摘要
背景与目的:
脑血管病是当今世界公认的三大主要疾病死因之一,脑出血(Cerebral hemorrhage,CH)占其中10～55%,其病死率、致残率高,严重危害人类健康。脑出血的病理机制复杂。目前认为,脑出血主要是由于多个易感基因的单核苷酸多态性(single nucleotidespolymorphisms,SNPs)微效作用的累加,并与环境因素共同作用而发病。对脑出血候选基因SNPs的研究将有助于阐明脑出血的遗传本质,为脑出血易感患者的早期检出和预防提供坚实的理论依据和实践指导。
动脉粥样硬化是脑出血的危险因素。而极低密度脂蛋白(Very lowdensity lipoprotein,VLDL)及低密度脂蛋白(Low density lipoprotein,LDL)是目前公认的重要致动脉粥样硬化因子,内源性VLDL/LDL代谢途径失调节,可能导致VLDL/LDL水平升高及动脉粥样硬化,增加脑出血的风险。迄今,有关VLDL/LDL代谢途径相关基因与脑出血的关系国内外少见报道。本研究旨在探讨该途径载脂蛋白AⅠ-CⅢ-AⅣ(Apolipoprotein AⅠ-CⅢ-AⅣ,ApoAⅠ-CⅢ-AⅣ),载脂蛋白B(Apolipoprotein B,ApoB)、脂蛋白脂酶(Lipoprotein lipase,LPL)、低密度脂蛋白受体(Low density lipoprotein receptor,LDLR)、人类枯草溶菌素转化酶9(Proprotein convertase subtilisin/kexin type 9,PCSK9)基因与长沙地区汉族人群脑出血的关系。
方法:
研究对象均来自长沙地区汉族人群,包括:1.有家族聚集现象的脑出血家系组(cerebral hemorrhage with family history,CHFH):共38个家系,包括家系成员200例,分为以下亚组:①家系组脑出血患者组:61例,男34例女27例,平均年龄53.26±10.60岁。②Ⅰ级亲属组:95例,男50例,女45例,平均年龄51.15±14.45岁。③Ⅱ级亲属组:23例,男9例女14例,平均年龄36.82±18.68岁。④健康无血缘关系亲属:共21例,男12例女9例,平均年龄52.32±12.74岁,来自家系中与先证者无血缘关系的家庭成员,为先证者及其Ⅰ、Ⅱ级亲属的配偶。2.散发性脑出血(Sporadic cerebralhemorrhage,SCH)组:273例,男138例,女135例,平均年龄55.38±12.08岁。3.正常对照(control)组:140例,其中男74例,女66例,平均年龄53.62±13.28岁。
血脂的检测:采用氧化酶法测定甘油三脂(Triglyceride,TG)、总胆固醇(Total cholesterol,TC);测定高密度脂蛋白(High densitylipoprotein,HDL)先用沉淀剂沉淀,再用氧化酶法测定上清液中的胆固醇;低密度脂蛋白(Low density lipoprotein,LDL)由Friedwald公式:LDL=(CHO-HDL)-TG/5计算。
基因分型:利用多重单碱基延伸技术与DNA测序结合相互印证的方法检测所有研究对象VLDL/LDL代谢途径5个基因12个SNPs位点多态性,包括:ApoAⅠ-CⅢ-AⅣ基因rs12721026、rs2854116、rs45487004、rs670,ApoB基因rs1367117、rs11279109,LPL基因rs320,LDLR基因rs2569542、rs688、rs5925,PCSK9基因rs11206510、rs505151。
统计:采用SPSS软件对散发性脑出血与正常对照组进行统计分析,两组间基因型与等位基因频率的差异用x~2检验,不同基因型亚组间血脂比较采用ANOVA方差分析。采用FBAT软件对有家族聚集现象脑出血家系的多态性位点及其构建的单体型进行传递不平衡检验(Transmission disequilibrium test,TDT)。
结果:
1.①长沙地区汉族人群存在ApoAⅠ-CⅢ-AⅣ基因rs12721026、rs2854116、rs45487004、rs670位点多态性。②散发性脑出血组ApoAⅠ-CⅢ-AⅣ基因rs12721026、rs2854116、rs45487004、rs670多态各基因型及等位基因频率分布与对照组比较差异无统计学意义(P>0.05)。③TDT分析未发现ApoAⅠ-CⅢ-AⅣ基因rs2854116、rs45487004、rs670多态性位点的等位基因存在传递不平衡现象(P>0.05)。④对rs12721026、rs2854116、rs45487004、rs670构成的单体型的TDT分析未发现单个特异单体型存在过度传递现象(P>0.05)。⑤散发性脑出血组及对照组rs12721026多态TT基因型亚组的HDL水平显著高于GT/GG基因型亚组(P<0.05),rs670多态AA基因型亚组的HDL水平显著高于GG、GA基因型亚组(P<0.05)。
