凝血酶激活的纤溶抑制物编码区基因CPB2多态性与2型糖尿病关系的研究
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摘要
目的:通过对TAFI编码区(CPB2基因)2个单核苷酸多态性位点(505A/G,1040C/T)基因亚型分布与2型糖尿病(T2DM)发病及病程进展的相关性进行检测与分析,同时测定T2DM患者血浆中凝血酶激活的纤溶抑制物(TAFI)的抗原含量(TAFI:Ag)及其活性水平(TAFI:Act),以探究T2DM患者体内TAFI浓度与凝血-纤溶紊乱的相关性以及505A/G,1040C/T的分布差异,为揭示TAFI在T2DM发病及病程进展中的作用机理提供实验基础。
方法:T2DM组患者的诊断均参照并符合1999年WHO专家委员会修订的诊断标准,组根据尿白蛋白排泄量与尿肌酐的比值(ACRs)将T2DM患者进一步分为初期T2DM患者及后期T2DM患者。研究个体包括157例T2DM患者和140例对照组个体。157例T2DM患者中男90例,女67例,39岁～80岁,平均(54.8±9.9)岁。对照组含男75例,女65例,42～83岁,平均(57.1±11.2)岁,其中病例组年龄、性别构成、体重指数(BMI)等与对照组相比较差异均无统计学意义。应用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)分析技术检测157例T2DM患者(T2DM组)和140例正常对照者(对照组)的TAFI505A/G、1040C/T两位点的多态性。同时应用ELISA及发色底物法分别检测患者和对照组个体血浆中的TAFI∶Ag及TAFI∶Act活性水平。
结果:本研究中CPB2基因的2个单核苷酸多态性位点为505A/G、1040C/T,其中505A/G多态性位点病例组及对照组中各基因型的分布差异无统计学意义,但在1040C/T位点T2DM组T等位基因的频率较对照组明显下降(15.6%对25.4%,P＜0.05),这主要由于病例组T/T纯合子型比例显著下降所致(P＜0.05,OR 0.33,95%CI 0.12～0.91),但这种显著性差异只呈现在初期T2DM组(P＜0.05,OR 0.20,95%CI 0.0～4-0.94)。初期T2DM患者血浆中TAFI:Ag与TAFI:Act水平分别为(119.82±35.53)%和(46.31±8.47)μg/ml,后期D2DM组患者血浆中TAFI:Ag与TAFI:Act水平分别为(130.52±46.39)%和(55.92±12.58)μg/ml,对照组个体血浆中TAFI抗原与活性水平分别为(85.2±25.24)%和(26.92±10.78)μg/ml,经方差分析,初、后期T2DM患者间TAFI:Ag与TAFI:Act差异无统计学意义(p＞0.05),T2DM组与对照组比较,TAFI:Ag与TAFI:Act均升高,差异具有统计学意义(p＜0.05)。
结论:
①TAFI1040C/T多态性位点与T2DM患病危险度存在关联;
②T等位基因可能在T2DM早期病情进展中起保护性作用;
③TAFI作为凝血与纤溶的调节因子,在T2DM患者体内的高凝血倾向中发挥重要作用,同时提示TAFI抑制物有望成为溶栓治疗的新途径。
Objective: Based on the role of TAFI(thrombin activated fibrinolysis inhibitor) in balancing between the fibrinolysis and coagulation and no studies thus far have investigated the contribution of the TAFI genetic polymorphisms to type 2 diabetes mellitus(T2DM), we investigated the possible association of the TAFI activity-related two polymorphisms(505A/G、1040C/T) with increased risk of T2DM. At the same time we also carried out as a pilot study to examine the antigen and activity of TAFI in both patients and control groups.
Methods: We studied the two allele frequencies of the 505A/G and 1040C/T polymorphisms which result in two amino acid substitutions: Ala for Thr at position 147 and Ile for Thr at position 325 in 157 type 2 T2DM patients and 140 healthy controls matched by age, gender, ethnicity and body mass index (BMI), using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) typing analysis. In addition, the TAFI-Ag and TAFI-Act were determined by enzyme link immunosorbent assay (ELISA) and chromogenic assay, respectively.
