype and allele,and the European and American have resemble frequency.
(3)IL-6-572 polymorphism is maybe associated with type 1 diabetes of children and the G allele maybe the predisposing gene of type 1 diabetes of children.
(4)The different genotype of IL-6-572 is maybe associated with the onset year,the onset year of child who take along GG+GC genotype is earlier than the CC genotype.
(5)The different genotype of IL-6-572 is not associated with C peptide.
1型糖尿病是儿童常见的内分泌疾病,它的发病是遗传,环境,免疫因素共同作用的结果。1型糖尿病是多基因疾病,白细胞介素6(IL-6)是近年研究认为可能与1型糖尿病相关的细胞因子。本研究检测1型糖尿病病例组及对照组外周血白细胞介素6的水平,探讨它在1型糖尿病患儿体内的变化,同时应用聚合酶链式反应-限制性片段长度多态性法(PCR-RFLP)对白细胞介素6基因启动子-572位点进行研究,探讨此位点基因多态性是否与1型糖尿病相关,对于不同基因型进一步探讨其是否与外周血IL-6的水平,发病年龄及发病时空腹C肽水平相关。
方法
1应用放射免疫分析法检测1型糖尿病患儿组及对照组外周血IL-6水平。
2应用盐析法提取病例组与对照组外周血的DNA,并在1%琼脂糖凝胶电泳上观察提取结果。
3应用聚合酶链式反应对病例组及对照组包含IL-6基因启动子-572位点的特异片段进行扩增,扩增的目的片段用2.5%琼脂糖凝胶电泳检测。
4将扩增产物用MbiⅠ内切酶进行酶切,酶切产物在3%琼脂糖凝胶电泳上检测,并对其进行定性分析。
5应用放射免疫分析法检测病例组外周血的空腹C肽水平。
6根据Hardy-Weinburg遗传平衡定律检查病例组及对照组所得基因型是否具有群体代表性。
7应用SPSS15.0统计软件对所得数据进行分析,其中病例组与对照组外周血IL-6水平的比较及病例组中首诊病人与复诊病人外周血IL-6水平的比较均采用两组独立样本的t检验。病例组与对照组的IL-6基因启动子-572位点基因型频率的比较采用Fisher精确概率法,等位基因频率的比较采用x~2检验,用相对比值比及95%可信区间表示相对危险度。不同国家IL-6基因启动子-572位点基因型频率的比较采用x~2检验或Fisher精确概率法。病例组不同基因型间IL-6水平,发病年龄及发病时空腹C肽水平的比较均采用两组独立样本的t检验。
结果
1病例组与对照组儿童性别及年龄的差异无统计学意义(P＞0.05),具有可比性。
2病例组与对照组儿童外周血IL-6水平的比较差异无统计学意义,病例组中首诊病人与复诊病人外周血IL-6水平的比较差异仍无统计学意义。(P＞0.05)
3 IL-6基因启动子-572位点经PCR扩增后产物片段为163bp,酶切后分为3种基因型,CC型为1条带(163bp),GC型为3条带(163bp,101bp,62bp),GG型为2条带(101bp,62bp)。
4病例组与对照组基因型频率符合Hardy-Weinburg遗传平衡定律,具有群体代表性。
5对照组IL-6基因启动子-572位点基因型及等位基因频率的分布与中国其他研究结果比较差异无统计学意义(P＞0.05),与日本比较差异无统计学意义(P＞0.05),与法国、美国比较差异有统计学意义(P＜0.05)。
6病例组与对照组IL-6基因启动子-572位点基因型频率及等位基因频率分布的差异均有统计学意义(P＜0.05),等位基因频率的相对风险分析示G等位基因的携带者患1型糖尿病的风险是C等位基因携带者的1.939倍(OR=1.939,95%CI=1.023～3.678)。
7病例组IL-6基因启动子-572位点不同基因型间IL-6水平的差异无统计学意义。(P＞0.05)
8病例组IL-6基因启动子-572位点不同基因型间发病年龄的差异有统计学意义(P＜0.05),其中携带G等位基因的患儿发病年龄早于CC基因型的患儿。
9病例组IL-6基因启动子-572位点不同基因型间空腹C肽水平的差异无统计学意义。(P＞0.05)
结论
11型糖尿病患儿体内IL-6水平无变化,IL-6基因启动子-572位点不同基因型患儿体内的IL-6水平亦无变化。
2不同种族IL-6基因启动子-572位点基因多态性存在差异,亚洲人群可能具有相似的基因型及等位基因分布,欧美国家可能具有相似的基因型及等位基因分布。
3 IL-6基因启动子-572位点基因多态性可能与1型糖尿病的发病存在相关性,其中G等位基因可能是1型糖尿病的易感基因。
4 IL-6基因启动子-572位点不同的基因型可能与患儿患病年龄存在相关性,其中GG+GC基因型的患儿的患病年龄早于CC基因型。
5 IL-6基因启动子-572位点不同的基因型患儿患病时空腹C肽水平无差别。
Objective Type 1 diabetes is a common disease of chinldren,The pathogenesis of type 1 diabetes involve genetically factors,environmental factors and immunological factors.Type 1 diabetes belongs to polygenic disease.IL-6 is considered to play a roal in the pathogenesis of type 1 diabetes,so we detected the level of IL-6 of patients and controls to study the change of IL-6 level in children of type 1 dianbetes,in the same time,we detected the genotype of IL-6-572 of patients and controls by Polymerase Chain Reaction-Restriction Fragment length Polymorphism(PCR-RFLP)to study the relationship between -572G/C polymorphism of IL-6 promoter and type 1 diabetes, we also studied the difference of IL-6 level,the onset year and the C peptide between different genotype of IL-6-572.