2.①长沙地区汉族人群apoB基因存在rs1367117、rs11279109位点多态性。②散发性脑出血组apoB基因rs1367117、rs11279109多态各基因型及等位基因频率分布与对照组比较差异无统计学意义(P>0.05)。⑧TDT分析未发现apoB基因rs1367117、rs11279109多态性位点的等位基因存在传递不平衡现象(P>0.05)。④对rs1367117、rs11279109构成的单体型的TDT分析未发现单个特异单体型存在过度传递现象(P>0.05)。⑤散发性脑出血组及对照组rs11279109多态DD/DI基因型亚组的TC水平显著高于Ⅱ基因型亚组(P<0.05),对照组rs1367117多态GA/AA基因型亚组的TC水平显著高于GG基因型亚组(P<0.05)。
3.①长沙地区汉族人群存在LPL基因rs320位点多态性。②散发性脑出血组与对照组的LPL基因rs320位点基因型分布有统计学差异(x~2=6.95,p=0.031),散发性脑出血组T等位基因频率显著高于对照组(x~2=5.05,p=0.025)。③TDT结果显示LPL基因rs320T等位基因传递显著增多(Z＝2.144,P=0.034)。④散发性脑出血组rs320位点TT/GT基因型亚组的TG水平显著高于GG基因型亚组(P<0.05)。
4.①长沙地区汉族人群LDLR基因存在rs2569542、rs688、rs5925位点多态性。②LDLR基因rs2569542、rs688、rs5925多态各基因型及等位基因频率分布与对照组比较差异无统计学意义(P>0.05)。③TDT分析未发现LDLR基因rs2569542、rs688、rs5925多态性位点的等位基因存在传递不平衡现象(P>0.05)。④对rs2569542、rs688、rs5925构成的单体型的TDT分析未发现单个特异单体型存在过度传递现象(P>0.05)。⑤散发性脑出血组及对照组LDLR基因rs2569542、rs688、rs5925位点不同基因型TG、TC、HDL及LDL水平无显著差异(P>0.05)。
5.①长沙地区汉族人群存在PCSK9基因rs11206510、rs505151位点多态性。②散发性脑出血组PCSK9基因rs11206510位点CC/CT基因型及C等位基因频率显著高于对照组(x~2=4.19,p=0.041;x~2=4.28,p=0.039)。散发性脑出血组rs505151位点基因型及等位基因频率分布与对照组比较差异无统计学意义(P>0.05)。③散发性脑出血组及对照组rs505151多态GA/GG基因型亚组的LDL水平显著高于AA基因型亚组(P<0.05)。
结论:
1.LPL基因rs320多态T等位基因、PCSK9基因rs11206510多态C等位基因可能与长沙汉族人群脑出血发病有关。
2.ApoAⅠ-CⅢ-AⅣ基因rs12721026、rs2854116、rs45487004、rs670,ApoB基因rs1367117、rs11279109,LDLR基因rs2569542、rs688、rs5925,PCSK9基因rs505151多态性可能与长沙汉族人群脑出血无关。
3.ApoAⅠ-CⅢ-AⅣ基因rs12721026、rs2854116、rs45487004、rs670,ApoB基因rs1367117、rs11279109,LDLR基因rs2569542、rs688、rs5925位点构建的单体型可能与长沙汉族人群脑出血无关。
4.ApoAⅠ-CⅢ-AⅣ基因rs670、rs12721026,ApoB基因rs11279109、rs1367117,LPL基因rs320,PCSK9基因rs505151多态性可能与长沙汉族人群的血脂代谢有关。
Background and objective:
Cerebrovascular disease is among the three leading causes of death worldwide,of which cerebral hemorrhage(CH) represents 10%to 55% with high morbidity and disability.CH is a heterogeneous disease caused by different pathogenic mechanisms.There are probably many alleles with small effect sizes interacting with environmental factors. Identification of gene polymorphisms that confer susceptibility to CH and the development of genetic risk diagnosis systems may contribute to the personalized prevention of these conditions.
