摘要
目的探讨纤维蛋白原β链(Fgp)-148C/T及-455G/A基因多态性与川崎病(KD)发病及并发冠状动脉损伤(CAL)之间的关系。
方法：应用聚合酶链反应-限制性内切酶片断长度多态性分析(PCR-RFLP)方法结合琼脂糖凝胶电泳技术,对47例川崎病患儿和60例正常对照组儿童进行纤维蛋白原β链-148C/T及-455G/A基因多态性分析。
结果(1)KD组Fgp-148C/T基因多态性的CC、CT、TT基因型分布频率和C、T等位基因频率与正常对照组比较差异无显著性(χ2=4.194、2.64,P均>0.05)。合并CAL组CT基因型明显高于无CAL组,差异有显著性(χ2=7.009,P<0.05)。合并CAL组和无CAL组等位基因频率比较差异无显著性(χ2=0.862,P>0.05)；(2)KD组Fgp-455G/A基因多态性的GG、GA、AA基因型分布频率和G、A等位基因频率与正常对照组比较差异无显著性(χ2=4.194、2.64,P均>0.05)。合并CAL组GA基因型明显高于无CAL组,差异有显著性(χ2=7.009,P<0.05)。合并CAL组和无CAL组等位基因频率比较差异无显著性(χ2=0.862,P>0.05)
结论(1)Fgp-148C/T(?)和-455G/A基因型和等位基因频率与KD的发生均无明显关联性。(2)Fgp-148C/T基因的CT基因型与KD合并CAL的发生存在关联。(3)Fgp-455G/A基因的GA基因型与KD合并CAL的发生存在关联。
Objective To investigate the genetic polymorphisms of children with Kawasaki Disease (KD) and that complicated with coronary artery lesion (CAL) in theβ-Fibrinogen gene-148C/T (Fgβ-148C/T) and theβ-Fibrinogen gene-455G/A(Fgβ-455G/A).
Methods 47 cases of patients with KD and 60 healthy children as controls were studied in this research. Polymorphism analysis of these genes (Fgβ-148C/T and Fgβ-455G/A respectively) were detected with polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP).
Results (1) For theβ-Fibrinogen gene-148C/T, there were no significant differences between genotype frequency of CC, CT and TT types in KD and healthy controls (χ2=4.194, P>0.05). There was no significant difference between allele frequency of C and T types in KD and controls (χ2=2.64, P>0.05). The CT genotype in KD patients with CAL is significantly higher than that without CAL (χ2=7.009, P<0.05). There were no significant difference between allele frequency of C and T types in KD complicated with CAL and without CAL (χ2=0.862, P> 0.05). (2) For theβ-Fibrinogen gene-455G/A, there were no significant differences between genotype frequency of GG, GA and AA types in KD and healthy controls (χ2=4.194, P>0.05). There was no significant difference between allele frequency of G and A types in KD and controls (χ2=2.64, P>0.05). The GA type in KD patients with CAL is significantly higher than that without CAL (χ2=7.009, P<0.05). There were no significant difference between allele frequency of G and A types in KD complicated with CAL and without CAL (χ2=0.862, P>0.05).