Methods
1 The level of IL-6 of patients and controls was detected by Radioimmunologic method.
2 The DNA of patients and controls was extracted by salt fractionation and the purity of DNA was detected by 1.0%agarose gel electrophoresis.
3 The promoter of IL-6-572 was amplificated by PCR and the amplification was detected by 2.5%agarose gel electrophoresis.
4 The amplification was cut by incision enzyme MbiⅠand the genotype was detected by 3.0%agarose gel electrophoresis to undertake qualitative analysis.
5 The C peptide of patients and controls was detected by Radioimmunologic method.
6 The representation of genotype of patients and controls was detected accorrding to Hardy-Weinberg equilibrium.
7 The data was analyzed by sofeware of spss15.0,The IL-6 level of patients and controls and the IL-6 level of preliminary diagnosed patients and re-examination diagnosed patients were all compared by two indepentent t test.The -572 genotype frequencies of IL-6 promoter of patients and controls were compared by Fisher exact probability test,the IL-6-572 allele frequencies were compared byχ~2 test and the relative risk was expressed by OR and 95%CI.The IL-6-572 disposition of different countries were compared byχ~2 test or Fisher exact probability test.The IL-6 level,the onset year,the C peptide of different genotype were also compared by two indepentent t test.
Results
1 There was no difference between patients and controls in spite of sex and age.
2 The level of IL-6 was not different between patients and controls,and the level of IL-6 was also not different between the preliminary diagnosed patients and re-examined diagnosd patients.
3 The amplification of IL-6 -572 was 163bp and there were three genotypes after cuting by incision enzyme,CC genotype was one bright bar(163bp)on the electropherogram,CG genotype was three bright bar(163bp,101bp,62bp)and GG genotype was two bright bar(101bp,62bp)on the electropherogram.
4 The genotype and allele frequencies of IL-6-572 were all in Hardy-Weinburg equilibrium,so the patients and controls were representative.
5 The IL-6-572 genotype and allele frequencies were not different between the controls and other Chinese people and Japanese,but which were different between the controls and France and American.
6 The IL-6-572 genotype and allele frequencies were different between the patients and the controls(P＜0.05),the relative risk of allele of type 1 diabetes indicated G allele was 1.939 times to the G allele,odds ratio is 1.939,95%confidence interval is 1.023～3.678.(OR=1.939,95%CI=1.023～3.678)
7 The comparison of the level of IL-6 between GG+GC genotype and CC genotype had no statistical significance.(P＞0.05)
8 The comparison of the onset year between GG+GC genotype and CC genotype had statistical significance(P＜0.05),the onset year of child who take along G allele was earlier than the C allele.
9 The comparison of C peptide between GG+GC genotype and CC genotype had no statistical significance.(P＞0.05)
Conelusion
(1)The level of IL-6 is not different between patients and controls,the IL-6 level is also not different between different genotypes of IL-6-572.
(2)Different race has different frequency of IL-6-572 genotype and allele,The Asian have resemble frequency of IL-6-572 genotype and allele,and the European and American have resemble frequency.
(3)IL-6-572 polymorphism is maybe associated with type 1 diabetes of children and the G allele maybe the predisposing gene of type 1 diabetes of children.
(4)The different genotype of IL-6-572 is maybe associated with the onset year,the onset year of child who take along GG+GC genotype is earlier than the CC genotype.
(5)The different genotype of IL-6-572 is not associated with C peptide.
引文
1 Karvonen M,Tuomilehto J,Libman I,et al.A review of the recent epidemiological data on the worldwide incidence of type 1(insulin-dependent)diabetes mellitus.World Health Organization DIAMOND Project Group[J].Diabetologia,1993,36(10):883- 892.
2 王克安,李天鳞,李新华,等。 中国儿童1型糖尿病发病率的研究[J].中华内分泌代谢杂志,1999,15(1):3-7。
3 李桂梅,高飞,蒋莎义,等。实用儿科内分泌与遗传代谢病[M]。山东:山东科学技术出版社,2004:230-244。
4 Strata DO.Tag SNP selection for association studies[J].Genet pidemiol,2004,27(4):365-374.
5 吕世静。临床免疫学检验[M]。北京:中国医药科技出版社。2004:245-247。
6 张维铭。现代分子生物学实验手册[M]。北京:科技出版社,2003:244-245。
7 Brull D J,Montgomery HE,Sanders J,et al.Interleukin-6 gene-174g＞cand-572g＞c promoter polymorphisms are strong predictors of plasma interleukin6 levels after coronary artery bypass surgery[J].Arterioscler Thromb Vasc Biol,2001,21(9):1458-1463.