Atherosclerosis is an important risk factor of CH.It is acknowledged that very low density lipoprotein(VLDL) and Low density lipoprotein(LDL) are important risk factors for atherosclerosis. Imbalance disturbance of endogenous VLDL/LDL metabolic pathway may influence VLDL/LDL levels and the processe of atherosclerosis, which in turn may increase the risk of CH.The relationship between genes associated with endogenous VLDL/LDL metabolic pathway and CH has been rarely reported.The aim is to study the relationship between genes associated with endogenous VLDL/LDL metabolic pathway and CH in Han people of Changsha area,which include apolipoprotein AⅠ-CⅢ-AⅣ(ApoAⅠ-CⅢ-AⅣ),apolipoprotein B(ApoB),lipoprotein lipase(LPL),low density lipoprotein receptor(LDLR),and proprotein convertase subtilisin/kexin type 9(PCSK9) genes.
Methods:
All subjects came from Changsha Han population which were composed of 3 groups:(1) 200 members of 38 family with CH aggregation,including:①61 CH patients with family history:34 men and 27 women,averagely aged 53.26±10.60 years;②95 first-degree relatives:50 men and 45 women,averagely aged 51.15±14.45 years;③23 second-degree relatives:9 men and 14 women,averagely aged 36.82±18.68 years;④21 relatives with no kinship with proband:12 men and 9 women,averagely aged 52.32±12.74 years,who are spouses of the proband or the first-degree and second-degree relatives.(2)Sporadic cerebral hemorrhage(SCH) group:273 patients with sporadic cerebral hemorrhage,138 men and 135 women,averagely aged 55.38±12.08 years.(3) Control group:140 healthy controls,74 men and 66 women, averagely aged 53.62±13.28 years.
Serum lipid levels were tested:Total cholesterol(TC),High density lipoprotein(HDL) and triglycerides(TG) were mesured by standard enzymatic methods.LDL cholesterol levels were calculated with the Friedewald formula(LDL=TC-HDL-TG/5).
Multiplex SNaPshot genotyping analysis and DNA sequencing were used to detect 12 SNPs in 5 genes associated with endogenous VLDL/LDL metabolism of all subjects,including:rs12721026、rs2854116、rs45487004、rs670 of Apo AⅠ-CⅢ-AⅣgene,rs1367117、rs11279109 of ApoB gene,rs320 of LPL gene,rs2569542、rs688、rs5925 of LDLR gene and rs11206510、rs505151 of PCSK9 gene.
The frequencies of the alleles and genotypes between the SCH group and control group were analyzed by x~2 analysis,and lipid levels were compared among genotypes by ANOVA using SPSS.The SNP and haplotype transmissions of the CH pedigrees were analyzed by transmission disequilibrium test(TDT) using FBAT computer program.
