磷酸二酯酶4D基因和缺血性脑血管病在中国汉族人群中的研究
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摘要
目的:探讨中国汉族人群中磷酸二酯酶4D(phosphodiesterase 4D,PDE4D)基因和缺血性脑血管病(ischemic cerebrovascular diseases,ICVD)的关系。
方法:采用病例-对照和聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测116名ICVD患者和110名对照者在SNP45、SNP83、SNP87和rs918592位点的突变情况,比较不同基因型在糖代谢指标和血脂方面的差异。运用PHASE2.1软件构建单倍体,分析不同单倍体型在两组间的分布差异。
结果:rs918592的A等位基因分布频率在病例组(58.6%)、腔隙性脑梗死亚组(63.8%)较对照组(48.6%)高(分别为P=0.033,OR=1.496[95%CI:1.032～2.170]和P=0.040,OR=1.861[95%CI:1.024～3.381])。rs918592位点基因型分布和SNP83、SNP87位点基因型、等位基因分布在各组间没有统计学差异(P＞0.05)。SNP45位点未见突变。SNP83位点的CT基因型在叠加模式下和ICVD相关,P=0.042,OR=1.803[95%CI:1.019～3.18]。rs918592位点在隐性模式下和ICVD相关,P=0.030,OR=1.949[95%CI:1.062～3.576];在叠加模式下其AA基因型和ICVD相关,P=0.031,OR=2.339[95%CI:1.076～5.348]。除SNP83不同的基因型在总胆固醇水平存在差异外,其他位点不同的基因型在糖代谢指标、血脂水平方面没有差异。SNP83位点TT基因型在总胆固醇水平较CT基因型高。由SNP83、SNP87和rs918592位点所组成的单倍体在病例组、对照组间的分布有统计学差异(P=0.002),与野生型TCG比较,TCA、CCA单倍体型在两组间分布有统计学差异,P=0.046,OR=1.385[95%CI:1.005～1.911]和P=0.016,OR=1.856[95%CI:1.017～3.084]。
结论:在中国汉族人群中,rs918592位点的A等位基因可能是ICVD发生的一个危险因素,可能增加腔隙性脑梗死的发生,其在隐性和叠加模式下可能和ICVD相关。SNP83在叠加模式下可能和ICVD相关。而SNP87可能和ICVD无相关性,SNP45则没有多态性。TCA、CCA单倍体型可能增加ICVD的发病风险。
Objective:To investigate the role of polymorphisms of phosphodiesterase 4D gene in the development of ischemic cerebrovascular diseases(ICVD)in Han people of China.
Methods:The base-variations in SNP45,SNP83,SNP87 and rs918592 of PDE4D gene,by means of PCR-RFLP were determined in 116 cases of ICVD and 110 healthy controls.And the concentrations of fasting glucose, insulin,QUICKI index and triglyceride,total cholesterol,high density lipoprotein and low density lipoprotein were compared between patients and controls.Using PHASE 2.1 software to construct the haplotype containing the SNPs in this research,compare the rates of the haplotype in cases and controls.
Results:The rate of A-allele in rs918592 was higher in cases(58.6%) and the subgroup of lacunar infarction(63.8%)than controls(48.6%) (P=0.033,OR=1.496[95%CI:1.032-2.170]and P=0.040,OR=1.861 [95%CI:1.024-3.381]respectively),but either the rates of its genotypes or the genotypes or alleles in SNP83 or SNP87 were not significantly different in the patients from those of the controls.No base-variation in SNP45 was found in this study.The CT genotype of SNP83 is associated with ICVD in an additive mode(P=0.042,OR=1.803,95%CI: 1.019～3.189),rs918592 in a recessive mode(P=0.030,OR=1.949,95%CI: 1.062～3.576)and AA genotype in an additive mode(P=0.031,OR=2.339, 95%CI:1.076～5.348).Except for the concentration of total cholesterol is different in the genotypes of SNP83,the other indexes for glucose and fat metabolism were not significantly different in different genotypes of other SNPs.The concentration of total cholesterol was higher in TT than CT genotype of SNP83.Compared with TCG haplotype,the rates of TCA and CCA haplotypes were higher in the cases than those in the controls (P=0.046,OR=1.385,95%CI:1.005～1.911and P=0.016,OR=1.856, 95%CI:1.017～3.084 respectively).