8 张维铭。现代分子生物学实验手册[M]。北京:科技出版社,2003:153-163。
9 徐维衡。医学遗传学基础[M]。北京:北京医科大学、协和医科大学联合出版社,1993:133-135。
10 韦叶生,蓝艳,刘运广,等。白细胞介素6基因多态性与冠心病的相关性研究及其对血脂的影响[J]。中国危重病急救医学,2006,18(4):233-236。
11 Woods A,Brull DJ,Humphries SE,et al.Genetics of inflammation and risk of coronary artery disease:the central role of interleukin-6[J].Eur Heart J,2000,21(19):1574-1583.
12 Georges JL,Loukaci V,Poirier O,et al.Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction:theECTIM study[J].J Mol Med,2001,79(5-6):300-305.
13 Ferrari SL,Ahn-Luong L,Garnero P,et al.Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women[J].J Clin Endocrinol Metab.2003,88(1):255-259.
14 经承学。遗传性疾病的研究现状[J]。广西医学,2004,5(26):611-613。
15 Hyoty H,Taylor KW.The role of viruses in human diabetes[J].Diabetologia,2002,45(10):1353-1361.
16 Strotmeyer ES,Yang Z,LaPorte RE,et al.Infant diet and type 1 diabetes in China [J].Diabetes Res Clin Pract,2004,65(3):283-292.
17 Pozzilli P,Manfrini S,Crino A,et al.Low levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in patients with newly diagnosed type 1 diabetes[J].Horm Metab Res,2005,37(11):680-683.
18 Betts P,Mulligan J,Ward P,et al.Increasing body weight predicts the earlier onset of insulin-dependant diabetes in childhood:testing the 'accelerator hypothesis'(2)[J].Diabet Med,2005,22(2):144-151.
19 Sepa A,Ludvigsson J.Psychological stress and the risk of diabetes-related autoimmunity:a review article[J].Neuroimmunomodulation,2006,13(5-6):301-308.
20 Kamimura D,Ishihara K,Hirano T.IL-6 signal transduction and its physiological roles:the signal orchestration model[J].Rev Physiol Biochem Pharmacol,2003,149:1-38.
21 Haddy N,Sass C,Maumus S,et al.Biological variations,genetic polymorphisms and familial resemblance of TNF-alpha and IL-6 concentrations:STANISLAS cohort[J].Eur J Hum Genet,2005,13(1):109-117.
22 Fishman D,Faulds G,Jeffery R,et al.The effect of novel polymorphisms in the interleukin-6(IL-6)gene on IL-6 transcription and plasma IL-6 levels,and an association with systemic-onset juvenile chronic arthritis[J].J Clin Invest,1998,102(7):1369-1376.
23 Osiri M,McNicholl J,Moreland LW,et al.A novel single nucleotide polymorphism and five probable haplotypes in the 5 flanking region of the IL-6gene in African-Americans[J].Genes Immun,1999,1(2):166-167.
24 Saha A,Bairwa NK,RanjanA,et al.Two novel somatic mutations in the human interleukin 6 promoter region in a patient with sporadic breast cancer[J].Eur J Immunogenet,2003,30(6): 397-400.
25 Muller-Steinhardt M,Fricke L,Muller B,et al.Cooperative influence of the interleukin-6 promoter polymorphisms -597, -572 and -174 on long-term kidney allograft survival[J]. Am J Transplant, 2004, 4(3): 402-406.
26 Mudter J, Neurath MR 11-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance[J].Inflamm Bowel Dis, 2007, 13(8):1016-1023.
27 Rivera-Chavez FA, Peters-Hybki DL, Barber RC,et al.Innate Immunity Genes Influence the Severity of Acute Appendicitis[J].Ann Surg,2004,240(2):269-277.
28 Dubinski A, Zdrojewicz Z. The role of interleukin-6 in development and progression of atherosclerosis[J].Pol Merkur Lekarski,2007,22(130):291-294.
29 Humphries SE,Luong LA,Ogg MS,et al.The interleukin-6-174G/C Promoter polymorphism is associated with risk of coronary heart disease And systolic blood pressure in healthymen[J].Eur Heart J,2001,22(24):2243-2252.
30 Bennermo M, Held C, Green F,et al.Prognostic value of plasma interleukin-6 concentrations and the -174 G > C and -572 G > C promoter polymorphisms of the interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis[J]. Atherosclerosis, 2004,174(1):157-163.
31 Zheng SX, Vrindts Y, Lopez M,et al.Increase in cytokine production (IL-1 beta, IL-6, TNF-alpha but not IFN-gamma, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis[J]. Maturitas, 1997,26(1):63-71.
32 Ferrari SL, Garnero P, Emond S,et al. A functional polymorphic variant in the interleukin-6 gene promoter associated with low bone resorption in postmenopausal women[J].Arthritis Rheum, 2001,44(1): 196-201.
33 Licastro F, Grimaldi LM, Bonafe M,et al. Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain[J]. Neurobiol Aging,2003,24(7):921-926.
34 Jeong HJ, Seo SY, Noh HS,et al.Regulation of TH1/TH2 cytokine production by Chungsim-Yeunja-Tang in patients with cerebral infarction[J]. Immunopharmacol Immunotoxicol,2003,25(1):29-39.