Results:
1.①There are apoAⅠ-CⅢ-AⅣgene rs12721026,rs2854116, rs45487004 and rs670 polymorphisms in Changsha Han population.②There is no significant difference of genotype and alleles frequencies of rs12721026,rs2854116,rs45487004 and rs670 between SCH group and control group(P＞0.05).③Application of TDT to genotype data from rs12721026,rs2854116,rs45487004 and rs670 polymorphisms revealed no evidence for transmission disequilibrium with CH(P＞0.05).④Haplotype analysis of rs12721026,rs2854116,rs45487004 and rs670 revealed no evidence for transmission disequilibrium with CH(P＞0.05).⑤Both in SCH group and in control group,the levels of HDL of the TT gene type of rs12721026 were significantly higer than that of the GT/GG gene type(p＜0.05),while the levels of HDL of the AA gene type of rs670 were significantly higer than those of the GG、GA gene type.
2.①There are ApoB gene rs1367117 and rs11279109 polymorphisms in Changsha Han population.②There is no significant difference of genotype and alleles frequencies of rs1367117 and rs11279109 between SCH group and control group(P＞0.05).③Application of TDT to genotype data from rs1367117 and rs11279109 polymorphisms revealed no evidence for transmission disequilibrium with CH(P＞0.05).④Haplotype analysis of rs1367117 and rs11279109 revealed no evidence for transmission disequilibrium with CH(P＞0.05).⑤Both in SCH group and in control group,the levels of TC of the DD/DI gene type of rs11279109 were significantly higer than those of theⅡgene type,while the levels of TC of the GA/AA gene type of rs1367117 were significantly higer than that of the GG gene type(p＜0.05).
3.①There are LPL gene rs320 polymorphism in Changsha Han population.②There is significant difference of genotype of rs320 between SCH group and control group(x~2=6.95,p=0.031).The frequencies of T allele were significantly higher in SCH group than these in control group(x~2=5.05,p=0.025).③TDT analysis revealed that the frequency of transmission(from parent to the offspring with CH) of alleles C of rs320 polymorphism in CH increased significantly(Z=2.144, p=0.034).④The levels of TG of the TT/GT gene type of rs320 in SCH group was significantly higer than that of the GG gene type(p＜0.05).
4.①There are LDLR gene rs2569542,rs688 and rs5925 polymorphisms in Changsha Han population.②There is no significant difference of genotype and alleles frequencies of rs2569542,rs688 and rs5925 polymorphisms between SCH group and control group(P＞0.05).③Application of TDT to genotype data from rs2569542,rs688 and rs5925 polymorphisms revealed no evidence for transmission disequilibrium with CH(P＞0.05).④Haplotype analysis of rs2569542, rs688 and rs5925 revealed no evidence for transmission disequilibrium with CH(P＞0.05).⑤There was no significant difference of levels of TG,TC,HDL and LDL of different gene types of rs2569542、rs688、rs5925 in SCH group and control group(p＜0.05).
5.①There are PCSK9 gene rs11206510 and rs505151 polymorphisms in Changsha Han population.②There is no significant difference of genotype and alleles frequencies of rs505151 between SCH group and control group(P＞0.05).The frequencies of CC/CT genotype and C allele of rs11206510 were significantly higher in SCH group than these in control group(x~2=4.19,p=0.041;x~2=4.28,p=0.039).③The levels of LDL of the GA/GG gene type of rs505151 were significantly higer than those of the AA gene type both in SCH group and in control group(p＜0.05).
Conclusions:
1.A allele in LPL gene rs11206510 polymorphism and C allele in PCSK9 gene rs11206510 polymorphism are associated with risks of CH in Changsha Han population.
2.There is no association of ApoAⅠ-CⅢ-AⅣgene rs12721026、rs2854116、rs45487004、rs670,apoB gene rs1367117、rs11279109, LDLR gene rs2569542、rs688、rs5925 and PCSK9 gene rs11206510 polymorphisms with CH in Changsha Han population.
3.There is no association of haplotypes of ApoAⅠ-CⅢ-AⅣgene rs12721026、rs2854116、rs45487004、rs670,ApoB gene rs1367117、rs11279109,LDLR gene rs2569542、rs688、rs5925 polymorphisms with CH in Changsha Han population.