Conclusions (1) The polymorphisms of the (3-Fibrinogen gene-148C/T and theβ-Fibrinogen gene-455G/A had not been found association with the pathogenesis of KD. (2) The polymorphisms of CT type of theβ-Fibrinogen gene-148C/T might be related with KD complicated with CAL. (3) The polymorphisms of GA type of theβ-Fibrinogen gene-455G/A might be related with KD complicated with CAL
引文
[1]Fong NC, Hui YW, Li CK, et al. Evaluation of the efficacy of treatment of Kawasaki disease before day 5 of illness[J]. Pediatr Cardiol,2004,25(1):31-34
[2]Rosenfeld EA, Corydon KE, Shulman ST. Kawasaki disease in infants less than one year age[J]. J Pediatr,1995,126(4):524-529
[3]Yokouchi Y, Oharaseki T, Ihara F, et al. Repeated stent thrombosis after DES implantation and localized hypersensitivity to a stent implanted in the distal portion of a coronary aneurysm thought to be a sequela of Kawasaki disease:autopsy report[J]. Pathol Int,2010,60(2):112-118
[4]Bartoloni G, Salvatrice DM, Carlo R. Sudden death in a 21-year-old man caused by thrombosed coronary aneurysm:late sequelae or a very late onset of Kawasaki disease?[J]. Cardiovasc Pathol,2002,11(6):318-321
[5]Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation[J]. Circulation.,2004,109(22):2698-2704
[6]董凤英,阮云军.纤维蛋白原与冠心病[J].医学综述,2000,6(2)：66
[7]Drouet L, Bal Dit Sollier C. Fibrinogen:factor and marker of cardiovascular risk[J]. J Mal Vasc,2002,27(3):143-156
[8]Weisel JW. Fibrinogen and fibrin[J]. Adv Protein Chem,2005,70:247-299
[9]Roy SN, Mukhopadhyay G, Redman CM, et al. Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen [J]. J Biol Chem,1990,265(11): 6389-6393
[10]Schmidt H, Schmidt R, Niederkorn K, et al. Beta-fibrinogen gene polymorphism (C148-->T) is associated with carotid atherosclerosis:results of the Austrian Stroke Prevention Study [J]. Arterioscler Thromb Vasc Biol,1998,18(3): 487-492
[11]Humphries SE, Ye S, Talmud P, et al. European Atherosclerosis Research Study:genotype at the fibrinogen locus (G-455-A beta-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Evidence for gender-genotype-environment interaction [J]. Arterioscler Thromb Vasc Biol,1995,15(1):96-104
[12]Humphries SE, Green FR, Temple A, et al. Genetic factors determining thrombosis and fibrinolysis [J]. Ann Epidemiol,1992,2(4):371-385
[13]Green F, Hamsten A, Blomback M, et al. The role of beta-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden [J]. Thromb Haemost,1993,70(6): 915-920
[14]梁翔常.皮肤粘膜淋巴结综合征.见：胡亚美,江载芳.使用儿科学[M].第七版.北京：人民卫生出版社,2002,698-704
[15]高虹,闵杰青,田秀玲,等.彩色多谱勒超声诊断川崎病冠状动脉损害及远期随访[J].临床儿科杂志,2008,26(11)：980-982
[16]Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease:a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association[J]. Circulation, 2004,110(17):2747-71