35 Lukaszewicz M, Mroczko B, Szmitkowski M. Clinical significance of interleukin-6(IL-6)as a prognostic factor of cancer disease[J].Pol Arch Med Wewn,2007,117(5-6):247-251.
36 Pawlik A,Wrzesniewska J,Florczak M,et al.IL-6 promoter polymorphism in patients with rheumatoid arthritis[J].cand J Rheumatol,2005,(2):109-113.
37 Kitamura A,Haseqawa G,Obayashi H,et al.Interleukin-6 polymorphism(-634C/G)in the promotor region and the progression of diabetic nephropathy in type 2diabetes[J].Diabet Med,2002,19(12):1000-1005.
38 Huth C,Heid IM,Vollmert C,et al.IL6 gene promoter polymorphisms and type 2diabetes:joint analysis of individual participants' data from 21 studies[J].Diabetes,2006,55(10):2915-2921.
39 Vgontzas AN,Trakada G,Bixler EO,et al.Plasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apnea[J].Metabolism,2006,55(8):1076-1082.
40 韦叶生,黄瑞雅,李壮,等。白细胞介素-6基因启动子-572C/G多态性与脑梗死关系的研究[J]。右江医学,2004,4(32):303-305。
41 付海霞,李艳,李庚山,等。白细胞介素6基因多态性与原发性高血压的关系[J]。临床心血管病杂志,2003,19(12):714-716。
42 史建国,周红。白细胞介素6及其基因启动子多态性在儿童急性阑尾炎中的表现[J]。中华小儿外科杂志,2006,27(3):127-131。
43 Targher G;Zenari L,Bertolini L,et al.Elevated levels of interleukin-6 in young adults with type 1 diabetes without clinical evidence of microvascular and macrovascular complications[J].Diabetes Care,2001,24(5):956-957.
44 Devaraj S,Glaser N,Griffen S,et al.Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes[J].Diabetes,2006,55(3):774-779.
45 Basu S,Larsson A,Vessby J,et al.Type 1 diabetes is associated with increased cyclooxygenase- and cytokine-mediated inflammation[J].Diabetes Care,2005,28(6):1371-1375.
46 辛颖,迟金华,王志超。1型糖尿病患儿血清白细胞介素-6水平的变化及意义[J]。临床儿科杂志,2001,19(6):348-349。
47 Jain SK,Kannan K,Lim G,et al.Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes[J].Diabetes Care,2003,26(7):2139-2143.
48 Saraheimo M,Teppo AM,Forsblom C,et al.Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients[J].Diabetologia,2003,46(10):1402-1407.
49 Privat SJ,Oo A,Waterbury LD.Production of interleukin-6,but not interleukin-8,induced by YNF-alpha or IL-1 beta in human fibroblast-like synoviocyte increases over cell passage[J].Proc West Pharmacol Soc,2001,44:9-13.
50 Dogan Y,Akarsu S,Ustundag B,et al.Serum IL-lbeta,IL-2,and IL-6 in insulin-dependent diabetic children[J].Mediators of Inflammation,2006,2006(1):59206.
51 刘静,金玉,李茂欣。Ⅰ型糖尿病患儿血清肿瘤坏死因子和白细胞介素水平的变化[J]。中华儿科杂志,2000,38(7):428-430。
52 Scholin A,Siegbahn A,Lind L,et al.CRP and IL-6 concentrations are associated with poor glycemic control despite preserved beta-cell function during the first year after diagnosis of type 1 diabetes[J].Diabetes Metab Res Rev,2004,20(3):205-210.
53 Choi SE,Choi KM,Yoon IH,et al.IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo[J].Transpl Immunol,2004,13(1):43-53.
54 Wedrychowicz A,Dziatkowiak H,Sztefko K,et al.Interleukin-6(IL-6)and IGF-IGFBP system in children and adolescents with type 1 diabetes mellitus[J].Exp Clin Endocrinol Diabetes,2004,112(8):435-439.
55 巩纯秀,颜纯,朱逞,等。不同病程的1型糖尿病患儿血清细胞因子的变化[J]。实用儿科临床杂志,2003,18(4):250-252。
56 Jahromi MM,Millward BA,Demaine AG,et al.A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1diabetes mellitus[J].J Interferon cytokine Res,2000,20(10):885-888.
57 Eerligh P,Koeleman BP,Dudbridge F,et al.Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes[J].Genes Immun,2004,5(1):36-40.
58 Kristiansen OP,Nolsoe RL,Larsen L,et al.Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females[J]. Hum Mol Genet,2003,12(10):1101-1110.
59 Gillespie KM,Nolsoe R,Betin VM,et al. Is puberty an accelerator of type 1 diabetes in IL6-174CC females[J]? Diabetes, 2005, 54(4):1245-1248.
60 Hermann C,Krikovszky D,Fust G,et al. Association between interleukin-6 polymorphism and age-at-onset of type 1 diabetes. Epistatic influences of the tumor necrosis factor-alpha and interleukin-lbeta polymorphisms [J]. Eur Cytokine Netw,2005,16(4):277-281.
61 Zhai R, Liu G, Yang C, et al. The G to C polymorphism at -174 of the interleukin-6 gene is rare in a Southern Chinese population[J]. Pharmacogenetics, 2001,11(8): 699-701.