Results: No significant differences of TAFI levels appeared between patients and controls at 505A/G. At 1040C/T ,the detected frequency for the T allele in the patients' group was significantly smaller in comparison to that of the control group (15.6% versus25.4%, respectively: P <0.05). This difference was due to the relative decrease of T/T homozygotes in the group of patients, in comparison to controls (P < 0.05, OR 0.33, 95%CI 0.12-0.91).The same pattern of significance was also observed between controls and the subgroups of patients with initial stages of T2DM categorized by the urine albumin excretion (UAEμg/ml)-to-creatinine (mg/ml) ratios (ACRs) while no significant difference was observed between controls and patients with latter stage of T2DM.Plasma TAFI:Ag and TAFI:Act were (119.82±35.53)% and (46.31±8.47)μg/ml in initial T2DM group, (130.52±46.39)% and (55.92±12.58)μg/ml in latter T2DM group, both being significantly higher than those of control group[TAFI:Ag(85.2±25.24)% and TAFI:Act(26.92±10.78)μg/ml].
Conclusion: This study clearly indicates that at 1040C/T the frequency for the T allele is strongly associated with increased risk for T2DM in a subset of the general population. These results are in accordance to previous studies of constitutive expression and secretion of TAFI in T2DM, implying that the T allele confers protection against the onset of T2DM only in homozygosity, It may function as a recessive trait. It may be due to either unidentified properties of the 1040C/T polymorphism or of a strong linkage disequilibrium undefined between this polymorphism and another genetic locus.
方法:T2DM组患者的诊断均参照并符合1999年WHO专家委员会修订的诊断标准,组根据尿白蛋白排泄量与尿肌酐的比值(ACRs)将T2DM患者进一步分为初期T2DM患者及后期T2DM患者。研究个体包括157例T2DM患者和140例对照组个体。157例T2DM患者中男90例,女67例,39岁～80岁,平均(54.8±9.9)岁。对照组含男75例,女65例,42～83岁,平均(57.1±11.2)岁,其中病例组年龄、性别构成、体重指数(BMI)等与对照组相比较差异均无统计学意义。应用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)分析技术检测157例T2DM患者(T2DM组)和140例正常对照者(对照组)的TAFI505A/G、1040C/T两位点的多态性。同时应用ELISA及发色底物法分别检测患者和对照组个体血浆中的TAFI∶Ag及TAFI∶Act活性水平。
结果:本研究中CPB2基因的2个单核苷酸多态性位点为505A/G、1040C/T,其中505A/G多态性位点病例组及对照组中各基因型的分布差异无统计学意义,但在1040C/T位点T2DM组T等位基因的频率较对照组明显下降(15.6%对25.4%,P＜0.05),这主要由于病例组T/T纯合子型比例显著下降所致(P＜0.05,OR 0.33,95%CI 0.12～0.91),但这种显著性差异只呈现在初期T2DM组(P＜0.05,OR 0.20,95%CI 0.0～4-0.94)。初期T2DM患者血浆中TAFI:Ag与TAFI:Act水平分别为(119.82±35.53)%和(46.31±8.47)μg/ml,后期D2DM组患者血浆中TAFI:Ag与TAFI:Act水平分别为(130.52±46.39)%和(55.92±12.58)μg/ml,对照组个体血浆中TAFI抗原与活性水平分别为(85.2±25.24)%和(26.92±10.78)μg/ml,经方差分析,初、后期T2DM患者间TAFI:Ag与TAFI:Act差异无统计学意义(p＞0.05),T2DM组与对照组比较,TAFI:Ag与TAFI:Act均升高,差异具有统计学意义(p＜0.05)。
结论:
①TAFI1040C/T多态性位点与T2DM患病危险度存在关联;
②T等位基因可能在T2DM早期病情进展中起保护性作用;
③TAFI作为凝血与纤溶的调节因子,在T2DM患者体内的高凝血倾向中发挥重要作用,同时提示TAFI抑制物有望成为溶栓治疗的新途径。
Objective: Based on the role of TAFI(thrombin activated fibrinolysis inhibitor) in balancing between the fibrinolysis and coagulation and no studies thus far have investigated the contribution of the TAFI genetic polymorphisms to type 2 diabetes mellitus(T2DM), we investigated the possible association of the TAFI activity-related two polymorphisms(505A/G、1040C/T) with increased risk of T2DM. At the same time we also carried out as a pilot study to examine the antigen and activity of TAFI in both patients and control groups.
