深部静脉血栓的遗传危险因素(英文)课件

書式設定,書式設定,第 2,第 3,第 4,第 5,*,深部静脉血栓的遗传危险因素（英文）,Advanced age is a risk for venous thromboembolism(VTE),All VTE,Blood,110,3097-3101,2007,among residents of Olmsted County,Minnesota,from 1966 to 1990,PE,DVT alone,Male,Female,Incidence rates of VTE increase dramatically at about age 55,and,by age 80,are nearly 1 in 100 per year,approximately 1000-fold higher than for those aged 45 or younger.,Risk factors for venous thromboembolism,N Engl J Med,358,1037-52,2008,Acquired factors,Reduced mobility,Advanced age,Cancer,Acute medical illness,Major surgery,Trauma,Spinal cord injury,Pregnancy and postpartum period,Polycythemia vera,Antiphospholipid antibody syndrome,Oral contraceptives,Hormone-replacement therapy,Heparins,Chemotherapy,Obesity,Central venous catheterization,Immobilizer or cast,Hereditary factors,Antithrombin,deficiency,Protein C deficiency,Protein S deficiency,Factor V Leiden,Prothrombin,gene mutation,Thrombo-,modulin,endothelium,EPCR,PC,PS,prothrombin,FVa,FXa,FVa,FVIIIa,HSPG,thrombin,APC,Protein C/protein S system,Proteoglycan,sulfate,system,Heparan sulfate,FVi,FVIIIi,IIa,AT,Anticoagulant Systems,on Endothelium,Caucasian,Japanese,Factor V Leiden,Prothrombin G20210A,Deficiencies of protein C,protein S,antithrombin,Low frequency,variation,Deficiencies of protein C,protein S,antithrombin,Very rare,mutation,Genetic risk factors for venous thromboembolism,Protein S K196E,Tokyo,General population,Suita study at NCVC,VTE patients:,Sub-group of,Blood Coagulation Abnormality Study Group,Suita,Osaka,NCVC,Osaka U,Nagoya U,Jichi Med U,Keio Univ,Kyoto Pref Med U,About 170 Japanese VTE patients,Case-control study for,VTE,more than 3,500 individuals from,a general population randomly selected from Suita city residents,Kimura et al.,Blood,2006,VTE,139,20,1,160,0.069,3290,332,17,3639,0.050,2.179,0.336,Pro,Ser,Major homo,Hetero,Minor homo,Total,MAF,Major homo,Hetero,Minor homo,Total,MAF,2,P,Major allele,Minor allele,General population(Suita study),152,9,0,161,0.028,3501,149,0,3650,0.020,0.987,0.320,Ala,Thr,146,13,2,161,0.053,3585,66,0,3651,0.009,75.464,T,61,69,30,160,0.403,1468,1686,497,3651,0.367,3.402,0.183,4G,5G,ADAMTS13,P475S,PLG,A620T,PS K196E,63,75,23,161,0.376,1513,1651,486,3650,0.359,0.372,0.830,T,C,PAI-1,4G/5G,MAF:minor allele frequency,Case-control association study,using Japanese VTE patients,Protein S K196E as a Risk for VTE,Population,based-control,n(%),Geno-,types,VTE,group,n(%),Protein S,K196E,(Protein S,Tokushima),KK,KE,EE,Total,KK,KE+EE,total,3585(98.2),66(1.8),0(0.0),3651(100.0),3585(98.2),66(1.8),3651(100.0),2,=75.464,P0.0001,2,=41.807,P0.0001 OR=5.58(95%CI 2.90-9.46),146(90.7),13(8.1),2(1.2),161(100.0),146(90.7),15(9.3),161(100.0),OR:odds ratio,CI:confidence interval,Gla,EGF-like 1-4,Sex hormone-binding,globulin,635 aa,Protein S K196E,Protein S Tokushima,Lys196Glu,PS K196E mutation has been identified in Japanese DVT patients in 1993 by two independent groups.,This mutation was referred to as protein S Tokushima.,It is present in the second EGF-like domain of protein S.,In vitro,study showed that this mutant exhibits the loss of the APC cofactor activity and the prothrombinase inhibitory activity.,Yamazaki et al,1993,Shigekiyo et al,1993,Hayashi et al,1994,Tokyo,Nagoya U,3 hetero/182 individuals,Heterozygosity:1.65%,Allele freq.:0.82%,Kyushu U,5 hetero/304 individuals,Heterozygosity:1.64%,Allele freq.:0.82%,Geographical distribution of,PROS1,K196E mutation,Natl Cardio Vasc Ctr at Suita,66 heterozygotes/3,651 individuals,Heterozygosity:1.81%,Allele freq.:0.90%,Heterozygotes,N=34,Wild-types,N=1,828,Staclot Protein S,(Diagnostica Stago),Protein S activity in wild-type and K196E heterozygous individuals,71.9+/-17.6%,87.9+/-19.8%,Protein S activity,P0.0001,Kimura et al.,JTH,4,2010-2013,2006,Acquired factors influencing plasma protein S activity,Gender and age dependency of plasma protein S levels,Sakata et al,JTH 2004,Men,N=1252,Women,N=1438,30,40,50,60,70,80,140,120,100,80,60,Protein S activity(%),Age band,Age,Gender,Pregnancy,Oral contraceptives,Anticoagulant drugs,DIC,Liver diseases,Kidney disease,PROS1,K196E mutation is a genetic risk factor for venous,thromboembolism,(VTE)in Japanese.,A,missense,mutation causing Lys196 to be replaced by,Glu,is located within the 2,nd,EGF-like domain.,The odds ratio of the mutant E allele for VTE was 5.58.,Individuals heterozygous for the mutant E-allele had lower(mean 16%)plasma protein S activity than,wildtype,subjects.,PROS1,K196E,Kimura et al.,Blood,2006,Kimura et al.,JTH 2006,Miyata et al.,IJH 2006,The allelic frequency of the E allele was 0.9%.We estimated a total of as many as 10,000 Japanese as,homozygotes,.,A substantial proportion of the Japanese population carries the,PROS1,E allele and is at risk of developing VTE.,Therefore,individuals with the,PROS1,E allele should avoid environmental risk factors known to be associated with VTE.,PROS1,K196E,cont.,Kimura et al.,Blood,2006,Kimura et al.,JTH 2006,Miyata et al.,IJH 2006,Caucasian,Japanese,Factor V Leiden,Pr