62 Lim CS,Zheng S,Kim YS,et al.The -174 G to C polymorphism of interleukin-6 gene is very rare in koreans[J]. Cytokine, 2002, 19(10):52-54.
63 Terry CF,Loukaci V,Green FR.Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation[J]. J Biol Chem, 2000, 275 (24): 18138-18144.
64 Palmer JP, Fleming GA, Greenbaum CJ, et al.C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001 [J]. Diabetes,2004,53(1):250-264.
65 Nakanishi K, Inoko H. Combination of HLA-A24, -DQAl*03, and -DR9 contributes to acute-onset and early complete beta-cell destruction in type 1 diabetes: longitudinal study of residual beta-cell function[J]. Diabetes, 2006,55(6): 1862-1868.
1 Haddy N,Sass C,Maumus S,et al.Biological variations,genetic polymorphisms and familial resemblance of TNF-alpha and IL-6 concentrations:STANISLAS cohort [J].Eur J Hum Genet,2005,13(1):109-117.
2 Saha A,Bairwa NK,RanjanA,et al.Two novel somatic mutations in the human interleukin 6 promoter region in a patient with sporadic breast cancer[J].Eur J Immunogenet,2003,30(6):397-400.
3 Muller-Steinhardt M,Fricke L,Muller B,et al.Cooperative influence of the interleukin-6 promoter polymorphisms -597,-572 and - 174 on long-term kidney allograft survival[J].Am J Transplant,2004,4(3):402-406.
4 Targher G,Zenari L,Bertolini L,et al.Elevated levels of interleukin-6 in young adults with type 1 diabetes without clinical evidence of microvascular and macrovascular complications[J].Diabetes Care,2001,24(5):956-957.
5 Devaraj S,Glaser N,Griffen S,et al.Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes[J].Diabetes,2006,55(3):774-779.
6 Basu S,Larsson A,Vessby J,et al.Type 1 diabetes is associated with increased cyclooxygenase- and cytokine-mediated inflammation[J].Diabetes Care,2005,28(6):1371 - 1375.
7 Wedrychowicz A ,Dziatkowiak H,Sztefko K,et al.Interleukin-6 (IL-6) and IGF-IGFBP system in children and adolescents with type 1 diabetes mellitus[J]. Exp Clin Endocrinol Diabetes,2004,112(8):435-439.
8 Jain SK, Kannan K, Lim G,et al. Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes[J]. Diabetes Care, 2003 ,26(7): 2139-2143.
9 Saraheimo M,Teppo AM,Forsblom C,et al. Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients[J]. Diabetologia, 2003, 46(10): 1402-1407.
10 Suzuki M,Saito M,Nagai T,et al. Systemic versus coronary levels of inflammation in acute coronary syndromes[J]. Angiology,2006, 57(4): 459-463.
11 Privat SJ,Oo A,Waterbury LD. Production of interleukin-6, but not interleukin-8, induced by TNF-alpha or IL-1 beta in human fibroblast-like synoviocyte increases over cell passage[J].Proc West Pharmacol Soc,2001,44:9-13.
12 Dogan Y,Akarsu S,Ustundag B,et al. Serum IL-1 beta, IL-2, and IL-6 in insulin-dependent diabetic children[J]. Mediators of Inflammation, 2006, 2006 (1): 59206.
13 Scholin A,Siegbahn A,Lind L,et al. CRP and IL-6 concentrations are associated with poor glycemic control despite preserved beta-cell function during the first year after diagnosis of type 1 diabetes[J]. Diabetes Metab Res Rev, 2004,20(3): 205-210.
14 Choi SE, Choi KM, Yoon IH,et al.IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo[J]. Transpl Immunol ,2004,13(1):43-53.
15 Jahromi MM,Millward BA,Demaine AG,et al. A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1 diabetes mellitus[J] J Interferon cytokine Res,2000,20(10):885-888.
16 Eerligh P,Koeleman BP,Dudbridge F,et al. Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes[J].Genes Immun, 2004 ,5(1):36-40.
17 Kristiansen OP, Nolsoe RL,Larsen L,et al. Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females[J]. Hum Mol Genet,2003,12(10):1101-1110.
18 Gillespie KM,Nolsoe R,Betin VM,et al. Is puberty an accelerator of type 1 diabetes in IL6-174CC females[J]? Diabetes, 2005, 54(4):1245-1248.
19 Hermann C,Krikovszky D,Fust G,et al. Association between interleukin-6 polymorphism and age-at-onset of type 1 diabetes. Epistatic influences of the tumor necrosis factor-alpha and interleukin-lbeta polymorphisms[J]. Eur Cytokine Netw,2005,16(4):277-281.
2 王克安,李天鳞,李新华,等。 中国儿童1型糖尿病发病率的研究[J].中华内分泌代谢杂志,1999,15(1):3-7。
3 李桂梅,高飞,蒋莎义,等。实用儿科内分泌与遗传代谢病[M]。山东:山东科学技术出版社,2004:230-244。
4 Strata DO.Tag SNP selection for association studies[J].Genet pidemiol,2004,27(4):365-374.
5 吕世静。临床免疫学检验[M]。北京:中国医药科技出版社。2004:245-247。
6 张维铭。现代分子生物学实验手册[M]。北京:科技出版社,2003:244-245。
7 Brull D J,Montgomery HE,Sanders J,et al.Interleukin-6 gene-174g＞cand-572g＞c promoter polymorphisms are strong predictors of plasma interleukin6 levels after coronary artery bypass surgery[J].Arterioscler Thromb Vasc Biol,2001,21(9):1458-1463.