Methods: We studied the two allele frequencies of the 505A/G and 1040C/T polymorphisms which result in two amino acid substitutions: Ala for Thr at position 147 and Ile for Thr at position 325 in 157 type 2 T2DM patients and 140 healthy controls matched by age, gender, ethnicity and body mass index (BMI), using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) typing analysis. In addition, the TAFI-Ag and TAFI-Act were determined by enzyme link immunosorbent assay (ELISA) and chromogenic assay, respectively.
Results: No significant differences of TAFI levels appeared between patients and controls at 505A/G. At 1040C/T ,the detected frequency for the T allele in the patients' group was significantly smaller in comparison to that of the control group (15.6% versus25.4%, respectively: P <0.05). This difference was due to the relative decrease of T/T homozygotes in the group of patients, in comparison to controls (P < 0.05, OR 0.33, 95%CI 0.12-0.91).The same pattern of significance was also observed between controls and the subgroups of patients with initial stages of T2DM categorized by the urine albumin excretion (UAEμg/ml)-to-creatinine (mg/ml) ratios (ACRs) while no significant difference was observed between controls and patients with latter stage of T2DM.Plasma TAFI:Ag and TAFI:Act were (119.82±35.53)% and (46.31±8.47)μg/ml in initial T2DM group, (130.52±46.39)% and (55.92±12.58)μg/ml in latter T2DM group, both being significantly higher than those of control group[TAFI:Ag(85.2±25.24)% and TAFI:Act(26.92±10.78)μg/ml].
Conclusion: This study clearly indicates that at 1040C/T the frequency for the T allele is strongly associated with increased risk for T2DM in a subset of the general population. These results are in accordance to previous studies of constitutive expression and secretion of TAFI in T2DM, implying that the T allele confers protection against the onset of T2DM only in homozygosity, It may function as a recessive trait. It may be due to either unidentified properties of the 1040C/T polymorphism or of a strong linkage disequilibrium undefined between this polymorphism and another genetic locus.
引文
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1.Boffa MB,Koschinsky ML.Curiouser and curiouser:recent advances in measurement of thrombin-activatable fibrinolysis inhibitor(TAFI) and in understanding its molecular genetics,gene regulation,and biological roles.Clin Biochem 2007,40:431-442.
2.Henry M,Aubert H,Morange PE,et al.Identification of polymorphisms in the promoter and the 3'region of the TAFI gene:evidence that plasma TAFI antigen levels are strongly genetically controlled.Blood 2001,97:2053-2058.
3.Frere C,Morange PE,Saut N,et al.Quantification of thrombin activatable fibrinolysis inhibitor(TAFI) gene polymorphism effects on plasma levels of TAFI measured with assays insensitive to isoform-dependent artefact.Thromb Haemost 2005,94:373-379.
4.Frere C,Tregouet DA,Morange PE,et al.Fine mapping of quantitative trait nucleotides underlying thrombin-activatable fibrinolysis inhibitor antigen levels by a transethnic study.Blood 2006,108:1562-1568.
5.Franco RF,Fagundes MG,Meijers JC,et al.Identification of polymorphisms in the 5'-untranslated region of the TAFI gene:relationship with plasma TAFI levels and risk of venous thrombosis.Haematologica 2001,86:510-517.
6.Bladbjerg EM,de Maat MP,Chfistensen K,et al.Genetic influence on thrombotic risk markers in the elderly—a Danish twin study.J Thromb Haemost 2006,4:599-607.