4.ApoAⅠ-CⅢ-AⅣgene rs670、rs12721026,ApoB gene rs11279109、rs1367117,LPL gene rs320,PCSK9 gene rs505151 polymorphisms may be associated with lipid metabolism in Changsha Han population.
引文
[1] Woo D, Sauerbeck L, Khoury J, et al. Familial aggregation of stroke and intracerebral hemorrhage. Stroke 2000; 31:316.
[2] Polychronopoulos P, Gioldasis G, Ellul J, et al. Family history of stroke in stroke types and subtypes. J Neurol Sci 2002; 195:117 - 22.
[3] Alberts MJ, McCarron MO, Hoffmann KL, et al. Familial clustering of intracerebral hemorrhage: A prospective study in North Carolina. Neuroepidemiology 2002;21:18 - 21.
[4] S. Bak, et al., Genetic liability in stroke: a long-term follow-up study of Danish twins, Stroke 2002; 33 (3):769-774.
[5] Woo D, Sauerbeck LR, Kissela BM, et al. Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke 2002; 33:1190-1196.
[6] Kokubo Y, Chowdhury AH, Date C, et al. Age-dependent association of apolipoprotein E genotypes with stroke subtypes in a Japanese rural population. Stroke, 2000, 31(6):1299-1306.
[7] Sun L, Li Z, Zhang H, et al. Pentanucleotide TTTTA repeat polymorphism of apolipoprotein(a) gene and plasma lipoprotein(a) are associated with ischemic and hemorrhagic stroke in Chinese: a multicenter case-control study in China. stroke, 2003, 34(7): 1617-1622.
[8] Gemmati D, Serino ML, Ongaro A, et al. A common mutation in the gene for coagulation factor ⅩⅢ-A (VAL34Leu): a risk factor for primary intracerebral hemorrhage is protective against atherothrombotic diseases . Am J Hematol, 2001, 67(3): 183-188.
[9] Sazci A, Ergul E, Tuncer N, et al. Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C. Brain Res Bull, 2006," 71(l-3):45-50.
[10] Dou XF, Zhang HY, Huang XH, et al. Alpha-adducin gene G/W460 polymorphism is associated with intracerebral hemorrhage in Chinese.Zhonghua Yi Xue Za Zhi,2004,84(3):186-188.
[11]Yang QD,Niu Q,Zhou YH,et al.Incidence of cerebral hemorrhage in the Changsha community.A prospective study from 1986 to 2000.Cerebrovasc Dis,2004,17(4):303-313.
[12]杨期东,周艳宏,刘运海等.长沙社区人群脑卒中患者发病的监测研究.中华医学杂志.2003,83(4):302-5.
[13]He J,Micheal JK,Wu Z,et al.Stroke in the People's Repulic of China.1.Geographic variations in incidence and risk factors.Stroke 1995;26:2222-2227.
[14]全国血压抽样调查协作组.中国人群高血压患病率极其变化趋势.高血压杂志,1995,3(增刊):7-13.
[15]夏健,杨期东,杨期明等.载脂蛋白H基因多态性与脑卒中的相关性研究.中华医学杂志.2003 83(7):537-40.
[16]张乐,杨期东,曾艺等.载脂蛋白B基因C7673T突变与有家族聚集现象脑出血的相关.中华医学遗传学杂志.2008;25(2):145-9.
[17]Inagawa T.Risk factors for primary intracerebral hemorrhage in patients in Izumo City,Japan.Neurosurg Rev.2007;30(3):225-34.
[18]Zhou JF,Wang JY,Luo YE,et al.Influence of hypertension,lipometabolism disorders,obesity and oth er lifestyles on spontaneous intracerebral hemorrhage.Biomed Environ Sci.2003;16(3):295-303.
[19]Cui R,Iso H,Toyoshima H,et al.Serum total cholesterol levels and risk of mortality from stroke and coronary heart disease in Japanese:the JACC study.Atherosclerosis.2007;194(2):415-20.
[20]Sturgeon JD,Folsom AR,Longstreth WT Jr,et al.Risk factors for intracerebral hemorrhage in a pooled prospective study.Stroke.2007;38(10):2718-25.