[17]Matsubara K, Fukaya T, Miwa K, et al. Development of serum IgM antibodies against superantigens of Staphylococcus aureus and Streptococcus pyogenes in Kawasaki disease[J]. Clin Exp Immunol,2006,143(3):427-434
[18]Esper F, Shapiro ED, Weibel C, et al. Association between a novel human coronavirus and Kawasaki disease[J]. J Infect Dis,2005,191(4):499-502
[19]Turkay S, Odemis E, Karadag A. Kawasaki disease onset during concomitant infections with varicella zoster and Epstein-Barr virus [J]. J Natl Med Assoc,2006,98(8):1350-1352
[20]邹先阶.肺炎支原体感染在川崎病及冠脉损害中的作用[J].中国当代医药,2009,16(19)：20-21
[21]Du ZD, Zhang T, Liang L, et al. Epidemiologic picture of Kawasaki disease in Beijing from 1995 through 1999 [J]. Pediatr Infect Dis J,2002,21(2):103-107
[22]Huang GY, Ma XJ, Huang M, et al. Epidemiologic pictures of Kawasaki disease in Shanghai from 1998 through 2002[J]. J Epidemiol,2006,16(1):9-14
[23]Ma XJ, Yu CY, Huang M, et al. Epidemiologic features of Kawasaki disease in Shanghai from 2003 through 2007 [J]. Chin Med J (Engl),2010, 123(19):2629-2634
[24]Huang WC, Huang LM, Chang IS, et al. Epidemiologic features of Kawasaki disease in Taiwan,2003-2006[J]. Pediatrics,2009,123(3):e401-405
[25]Park YW, Han JW, Hong YM, et al. Epidemiological features of Kawasaki disease in Korea,2006-2008 [J]. Pediatr Int,2011,53(1):36-39
[26]Belay ED, Holman RC, Clarke MJ, et al. The incidence of Kawasaki syndrome in West Coast health maintenance organizations [J]. Pediatr Infect Dis J, 2000,19(9):828-832
[27]Holman RC, Shahriari A, Effler PV, et al. Kawasaki syndrome hospitalizations among children in Hawaii and Connecticut[J]. Arch Pediatr Adolesc Med,2000,154(8):804-808
[28]Chang RK. Epidemiologic characteristics of children hospitalized for Kawasaki disease in California [J]. Pediatr Infect Dis J,2002,21(12):1150-1155
[29]万根平,顾晓琼,曾华松,等.ACE基因多态性及血清ACE水平与儿童川崎病相关性[J].广东医学,2006,27(12)：1543-1544
[30]杨军,李成荣,李永柏,等.甘露糖结合凝集素基因54号密码子多态性与川崎病易感性的研究[J].中华儿科杂志,2004,42(3)：176-179
[31]Ouchi K, Suzuki Y, Shirakawa T, et al. Polymorphism of SLC11A1 (formerly NRAMP1) gene confers susceptibility to Kawasaki disease [J]. J Infect Dis, 2003,187(2):326-329
[32]Kariyazono H, Ohno T, Khajoee V, et al. Association of vascular endothelial growth factor (VEGF) and VEGF receptor gene polymorphisms with coronary artery lesions of Kawasaki disease[J]. Pediatr Res,2004,56(6):953-959
[33]杨军,李成荣,李永柏,等.肿瘤坏死因子-α和白细胞介素10基因启动子区多态性与川崎病的相关性研究[J].中华儿科杂志,2003,41(8)：598-602
[34]袁雄伟,杨军,刘琮,等.纤溶酶原激活物抑制物-1基因启动子区4G/5G多态性与川崎病冠状动脉损伤的关系[J].中国实用儿科杂志,2006,21(6)：439-441
[35]Ikeda K, Ihara K, Yamaguchi K, et al. Genetic analysis of MMP gene polymorphisms in patients with Kawasaki disease[J]. Pediatr Res,2008, 63(2):182-185
[36]李卓颖,杨作成.川崎病患儿内皮素-1及内皮素A、B受体基因多态性研究.中华风湿病学杂志,2009,13(11)：795-796
[37]常玉荣,杨德全,唐福美,等.血栓栓塞性疾病血栓前状态的实验室诊断[J].中国综合临床,2001,17(2)：83-84
[38]Kuramochi Y, Ohkubo T, Takechi N, et al. Hemodynamic factors of thrombus formation in coronary aneurysms associated with Kawasaki disease [J]. Pediatr Int,2000,42(5):470-475