Conclusion:The A-allele in rs918592 may play a part in the development of ICVD in the Han people in China,as a risk factor.It may influence the development of lacunar infarction.It may be associated with ICVD in a recessive mode or in an additive mode and SNP83 in an additive mode.SNP87 may not take part in the development of ICVD, and neither does SNP45 because of lack of polymorphism.The TCA and CCA haplotypes may increase the risk of ICVD.
方法:采用病例-对照和聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测116名ICVD患者和110名对照者在SNP45、SNP83、SNP87和rs918592位点的突变情况,比较不同基因型在糖代谢指标和血脂方面的差异。运用PHASE2.1软件构建单倍体,分析不同单倍体型在两组间的分布差异。
结果:rs918592的A等位基因分布频率在病例组(58.6%)、腔隙性脑梗死亚组(63.8%)较对照组(48.6%)高(分别为P=0.033,OR=1.496[95%CI:1.032～2.170]和P=0.040,OR=1.861[95%CI:1.024～3.381])。rs918592位点基因型分布和SNP83、SNP87位点基因型、等位基因分布在各组间没有统计学差异(P＞0.05)。SNP45位点未见突变。SNP83位点的CT基因型在叠加模式下和ICVD相关,P=0.042,OR=1.803[95%CI:1.019～3.18]。rs918592位点在隐性模式下和ICVD相关,P=0.030,OR=1.949[95%CI:1.062～3.576];在叠加模式下其AA基因型和ICVD相关,P=0.031,OR=2.339[95%CI:1.076～5.348]。除SNP83不同的基因型在总胆固醇水平存在差异外,其他位点不同的基因型在糖代谢指标、血脂水平方面没有差异。SNP83位点TT基因型在总胆固醇水平较CT基因型高。由SNP83、SNP87和rs918592位点所组成的单倍体在病例组、对照组间的分布有统计学差异(P=0.002),与野生型TCG比较,TCA、CCA单倍体型在两组间分布有统计学差异,P=0.046,OR=1.385[95%CI:1.005～1.911]和P=0.016,OR=1.856[95%CI:1.017～3.084]。
结论:在中国汉族人群中,rs918592位点的A等位基因可能是ICVD发生的一个危险因素,可能增加腔隙性脑梗死的发生,其在隐性和叠加模式下可能和ICVD相关。SNP83在叠加模式下可能和ICVD相关。而SNP87可能和ICVD无相关性,SNP45则没有多态性。TCA、CCA单倍体型可能增加ICVD的发病风险。
Objective:To investigate the role of polymorphisms of phosphodiesterase 4D gene in the development of ischemic cerebrovascular diseases(ICVD)in Han people of China.
Methods:The base-variations in SNP45,SNP83,SNP87 and rs918592 of PDE4D gene,by means of PCR-RFLP were determined in 116 cases of ICVD and 110 healthy controls.And the concentrations of fasting glucose, insulin,QUICKI index and triglyceride,total cholesterol,high density lipoprotein and low density lipoprotein were compared between patients and controls.Using PHASE 2.1 software to construct the haplotype containing the SNPs in this research,compare the rates of the haplotype in cases and controls.
Results:The rate of A-allele in rs918592 was higher in cases(58.6%) and the subgroup of lacunar infarction(63.8%)than controls(48.6%) (P=0.033,OR=1.496[95%CI:1.032-2.170]and P=0.040,OR=1.861 [95%CI:1.024-3.381]respectively),but either the rates of its genotypes or the genotypes or alleles in SNP83 or SNP87 were not significantly different in the patients from those of the controls.No base-variation in SNP45 was found in this study.The CT genotype of SNP83 is associated with ICVD in an additive mode(P=0.042,OR=1.803,95%CI: 1.019～3.189),rs918592 in a recessive mode(P=0.030,OR=1.949,95%CI: 1.062～3.576)and AA genotype in an additive mode(P=0.031,OR=2.339, 95%CI:1.076～5.348).Except for the concentration of total cholesterol is different in the genotypes of SNP83,the other indexes for glucose and fat metabolism were not significantly different in different genotypes of other SNPs.The concentration of total cholesterol was higher in TT than CT genotype of SNP83.Compared with TCG haplotype,the rates of TCA and CCA haplotypes were higher in the cases than those in the controls (P=0.046,OR=1.385,95%CI:1.005～1.911and P=0.016,OR=1.856, 95%CI:1.017～3.084 respectively).