8 张维铭。现代分子生物学实验手册[M]。北京:科技出版社,2003:153-163。
9 徐维衡。医学遗传学基础[M]。北京:北京医科大学、协和医科大学联合出版社,1993:133-135。
10 韦叶生,蓝艳,刘运广,等。白细胞介素6基因多态性与冠心病的相关性研究及其对血脂的影响[J]。中国危重病急救医学,2006,18(4):233-236。
11 Woods A,Brull DJ,Humphries SE,et al.Genetics of inflammation and risk of coronary artery disease:the central role of interleukin-6[J].Eur Heart J,2000,21(19):1574-1583.
12 Georges JL,Loukaci V,Poirier O,et al.Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction:theECTIM study[J].J Mol Med,2001,79(5-6):300-305.
13 Ferrari SL,Ahn-Luong L,Garnero P,et al.Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women[J].J Clin Endocrinol Metab.2003,88(1):255-259.
14 经承学。遗传性疾病的研究现状[J]。广西医学,2004,5(26):611-613。
15 Hyoty H,Taylor KW.The role of viruses in human diabetes[J].Diabetologia,2002,45(10):1353-1361.
16 Strotmeyer ES,Yang Z,LaPorte RE,et al.Infant diet and type 1 diabetes in China [J].Diabetes Res Clin Pract,2004,65(3):283-292.
17 Pozzilli P,Manfrini S,Crino A,et al.Low levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in patients with newly diagnosed type 1 diabetes[J].Horm Metab Res,2005,37(11):680-683.
18 Betts P,Mulligan J,Ward P,et al.Increasing body weight predicts the earlier onset of insulin-dependant diabetes in childhood:testing the 'accelerator hypothesis'(2)[J].Diabet Med,2005,22(2):144-151.
19 Sepa A,Ludvigsson J.Psychological stress and the risk of diabetes-related autoimmunity:a review article[J].Neuroimmunomodulation,2006,13(5-6):301-308.
20 Kamimura D,Ishihara K,Hirano T.IL-6 signal transduction and its physiological roles:the signal orchestration model[J].Rev Physiol Biochem Pharmacol,2003,149:1-38.
21 Haddy N,Sass C,Maumus S,et al.Biological variations,genetic polymorphisms and familial resemblance of TNF-alpha and IL-6 concentrations:STANISLAS cohort[J].Eur J Hum Genet,2005,13(1):109-117.
22 Fishman D,Faulds G,Jeffery R,et al.The effect of novel polymorphisms in the interleukin-6(IL-6)gene on IL-6 transcription and plasma IL-6 levels,and an association with systemic-onset juvenile chronic arthritis[J].J Clin Invest,1998,102(7):1369-1376.
23 Osiri M,McNicholl J,Moreland LW,et al.A novel single nucleotide polymorphism and five probable haplotypes in the 5 flanking region of the IL-6gene in African-Americans[J].Genes Immun,1999,1(2):166-167.
24 Saha A,Bairwa NK,RanjanA,et al.Two novel somatic mutations in the human interleukin 6 promoter region in a patient with sporadic breast cancer[J].Eur J Immunogenet,2003,30(6): 397-400.
25 Muller-Steinhardt M,Fricke L,Muller B,et al.Cooperative influence of the interleukin-6 promoter polymorphisms -597, -572 and -174 on long-term kidney allograft survival[J]. Am J Transplant, 2004, 4(3): 402-406.
26 Mudter J, Neurath MR 11-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance[J].Inflamm Bowel Dis, 2007, 13(8):1016-1023.
27 Rivera-Chavez FA, Peters-Hybki DL, Barber RC,et al.Innate Immunity Genes Influence the Severity of Acute Appendicitis[J].Ann Surg,2004,240(2):269-277.
28 Dubinski A, Zdrojewicz Z. The role of interleukin-6 in development and progression of atherosclerosis[J].Pol Merkur Lekarski,2007,22(130):291-294.
29 Humphries SE,Luong LA,Ogg MS,et al.The interleukin-6-174G/C Promoter polymorphism is associated with risk of coronary heart disease And systolic blood pressure in healthymen[J].Eur Heart J,2001,22(24):2243-2252.
30 Bennermo M, Held C, Green F,et al.Prognostic value of plasma interleukin-6 concentrations and the -174 G > C and -572 G > C promoter polymorphisms of the interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis[J]. Atherosclerosis, 2004,174(1):157-163.
31 Zheng SX, Vrindts Y, Lopez M,et al.Increase in cytokine production (IL-1 beta, IL-6, TNF-alpha but not IFN-gamma, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis[J]. Maturitas, 1997,26(1):63-71.
32 Ferrari SL, Garnero P, Emond S,et al. A functional polymorphic variant in the interleukin-6 gene promoter associated with low bone resorption in postmenopausal women[J].Arthritis Rheum, 2001,44(1): 196-201.