[39]杨志刚,李凤芹,孙川,刘国勋,等.纤维蛋白原P-455G/A、-148C/T、 448G/A基因多态性与血浆纤维蛋白原水平的关系[J].中国血液学杂志,2000,21(9)：463-465
[40]Verschuur M, de Jong M, Felida L, et al. A hepatocyte nuclear factor-3 site in the fibrinogen beta promoter is important for interleukin 6-induced expression, and its activity is influenced by the adjacent-148C/T polymorphism[J]. J Biol Chem, 2005,280(17):16763-16771
[41]Xing HY, Cai WW, Li XM, et al. Association of fibrinogen B beta-1420G/A,-993C/T and-854G/A gene polymorphism with coronary heart disease[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi.2006,23(6):622-626
[42]孙川,梁亮,李巍景,等.a和β纤维蛋白原基因核苷酸多态性及其单体型与冠心病的关系[J].中国动脉硬化杂志,2007,15(9)：699-702
[43]邹宏丽,宋玉强,杨凤.冠心病病人纤维蛋白原β-148C/T基因多态性的检测[J].齐鲁医学杂志,2007,22(5)：397-398,401
[44]里震,包进.纤维蛋白原p-455G/A基因多态性与冠心病的相关性[J].中国老年医学杂志,2008,28(24)：2472-2473
[45]高捷,王红阳,吴乃君,等.川崎病冠状动脉损伤与纤维蛋白原Bβ-148C/T基因多态性的关系[J].中国当代儿科杂志,2010,12(7)：518-520
[46]钱进军,刘春风,赵康仁.脑梗死患者p纤维蛋白原-455G/A、-148C/T基因多态性和血浆纤维蛋白原水平研究[J].中风与神经疾病杂志,2004,21(2)：147-149
[1]Gruys E, Toussaint MJM, Landman WJM, et al. Infection, Inflammation and Stress Inhibit Growth. Mechanisms and Non-specific Assessment of the Processes by Acute Phase Proteins. In:Wensing T, editor. Production Diseases in Farm Animals [C]. 10th International Conference,1998. Wageningen:Wageningen Press,1999:72-87
[2]Tillet WS, Francis T, Jr. Serological reactions in pneumonia with a non-protein fraction from pneumococcus [J]. J Exp Med,1930,52(4):561-571
[3]Maes M, Delange J, Ranjan R, et al. Acute phase proteins in schizophrenia, mania and major depression:modulation by psychotropic drugs [J]. Psychiatry Res, 1997,66(1):1-11
[4]Castell JV, Gomez-Lechon MJ, David M, et al. Acute-phase response of human hepatocytes:regulation of acute-phase protein synthesis by interleukin-6 [J]. Hepatology,1990,12(5):1179-1186
[5]Andus T, Geiger T, Hirano T, et al. Action of recombinant human interleukin 6, interleukin 1 beta and tumor necrosis factor alpha on the mRNA induction of acute-phase proteins [J]. Eur J Immunol,1988,18(5):739-746
[6]Johnson RW. Inhibition of growth by pro-inflammatory cytokines:an integrated view [J]. J Anim Sci,1997,75(5):1244-1255
[7]Trautwein C, Boker K, Manns MP. Hepatocyte and immune system:acute phase reaction as a contribution to early defence mechanisms [J]. Gut,1994,35(9): 1163-1166
[8]Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation [J]. N Engl J Med,1999,340(6):448-454
[9]Blackburn WD Jr. Validity of acute phase proteins as markers of disease activity[J]. J Rheumatol,1994; 42(Suppl):9-13
[10]Kushner I, Gewurz H, Benson MD. C-reactive protein and the acute-phase response [J]. J Lab Clin Med,1981,97(6):739-749
[11]Moshage HJ, Janssen JA, Franssen JH, et al. Study of the molecular mechanism of decreased liver synthesis of albumin in inflammation [J]. J Clin Invest, 1987,79(6):1635-1641