Conclusion:The A-allele in rs918592 may play a part in the development of ICVD in the Han people in China,as a risk factor.It may influence the development of lacunar infarction.It may be associated with ICVD in a recessive mode or in an additive mode and SNP83 in an additive mode.SNP87 may not take part in the development of ICVD, and neither does SNP45 because of lack of polymorphism.The TCA and CCA haplotypes may increase the risk of ICVD.
引文
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[1]Gretarsdottir S,Thorleifsson G,Reynisdottir ST,et al.The gene encoding phosphodiesterase 4D confers risk of ischemic stroke[J].Nat Genet,2003,35:131-138.
[2]张颖冬.2006年卒中遗传学研究进展[J].中国卒中杂志,2007,2:136-139.
[3]Houslay MD.PDE4 cAMP-specific phosphodiesterases[J].Prog Nucleic Acid Res Mol Biol,2001,69:249-315.
[4]Lim J,Pahlke G,Conti M.Activation of the cAMP-specific phosphodiesterase PDE4D3 by phosphorylation.Identification and function of an inhibitory domain[J].J Biol Chem,1999,274:19677-19685.
[5]MacKenzie SJ,Baillie GS,McPhee I,etal.ERK2 mitogen-activated protein kinase binding,phosphoylation and regulation of PDE4D cAMP specific phosphodiesterases.The involvement of COOH-terminal docking sites and NH_2-terminal UCR regions[J].J Biol Chem,2000,275:16609-16617.
[6]Wang D,Deng C,Bugaj-Gaweda B,et al.Cloning and characterization of novel PDE4D isoforms PDE4D6 and PDE4D7[J].Cell Signal,2003,15:883-891.
[7]Barnes AP,Livera G,Huang P,et al.Phosphodiesterase 4D forms a cAMP diffusion barrier at the apical membrane of the airway epithelium[J].J Biol Chem,2005,280:7997-8003.
[8]Richter W,Jin SL,Conti M.Splice variants of the cyclic nucleotide phosphodiesterase PDE4D are differentially expressed and regulated in rat tissue[J].Biochem J,2005,388:803-811.
[9] Dodge-Kafka KL, Soughayer J, Pare GC, et al. The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways[J]. Nature, 2005,437:574-578.
[10] O'Donnell JM, Zhang HT. Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4) [J]. Trends Pharmacol Sci, 2004, 25:158-163.
[11] Kalgutkar AS, Choo E, Taylor TJ, et al. Disposition of CP-671,305, a selective phosphodiesterase 4 inhibitor in preclinical species [J]. Xenobiotica, 2004,34:755-770.
[12] Shepherd MC, Baillie GS, Stirling DI, et al. Remodelling of the PDE4 cAMP phosphodiesterase isoform profile upon monocyte-macrophage differentiation of human U937 cells[J]. Br J Pharmacol, 2004,142:339-351.
[13] Le Jeune IR, Shepherd M, Van Heeke G, et al. Cyclic AMP-dependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter[J]. J Biol Chem,2002,277:35980-35989.
[14] Gretarsdottir S, Sveinbjornsdottir S, Jonesson HH, et al. Localization of a susceptibility gene for common forms of stroke to 5ql2[J]. Am J Hum Genet, 2002,70:593-603.
[15] Bevan S, Porteous L, Sitzer M, et al. Phosphodiesterase 4D gene, ischemic stroke, and asymptomatic carotid atherosclerosis[J]. Stroke, 2005,36(5):949-953.
[16] Zee RY, Brophy VH, Cheng S, et al. Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation[J]. Stroke, 2006,37:2012-2017.
[17]Fidani L,Clarimon J,Goulas A,et al.Association of phosphodiesterase 4D gene GO haplotype and ischaemic stroke in a Greek population[J].Eur J Neurol,2007,14:745-749.