[21]Xu HW,Yuan N,Zhao Z,et al.Study of the relationship between gene polymorphisms of paraoxonase 2 and stroke in a Chinese population.Cerebrovasc Dis.2008;25(1-2):87-94.
[22]肖志杰,赵水平,聂赛等.老年脑出血患者对氧磷酯酶1基因192位Gln-Arg 多态性的研究.中华老年心脑血管病杂志,2004,6(5):326-328.
[23]王维治,罗祖明.神经病学,2005年第5版:146.
[24]Ruby C,Brain,hypertensive hemorrhage.Emedicine 2004.
[25]Fisher CM.Pathological observations in hypertensive cerebral hemorrhage.J Neuropathol Exp Neurol.1971;30:536-550.
[26]Edward M Manno,John L D Atkinson,Jimmy R Fulgham,et al.Emerging Medical and Surgical Management Strategies in the Evaluation and Treatment of intracerebral hemorrhage.Mayo Clinic Proceedings.2005;80,3:420-433
[27]Tamaki T,Oyama K,Uematsu M,et al.An ultrasonic study of the relationship between extracranial carotid atherosclerosis and intracerebral hemorrhage.No Shinkei Geka.2000;28(2):147-52.
[28]Mazighi M,Labreuche J,Gongora-Rivera F,et al.Autopsy prevalence of proximal extracranial atherosclerosis in patients with fatal stroke.Stroke.2009;40(3):713-8.
[29]Mazighi M,Labreuche J,Gongora-Rivera F,et al.Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke.Stroke.2008;39(4):1142-7.
[30]Zhang B,Miura SI,Yanagi D,et al.Reduction of charge-modified LDL by statin therapy in patients with CHD or CHD risk factors and elevated LDL-C levels:The SPECIAL Study.Atherosclerosis.2008;201:353-359.
[31]Zlatohlávek L,Zídková K,Vrablík M,et al.Lipoprotein(a) and its position among other risk factors of atherosclerosis.Physiol Res.2008;57(5):777-83.
[32]Altshuler D,Brooks LD,Chakravarti A,et al.Internation HapMap Consortium.A haplotype map of the human genome.Nature.2005;1299-1230.
[33]Stacey B,StePhen F,Nguyen H,et al.Tbe structure of haplotypeblocks in the human genome.Science.2002;296:2225-2229.
[34]David E,Cargill M,Bolk S,et al.Linkkage disequilibrium in the human genome.Nature.2001;411:199-204.
[35]Akey J,Jin L,Xiong M.Haplotypes VS single marker linkage disequilibrium tests:what do we gain? Eru J Hum Genet.2001;9(4):291-300.
[36]Zoliner S,yon Haeseler A.A coalescent approach to study linkage disequilibrium between single nucleotide polymorphisms.Am J Hum Genet. 2000; 66 (2):615-628.
[37] Ewens WJ, Spielman RS. The transmission/disequilibrium test: history, subdivision, and admixture. Am J Hum Genet. 1995; 57(2):455-64.
[38] Sandra Filippini, Ana Blanco, Ana Fernandez-Marmiesse, et al. Multiplex SNaPshot for detection of BRCA1/2 common mutations in Spanish and Spanish related breast/ovarian cancer families. BMC Med Genet. 2007; 8: 40.
[39] Frikke-Schmidt R, Nordestgaard BG, Schnohr P, et al. Single nucleotide polymorphism in the low-density lipoprotein receptor is associated with a threefold risk of stroke. A case-control and prospective study.Eur Heart J. 2004; 25(11):943-51.
[40] Guo Y, Guo J, Zheng D, et al. Relationship between the Nco I, Ava Ⅱ polymorphism of low density lipoprotein receptor gene and atherosclerotic cerebral infarction. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2002; 19(3):209-12.
[41] Salazar LA, Hirata MH, Giannini SD, et al. Effects of Ava Ⅱ and Hinc Ⅱ polymorphisms at the LDL receptor gene on serum lipid levels of Brazilian individuals with high risk for coronary heart disease. J Clin Lab Anal. 1999; 13(6):251-8.