33 Licastro F, Grimaldi LM, Bonafe M,et al. Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain[J]. Neurobiol Aging,2003,24(7):921-926.
34 Jeong HJ, Seo SY, Noh HS,et al.Regulation of TH1/TH2 cytokine production by Chungsim-Yeunja-Tang in patients with cerebral infarction[J]. Immunopharmacol Immunotoxicol,2003,25(1):29-39.
35 Lukaszewicz M, Mroczko B, Szmitkowski M. Clinical significance of interleukin-6(IL-6)as a prognostic factor of cancer disease[J].Pol Arch Med Wewn,2007,117(5-6):247-251.
36 Pawlik A,Wrzesniewska J,Florczak M,et al.IL-6 promoter polymorphism in patients with rheumatoid arthritis[J].cand J Rheumatol,2005,(2):109-113.
37 Kitamura A,Haseqawa G,Obayashi H,et al.Interleukin-6 polymorphism(-634C/G)in the promotor region and the progression of diabetic nephropathy in type 2diabetes[J].Diabet Med,2002,19(12):1000-1005.
38 Huth C,Heid IM,Vollmert C,et al.IL6 gene promoter polymorphisms and type 2diabetes:joint analysis of individual participants' data from 21 studies[J].Diabetes,2006,55(10):2915-2921.
39 Vgontzas AN,Trakada G,Bixler EO,et al.Plasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apnea[J].Metabolism,2006,55(8):1076-1082.
40 韦叶生,黄瑞雅,李壮,等。白细胞介素-6基因启动子-572C/G多态性与脑梗死关系的研究[J]。右江医学,2004,4(32):303-305。
41 付海霞,李艳,李庚山,等。白细胞介素6基因多态性与原发性高血压的关系[J]。临床心血管病杂志,2003,19(12):714-716。
42 史建国,周红。白细胞介素6及其基因启动子多态性在儿童急性阑尾炎中的表现[J]。中华小儿外科杂志,2006,27(3):127-131。
43 Targher G;Zenari L,Bertolini L,et al.Elevated levels of interleukin-6 in young adults with type 1 diabetes without clinical evidence of microvascular and macrovascular complications[J].Diabetes Care,2001,24(5):956-957.
44 Devaraj S,Glaser N,Griffen S,et al.Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes[J].Diabetes,2006,55(3):774-779.
45 Basu S,Larsson A,Vessby J,et al.Type 1 diabetes is associated with increased cyclooxygenase- and cytokine-mediated inflammation[J].Diabetes Care,2005,28(6):1371-1375.
46 辛颖,迟金华,王志超。1型糖尿病患儿血清白细胞介素-6水平的变化及意义[J]。临床儿科杂志,2001,19(6):348-349。
47 Jain SK,Kannan K,Lim G,et al.Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes[J].Diabetes Care,2003,26(7):2139-2143.
48 Saraheimo M,Teppo AM,Forsblom C,et al.Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients[J].Diabetologia,2003,46(10):1402-1407.
49 Privat SJ,Oo A,Waterbury LD.Production of interleukin-6,but not interleukin-8,induced by YNF-alpha or IL-1 beta in human fibroblast-like synoviocyte increases over cell passage[J].Proc West Pharmacol Soc,2001,44:9-13.
50 Dogan Y,Akarsu S,Ustundag B,et al.Serum IL-lbeta,IL-2,and IL-6 in insulin-dependent diabetic children[J].Mediators of Inflammation,2006,2006(1):59206.
51 刘静,金玉,李茂欣。Ⅰ型糖尿病患儿血清肿瘤坏死因子和白细胞介素水平的变化[J]。中华儿科杂志,2000,38(7):428-430。
52 Scholin A,Siegbahn A,Lind L,et al.CRP and IL-6 concentrations are associated with poor glycemic control despite preserved beta-cell function during the first year after diagnosis of type 1 diabetes[J].Diabetes Metab Res Rev,2004,20(3):205-210.
53 Choi SE,Choi KM,Yoon IH,et al.IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo[J].Transpl Immunol,2004,13(1):43-53.
54 Wedrychowicz A,Dziatkowiak H,Sztefko K,et al.Interleukin-6(IL-6)and IGF-IGFBP system in children and adolescents with type 1 diabetes mellitus[J].Exp Clin Endocrinol Diabetes,2004,112(8):435-439.
55 巩纯秀,颜纯,朱逞,等。不同病程的1型糖尿病患儿血清细胞因子的变化[J]。实用儿科临床杂志,2003,18(4):250-252。
56 Jahromi MM,Millward BA,Demaine AG,et al.A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1diabetes mellitus[J].J Interferon cytokine Res,2000,20(10):885-888.
57 Eerligh P,Koeleman BP,Dudbridge F,et al.Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes[J].Genes Immun,2004,5(1):36-40.
58 Kristiansen OP,Nolsoe RL,Larsen L,et al.Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females[J]. Hum Mol Genet,2003,12(10):1101-1110.
59 Gillespie KM,Nolsoe R,Betin VM,et al. Is puberty an accelerator of type 1 diabetes in IL6-174CC females[J]? Diabetes, 2005, 54(4):1245-1248.