[18]Nakayama T,Asai S,Sato N,et al.Genotype and haplotype association study of the STRK1 region on 5q12 among Japanese[J].Stroke,2006,37:69-76.
[19]李才明,张成,张鸿炼,等.磷酸二酯酶4D基因与缺血性卒中的遗传易患性研究[J].中华神经科杂志,2006,39:180-183.
[20]Song Q,Cole JW,O'Connell JR,et al.Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population:the stroke prevention in young women study[J].Hum Mol Genet,2006,15:2468-2478.
[21]Brophy VH,Ro SK,Rhees BK,et al.Association of phosphodiesterase 4D polymorphisms with ischemic stroke in a US population stratified by hypertension status[J].Stroke,2006,37:1385-1390.
[22]Baillie G,MacKenzie SJ,Houslay MD.Phorbol 12-myristate 13-acetate triggers the protein kinase A-mediated phosphorylation and activation of the PDE4D5 cAMP phosphodiesterase in human aortic smooth muscle cells through a route involving extracellular signal related kinase(ERK)[J].Mol Pharmacol,2001,60:1100 -1111.
[23]Allessie MA,Boyden PA,Camm AJ,et al.Pathophysiology and prevention of atrial fibrillation[J].Circulation,2001,103:769-777.
[24]Greenberg SM,Rosand J.The phosphodiesterase puzzlebox:PDE4D and stroke[J].Ann Neurol,2005.58:345-346.
[25]Giorgi M,Modica A,Pompili A,et al.The induction of cyclic nucleotide phosphodiesterase 4 gene(PDE4D)impairs memory in a water maze task[J]. Behav Brain Res,2004,154 : 99-106.
[26]Sanz MJ, Cortijo J, Morcillo EJ. PDE4 inhibitors as new anti-inflammatory drugs: Effects on cell trafficking and cell adhesion molecules expression. Pharmacol Ther, 2005,106: 269- 297.
[27]Kroegel C, Foerster M. Phosphodiesterase-4 inhibitors as a novel approach for the treatment of respiratory disease: cilomilast. Expert Opin Investig Drugs, 2007,16:109-124.
[2]张颖冬,葛剑青,石静萍,等.血管紧张素原及其基因多态性与缺血性脑血管病的相关性研究[J].中国临床神经科学,2004,12(03):230-233.
[3]胡均培,严为宏,邹丽芳,等.脑梗死患者纤溶酶原激活物抑制剂-14G/5G基因多态性的研究[J].血栓与止血学,2005,11(03):112-113.
[4]Gretarsdottir S,Thorleifsson G,Reynisdottir ST,et al.The gene encoding phosphodiesterase 4D confers risk of ischemic stroke[J].Nat Genet,2003,35(2):131-138.
[5]张颖冬.2006年卒中遗传学研究进展[J].中国卒中杂志,2007,2(2):136-139.
[6]Sanz MJ,Cortijo J,Morcillo EJ.PDE4 inhibitors as new anti-inflammatory drugs:Effects on cell trafficking and cell adhesion molecules expression[J].Pharmacol Ther,2005,106(3):269-297.
[7]Kroegel C,Foerster M.Phosphodiesterase-4 inhibitors as a novel approach for the treatment of respiratory disease:cilomilast[J].Expert Opin Investig Drugs,2007,16(1):109-124.
[8]王志宏,韩仲岩.急性缺血性脑卒中的TOAST分型标准[J].临床神经病学杂志,2007,20(5):392.
[9]Katz A,Nambi SS,Mather K,et al.Quantitative insulin sensitivity check index:a simple,accurate method for assessing insulin sensitivity in humans[J].J Clin Endocrinol Metab,2000,85(7):2402-2410.
[10]Conti M,Richter W,Mehats C,et al.Cyclic AMP-specific PDE4phosphodiesterases as critical components of cyclic AMP signaling[J].J Biol Chem.2003,278(8):5493-5496.
[11]Houslay MD. PDE4 cAMP-specific phosphodiesterases[J]. Prog Nucleic Acid Res Mol Biol, 2001, 69:249-315.
[12]Song Q, Cole JW, O'Connell JR, et al. Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study [J]. Hum Mol Genet, 2006, 15(16):2468-2478.
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