[42] Kostulas K, Brophy VH, Moraitis K, et al. Genetic profile of ischemic cerebrovascular disease and carotid stenosis.Acta Neurol Scand. 2008; 118: 146-152.
[43] Parfenov MG. Polymorphism of apolipoprotein E (APOE) and lipoprotein lipase (LPL) genes and ischaemic stroke in individuals of Yakut ethnicity.J Neurol Sci. 2007; 255(l-2):42-9.
[44] Baum L, Ng HK, Wong KS, et al. Associations of apolipoprotein E exon 4 and lipoprotein lipase S447X polymorphisms with acute ischemic stroke and myocardial infarction. Clin Chem Lab Med. 2006; 44(3):274-81
[45] Shimo-Nakanishi Y, Urabe T, Hattori N, et al. Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese. Stroke. 2001 32(7):1481-6.
[46] Singh P, Singh M, Gaur S, et al. The ApoAⅠ-CⅢ-AⅣ gene cluster and its relation to lipid levels in type 2 diabetes mellitus and coronary heart disease: determination of a novel susceptible haplotype.Diab Vasc Dis Res. 2007; 4(2):124-9.
[47] Groenendijk M, Cantor RM, Funke H, et al. Two newly identified SNPs in the APO AⅠ-CⅢ intergenic region are strongly associated with familial combined hyperlipidaemia. Eur J Clin Invest. 2001; 31(10):852-9.
[48] Morcillo S, Cardona F, Rojo-Martinez G, et al. Association between MspI polymorphism of the APO AI gene and Type 2 diabetes mellitus.Diabet Med. 2005; 22(6):782-8.
[49] Wang L, Gu Y, Wu G, et al. A case control study on the distribution of apolipoprotein AI gene polymorphisms in the survivors of atherosclerosis cerebral infarction. Zhonghua Liu Xing Bing Xue Za Zhi. 2000; 21(l):22-5.
[50] Kasturi R, Yatsu FM, Alam R, et al. Stroke. Restriction fragment length polymorphism of the apoprotein A-Ⅰ-C-Ⅲ gene cluster in control and stroke-prone white and black subjects: racial differences. 1992; 23(9): 1257-64.
[51] Islam MS, Raitakari OT, Juonala M, et al. Apolipoprotein A-Ⅰ/C-Ⅲ/A-Ⅳ SstI and apolipoprotein B XbaI polymorphisms and their association with carotid artery intima-media thickness in the Finnish population. The Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2005; 180(l):79-86.
[52] N. Maeda, H. Li, D. Lee, et al. Targeted disruption of the apolipoprotein C-Ⅲ gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia. J. Biol. Chem. 1994; 269: 23610-23616.
[53] J. McConathy, J.C. Gesquiere, H. Bass, et al. Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C-III. J. Lipid Res. 1992; 33:995-1003.
[54] C.-S. Wang, J. McConathy, H.U. Kloer, et al. Modulation of lipoprotein lipase activity by apolipoproteins: effect of apolipoprotein CⅢ. J. Clin. Invest. 1985; 75: 384-390.
[55] Y. Ito, N. Azrolan, A. O'Connell, et al. Hypertriglyceridemia as a result of human apoCⅢ gene expression in transgenic mice. Science. 1990;249: 790-793.
[56] K.Fujimoto, J.A. Cardelli, P. Tso, et al. Increased apolipoprotein A-Ⅳ in rat mesenteric lymph after lipid meal acts as a physiological signal for satiation. Am. J. Physiol. 1992; 262:1002-G1006.
[57] P.H. Green, R.M. Glickman, J.W. Riley et al. Human apolipoprotein A-Ⅳ. Intestinal origin and distribution in plasma. J. Clin. Invest.1980; 65: 911-919.
[58] C.L. Bisgaier, O.P. Sachdev, L. Megna et al. Distribution of apolipoprotein A-Ⅳ in human plasma. J. Lipid Res. 1985; 26:11-25.