[12]谷月丽,谷春燕,史俊霞.40例急性白血病合并DIC用凝血酶原复合物和纤维蛋白原治疗的临床观察[J].白血病.淋巴瘤,2003,12(5)：299
[13]卓光生,张学敏,吕联煌,等.急性白血病者纤维蛋白原和纤维蛋白降解产物的变化与DIC的关系[J].福建医科大学学报,1985,19(2)：42-45
[14]冯仁丰.急性相和C反应蛋白[J].上海医学检验杂志,1999,14(5)：258-260
[15]Goldstein IM, Kaplan HB, Edelson HS, et al. Ceruloplasmin. A scavenger of superoxide anion radicals[J]. J Biol Chem,1979,254(10):4040-4045
[16]洪兴金,杨长仁,周华友,等.烧伤后血浆纤维连接蛋白的动态观察[J].中国实验诊断学,1998,2(6)：305-306
[17]Yokouchi Y, Oharaseki T, Ihara F, et al. Repeated stent thrombosis after DES implantation and localized hypersensitivity to a stent implanted in the distal portion of a coronary aneurysm thought to be a sequela of Kawasaki disease:autopsy report[J]. Pathol Int,2010,60(2):112-118
[18]Bartoloni G, Salvatrice DM, Carlo R. Sudden death in a 21-year-old man caused by thrombosed coronary aneurysm:late sequelae or a very late onset of Kawasaki disease? [J]. Cardiovasc Pathol,2002,11(6):318-321
[19]Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation [J]. Circulation,2004,109(22):2698-2704
[20]Levy DM, Silverman ED, MassicotteMP, et al. Longterm outcomes in patients with giant aneurysms secondary to Kawasaki disease [J]. J Rheumatol,2005, 32(5):928-934
[21]彭莤,吴青,陈昌辉,等.血清sIL-2R, IL-6与hs-CRP水平的测定在川崎病早期诊断中的临床意义[J].中国当代儿科杂志,2006,8(3)：208-210
[22]董凤英,阮云军.纤维蛋白原与冠心病[J].医学综述,2000,6(2)：66
[23]Asleh R, Marsh S, Shilkrut M, et al. Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease [J]. Circ Res,2003,92(11):1193-1200
[24]Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina[J]. N Engl J Med,1994,331(7):417-424
[25]陈蕾,乔薇,郑知刚.前白蛋白和超敏C反应蛋白与老年冠心病严重程度的关系[J].中日友好医院学报,2008,22(3)：150-151
[26]Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women [J]. N Engl J Med,2000,342(12):836-843
[27]Danesh J, Wheeler JG, Hirschfield GM, et al. C-Reactive Protein and Other Circulating Markers of Inflammation in the Prediction of Coronary Heart Disease [J]. N Engl J Med,2004,350(14):1387-1397
[28]杨胜利,何秉贤,何作云,等.急性冠脉综合征患者血清C-反应蛋白浓度的变化及意义[J].中国急救医学,2003,23(3)：135-138
[29]Paramonov AD, Moiseev SV, Fomin VV, et al. Ferritin and other acute phase proteins in various forms of coronary heart disease [J]. Klin Med (Mosk),2005, 83(2):25-29
[30]Mitani Y, Sawada H, Hayakawa H, et al. Elevated levels of high sensitivity C reactive protein and serum amyloi a late after Kawasak idisease:Association between inflammation and late coronary sequelae in Kawasaki disease [J]. Circulation, 2005,11(1):38-43
[31]张涛,李自成,巫少荣.基质金属蛋白酶-9和C反应蛋白与冠心病的相关性研究[J]. J Clin Cardiol (China),2008,24(2):88-89
[32]Scirica BM, Morrow DA, Cannon CP, et al. Clinical application of C-reactive protein across the spectrum of acute coronary syndromes[J]. Clin Chem, 2007,53(10):1800-1807
[33]Rifai N, Ridker PM. High-sensitivity C-reactive protein:a novel and promising marker of coronary heart disease [J]. Clin Chem,2001,47(3):403-411.