7. Morange PE,Henry M,Frere C, et al. Thr325IIe polymorphism of the TAFI gene does not influence the risk of myocardial infarction. Blood 2002,99:1878-1879.
8. Schneider M, Boffa M, Stewart R, et al. Two naturally occurring variants of TAFI (Thr-325 and Ue-325) differ substantially with respect to thermal stability and antifibrinolytic activity of the enzyme. J Biol Chem 2002, 277:1021-1030.
9. Ceresa E, Van de Borne K, Peeters M ,et al. Generation of a stable activated thrombin activable fibrinolysis inhibitor variant. J Biol Chem 2006,281: 15878-15883.
10. Peetz D, Victor A, Adams P, et al. Genetic and environmental influences on the fibrinolytic system: a twin study. Thromb Haemost 2004 ,92:344-351.
11. Martini CH, Brandts A,.De Bruijne EL, et al. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. Br J Haematol 2006,134: 92-94.
12. Morange PE, Juhan-Vague I, Scarabin PY, et al. Association between TAFI antigen and Alal47Thr polymorphism of the TAFI gene and the angina pectoris incidence. The PRIME Study (Prospective Epidemiological Study of MI). Thromb Haemost 2003,89:554-560.
13. Lau HK, Segev A, Hegele RA, et al. Thrombin-activatable fibrinolysis inhibitor (TAFI): a novel predictor of angiographic coronary restenosis. Thromb Haemost 2003,90:1187-1191.
14. Brouwers GJ, Leebeek FW, Tanck MW, et al. Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris. Thromb Haemost 2003, 90 : 92-100.
15. Morange PE,Aillaud MF,Nicaud V, et al. Ala147Thr and C+1542G polymorphisms in the TAFI gene are not asssociated with a higher risk of venous thrombosis in FV Leiden carriers. Thromb Haemost 2001,86: 1583-1584.
16. Zorio E, Castello R, Falco C, et al. Thrombin-activatable fibrinolysis inhibitor in young patients with myocardial infarction and its relationship with the fibrinolytic function and the protein C system. Br J Haematol 2003,122:958-965.
17. Juhan-Vague I, Morange PE, Aubert H, et al. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe. Arterioscler Thromb Vasc Biol 2002, 22:867-873.
18. Morange PE, Tregouet DA, Frere C, et al. TAFI gene haplotypes, TAFI plasma levels and future risk of coronary heart disease: the PRIME Study. J Thromb Haemost 2005,3:1503-1510.
19. Santamaria A, Oliver A, Borrell M, et al. Risk of ischemic stroke associated with functional thrombin-activatable fibrinolysis inhibitor plasma levels. Stroke 2003,34: 2387-2391.
20. Lichy C, Dong-Si T, Reuner K, et al. Risk of cerebral venous thrombosis and novel gene polymorphisms of the coagulation and fibrinolytic systems. J Neurol 2006,253:316-320.
21. Akatsu H,Yamagata H,Chen Y,et al. TAFI polymorphisms at amino acids 147 and 325 are not risk factors for cerebral infarction. Br J Haematol 2004,127:440-447.
22. de Bruijne EL, Murad SD, de Maat MP, et al. Genetic variation in thrombin-activatable fibrinolysis inhibitor (TAFI) is associated with the risk of splanchnic vein thrombosis. Thromb Haemost 2007,97,181-185.
23. Sucker C, Hetzel GR, Farokhzad F, et al. Association of genotypes of thrombin-activatable fibrinolysis inhibitors with thrombotic microangiopathies: a pilot study. Nephrol Dial Transplant 2007,22:1347-1350.
24. Hori Y, Gabazza EC,Yano Y, et al. Insulin resistance is associated with increased circulating level of thrombin-activatable fibrinolysis inhibitor in type 2 diabetic patients. J Clin Endocrinol Metab 2002,87: 660-665.