60 Hermann C,Krikovszky D,Fust G,et al. Association between interleukin-6 polymorphism and age-at-onset of type 1 diabetes. Epistatic influences of the tumor necrosis factor-alpha and interleukin-lbeta polymorphisms [J]. Eur Cytokine Netw,2005,16(4):277-281.
61 Zhai R, Liu G, Yang C, et al. The G to C polymorphism at -174 of the interleukin-6 gene is rare in a Southern Chinese population[J]. Pharmacogenetics, 2001,11(8): 699-701.
62 Lim CS,Zheng S,Kim YS,et al.The -174 G to C polymorphism of interleukin-6 gene is very rare in koreans[J]. Cytokine, 2002, 19(10):52-54.
63 Terry CF,Loukaci V,Green FR.Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation[J]. J Biol Chem, 2000, 275 (24): 18138-18144.
64 Palmer JP, Fleming GA, Greenbaum CJ, et al.C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001 [J]. Diabetes,2004,53(1):250-264.
65 Nakanishi K, Inoko H. Combination of HLA-A24, -DQAl*03, and -DR9 contributes to acute-onset and early complete beta-cell destruction in type 1 diabetes: longitudinal study of residual beta-cell function[J]. Diabetes, 2006,55(6): 1862-1868.
1 Haddy N,Sass C,Maumus S,et al.Biological variations,genetic polymorphisms and familial resemblance of TNF-alpha and IL-6 concentrations:STANISLAS cohort [J].Eur J Hum Genet,2005,13(1):109-117.
2 Saha A,Bairwa NK,RanjanA,et al.Two novel somatic mutations in the human interleukin 6 promoter region in a patient with sporadic breast cancer[J].Eur J Immunogenet,2003,30(6):397-400.
3 Muller-Steinhardt M,Fricke L,Muller B,et al.Cooperative influence of the interleukin-6 promoter polymorphisms -597,-572 and - 174 on long-term kidney allograft survival[J].Am J Transplant,2004,4(3):402-406.
4 Targher G,Zenari L,Bertolini L,et al.Elevated levels of interleukin-6 in young adults with type 1 diabetes without clinical evidence of microvascular and macrovascular complications[J].Diabetes Care,2001,24(5):956-957.
5 Devaraj S,Glaser N,Griffen S,et al.Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes[J].Diabetes,2006,55(3):774-779.
6 Basu S,Larsson A,Vessby J,et al.Type 1 diabetes is associated with increased cyclooxygenase- and cytokine-mediated inflammation[J].Diabetes Care,2005,28(6):1371 - 1375.
7 Wedrychowicz A ,Dziatkowiak H,Sztefko K,et al.Interleukin-6 (IL-6) and IGF-IGFBP system in children and adolescents with type 1 diabetes mellitus[J]. Exp Clin Endocrinol Diabetes,2004,112(8):435-439.
8 Jain SK, Kannan K, Lim G,et al. Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes[J]. Diabetes Care, 2003 ,26(7): 2139-2143.
9 Saraheimo M,Teppo AM,Forsblom C,et al. Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients[J]. Diabetologia, 2003, 46(10): 1402-1407.
10 Suzuki M,Saito M,Nagai T,et al. Systemic versus coronary levels of inflammation in acute coronary syndromes[J]. Angiology,2006, 57(4): 459-463.
11 Privat SJ,Oo A,Waterbury LD. Production of interleukin-6, but not interleukin-8, induced by TNF-alpha or IL-1 beta in human fibroblast-like synoviocyte increases over cell passage[J].Proc West Pharmacol Soc,2001,44:9-13.
12 Dogan Y,Akarsu S,Ustundag B,et al. Serum IL-1 beta, IL-2, and IL-6 in insulin-dependent diabetic children[J]. Mediators of Inflammation, 2006, 2006 (1): 59206.
13 Scholin A,Siegbahn A,Lind L,et al. CRP and IL-6 concentrations are associated with poor glycemic control despite preserved beta-cell function during the first year after diagnosis of type 1 diabetes[J]. Diabetes Metab Res Rev, 2004,20(3): 205-210.
14 Choi SE, Choi KM, Yoon IH,et al.IL-6 protects pancreatic islet beta cells from pro-inflammatory cytokines-induced cell death and functional impairment in vitro and in vivo[J]. Transpl Immunol ,2004,13(1):43-53.
15 Jahromi MM,Millward BA,Demaine AG,et al. A polymorphism in the promoter region of the gene for interleukin-6 is associated with susceptibility to type 1 diabetes mellitus[J] J Interferon cytokine Res,2000,20(10):885-888.
16 Eerligh P,Koeleman BP,Dudbridge F,et al. Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes[J].Genes Immun, 2004 ,5(1):36-40.
17 Kristiansen OP, Nolsoe RL,Larsen L,et al. Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females[J]. Hum Mol Genet,2003,12(10):1101-1110.
18 Gillespie KM,Nolsoe R,Betin VM,et al. Is puberty an accelerator of type 1 diabetes in IL6-174CC females[J]? Diabetes, 2005, 54(4):1245-1248.
19 Hermann C,Krikovszky D,Fust G,et al. Association between interleukin-6 polymorphism and age-at-onset of type 1 diabetes. Epistatic influences of the tumor necrosis factor-alpha and interleukin-lbeta polymorphisms[J]. Eur Cytokine Netw,2005,16(4):277-281.