[34]陈瑞,张爱荣,赵信喜,等.川崎病患儿血清中hs-CRP与基质金属蛋白酶及抑制剂联合检测的临床意义[J].中国当代儿科杂志,2009,11(12)：989-991
[35]Ou CY, Tseng YF, Lee CL, et al. Significant relationship between serum high-sensitivity C-reactive protein, high-density lipoprotein cholesterol levels and children with Kawasaki disease and coronary artery lesions[J]. J Formos Med Assoc, 2009,108(9):719-724
[36]王志敏.高敏C反应蛋白对冠心病患者的测定及意义[J].中国实用医药,2010,5(32)：86
[37]范小斌,罗燕飞,谢红东,等.超敏C反应蛋白和纤维蛋白原在急性冠状动脉综合征患者中的检测意义[J].中国误诊学杂志,2010,10(27)：6596-6597
[38]Weisel JW. Fibrinogen and fibrin[J]. Adv Protein Chem,2005,70:247-299
[39]周敏,徐酉华,李晓辉.川崎病血液高凝状态的研究进展[J].国际儿科学杂志,2007,34(3)：190-192
[40]Roy SN, Mukhopadhyay G, Redman CM, et al. Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen[J]. J Biol Chem,1990,265(11): 6389-6393
[41]Schmidt H, Schmidt R, Niederkorn K, et al. Beta-fibrinogen gene polymorphism (C148-->T) is associated with carotid atherosclerosis:results of the Austrian Stroke Prevention Study [J]. Arterioscler Thromb Vase Biol,1998,18(3): 487-492
[42]Humphries SE, Ye S, Talmud P, et al. European Atherosclerosis Research Study:genotype at the fibrinogen locus (G-455-A beta-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Evidence for gender-genotype-environment interaction[J]. Arterioscler Thromb Vasc Biol,1995,15(1):96-104
[43]孙川,梁亮,李巍景,等.α和β纤维蛋白原基因核苷酸多态性及其单体型与冠心病的关系[J].中国动脉硬化杂志,2007,15(9)：699-702
[44]Xing HY, Cai WW, Li XM, et al. Association of fibrinogen B beta-1420G/A,-993C/T and-854G/A gene polymorphism with coronary heart disease[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi.2006,23(6):622-626
[45]Castaman G, Ghiotto R, Duga S, et al. A novel fibrinogen gamma chain mutation (gamma 239 Gin-->His) is the cause of dysfibrinogenemia Vicenza[J]. J Thromb Haemost,2005,3(3):600-601
[46]高捷,王红阳,吴乃君,等.川崎病冠状动脉损伤与纤维蛋白原Bβ-148C/T基因多态性的关系[J].中国当代儿科杂志,2010,12(7)：518-520
[47]Langlois MR, Delanghe JR. Biological and clinical significance of haptoglobin polymorphism in humans [J]. Clin Chem,1996,42(10):1589-1600
[48]Pernod G, Bosson JL, Golshayan D, et al. The Diamant Alpin Dialysis cohort study:clinico-biological characteristics and cardiovascular genetic risk profile of incident patients [J]. J Nephrol,2004,17(1):66-75
[49]Lavie L, Lotan R, Hochberg I, et al. Haptoglobin polymorphism is a risk factor for cardiovascular disease in patients with obstructive sleep apnea syndrome[J]. Sleep,2003,26(5):592-595
[50]Liu HB, Shi YP, Guo XF, et al. Association of haptoglobin 1/2 polymorphism with coronary heart disease in Chinese[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi.2011,28(1):60-63
[51]De Bacquer D, De Backer G, Langlois M, et al. Haptoglobin polymorphism as a risk factor for coronary heart disease mortality[J]. Artherosclerosis,2001,157(1): 161-166
[52]Lee WC, Hwang KP, King YT, et al. Late diagnosis of Kawasaki disease is associated with haptoglobin phenotype [J]. Eur J Clin Invest,2000,30(5):379-382
[53]张瑞英,许小进,富路,等.血清淀粉样蛋白A和血清淀粉样A-低密度脂蛋白复合物与冠心病的临床研究[J].中华老年心脑血管病杂志,2010,12(2)：123-126
[54]洪华,传良敏,袁红,等.川崎病患儿血清淀粉样蛋白A的测定及临床意义[J].检验医学,2005,20(6)：524-52
[55]张春雨,金红芳,杜军保.川崎病患儿血浆前白蛋白的变化及其义[J].临床儿科杂志,2010,28(7)：628-629,658