25. Aso Y, Wakabayashi S, Yamamoto R, et al. Metabolic syndrome accompanied by hypercholesterolemia is strongly associated with proinflammatory state and impairment of fibrinolysis in patients with type 2 diabetes: synergistic effects of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. Diabetes Care 2005,28: 2211-2216.
26. Harmanci A, Kandemir N,Dagdelen S, et al. Thrombin-activatable fibrinolysis inhibitor activity and global fibrinolytic capacity in Type 1 diabetes: evidence for normal fibrinolytic state. J Diabetes Complications 2006,20:40-44.
27. Asai S, Sato T, Tada T ,et al. Absence of procarboxypeptidase R induces complement-mediated lethal inflammation in lipopolysaccharide-primed mice. J Immunol 2004,173:4669-4674.
28. Boffa MB,Hamill JD,Maret D ,et al. Acute phase mediators modulate thrombin-activable fibrinolysis inhibitor (TAFI) gene expression in HepG2 cells. J Biol Chem 2003,278: 9250-9257.
29. Hataji O, Taguchi O, Gabazza EC, et al. Increased circulating levels of thrombin-activatable fibrinolysis inhibitor in lung cancer patients. Am J Hematol 2004 ,76:214-219.
30. Vairaktaris E, Yapijakis C, Nkenke E,et al. The 1040C/T polymorphism influencing thermal stability and activity of thrombin activatable fibrinolysis inhibitor is associated with risk for oral cancer. Am J Hematol 2007,82:1010-1012.
31. Kremer Hovinga JA, Franco RF, Zago MA, et al. A functional single nucleotide polymorphism in the thrombin-activatable fibrinolysis inhibitor (TAFI) gene associates with outcome of meningococcal disease. J Thromb Haemost 2004,2:54-57.
32. Koschinsky ML,Boffa MB,Nesheim ME, et al. Association of a single nucleotide polymorphism in CPB2 encoding the thrombin-activable fibrinolysis inhibitor (TAFI) with blood pressure. Clin Genet 2001,60:345-349.
2. Campbell W, Okada H. An arginine specific carboxypeptidase generated in blood during coagulation or inflammation which is unrelated to carboxypeptidase N or its subunits. Biochem Biophys Res Commun 1989; 162:933-939.
3. Eaton DL, Malloy BE, Tsai SP, HenzelW, Drayna D. Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma. J Biol Chem 1991;266:21833-21838.
4. Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem 1995; 270 :14477-14484.
5. Boffa MB, Wang W, Bajzar L, Nesheim ME. Plasma and recombinant. thrombin-activable fibrinolysis inhibitor (TAFI) and activated TAFI compared with respect to glycosylation, thrombin/thrombomodulindependent activation, thermal stability, and enzymatic properties. J Biol Chem 1998 ;273:2127-2135.
6. Wang W, Boffa MB, Bajzar L, Walker JB, Nesheim ME. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998;273:27176-27181.
7. Walker JB, Nesheim ME. A kinetic analysis of the tissue plasminogen activator and DSPAalphal cofactor activities of untreated and TAFIatreated soluble fibrin degradation products of varying size. J Biol Chem 2001 ;276:3138—3148.
8. Sakharov DV, Plow EF, Rijken DC. On the mechanism of the antifibrinolytic activity of plasma carboxypeptidase B. J Biol Chem 1997;272:14477-14482.
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7. Morange PE,Henry M,Frere C, et al. Thr325IIe polymorphism of the TAFI gene does not influence the risk of myocardial infarction. Blood 2002,99:1878-1879.
8. Schneider M, Boffa M, Stewart R, et al. Two naturally occurring variants of TAFI (Thr-325 and Ue-325) differ substantially with respect to thermal stability and antifibrinolytic activity of the enzyme. J Biol Chem 2002, 277:1021-1030.
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25. Aso Y, Wakabayashi S, Yamamoto R, et al. Metabolic syndrome accompanied by hypercholesterolemia is strongly associated with proinflammatory state and impairment of fibrinolysis in patients with type 2 diabetes: synergistic effects of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. Diabetes Care 2005,28: 2211-2216.
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