[59] K. Imaizumi, M. Fainaru, R.J. Havel. Composition of proteins of mesenteric lymph chylomicrons in the rat and alterations produced upon exposure of chylomicrons to blood serum and serum proteins. J. Lipid Res. 1978; 19:712-722.
[60] J.M. Ordovas, D.K. Cassidy, F. Civeira, et al. Familial apolipoprotein A-Ⅰ, C-Ⅲ, A-Ⅳ deficiency and premature atherosclerosis due to deletion of a gene complex on chromosome 11. J. Biol. Chem. 1989; 264:16339-16342.
[61] A.M. Gotto, Jr, H.J. Pownall et al. Introduction to the plasma lipoproteins. Methods Enzymol. 1986; 128:3-41.
[62] C.J. Fielding, V.G. Shore, P.E. Fielding, et al. A protein cofactor of lecithin: cholesterol acyltransferase. Biochem. Biophys. Res. Commun. 1972; 46: 1493-1498.
[63] A.K. Soutar, C.W. Garner, H.N. Baker et al., Effect of the human plasma apolipoproteins and phosphatidylcholine acyl donor on the activity of lecithin: cholesterol acyltransferase. Biochemistry. 1975; 14: 3057-3064.
[64] Cardona F, Tinahones FJ, Collantes E, et al. Contribution of polymorphisms in the apolipoprotein AⅠ-CⅢ-AⅣ cluster to hyperlipidaemia in patients with gout. Ann Rheum Dis. 2005; 64:85-88.
[65] Liu S, Song Y, Hu FB, et al. A prospective study of the APOA1 XmnI and APOC3 SstI polymorphisms in the APOA1/C3/A4 gene cluster and risk of incident myocardial infarction in men. Atherosclerosis. 2004; 177:119-126.
[66] Han Z, Heath SC, Shmulewitz D, et al. Candidate genes involved in cardiovascular risk factors by a family-based association study on the island of Kosrae, Federated States of Micronesia. Am J Med Genet. 2002; 110:234-242.
[67]Voors-Pette C,de Bruin TW.Excess coronary heart disease in Familial Combined Hyperlipidemia,in relation to genetic factors and central obesity.Atherosclerosis.2001;157:481-489.
[68]Waterworth DM,Ribalta J,Nicaud V,et al.ApoCⅢ gene variants modulate postprandial response to both glucose and fat tolerance tests.Circulation 1999;99:1872-1877.
[69]Wile DB,Barbir M,Gallagher J,et al.Apolipoprotein A-I gene polymorphisms:frequency in patients with coronary artery disease and healthy controls and association with serum apo A-I and HDL-cholesterol concentration.Atherosclerosis.1989;78:9-18.
[70]Shoulders CC,Harry PJ,Lagrost L,et al.Variation at the apo AI/CⅢ/AIV gene complex is associated with elevated plasma levels of apo CⅢ.Atherosclerosis 1991;87:239-247.
[71]Campbell DJ,Neal BC,Chalmers JP,et al.Low-density lipoprotein particles and risk of intracerebral haemorrhage in subjects with cerebrovascular disease.Eur J Cardiovasc Prev Rehabil.2007 14(3):413-8.
[72]芮凤,邵剑明,张雪英.急性脑出血中风与高血压和异常脂代谢关系的研究.浙江创伤外科.2003 8(2):79-81.
[73]张进,陆磊,施弘等,急性脑血管病与代谢紊乱的关系.上海医学.2003 26(1):35-58.
[74]万继峰,徐云燕,郝丽梅,等.92例脑出血患者血脂结果临床分析.2007年22期.
[75]芮凤,周君富,自发性脑出血与血压、脂代谢及不当生活方式的关系.中华急诊医学杂志.2003 12(12):833-835.
[76]杨南林,王晓兵.高血压性脑出血、血糖及血脂间的关系.高血压杂志.20056(13):129-130.
[77]J.M.Ordovas,E.J.Schaefer,D.Salem et al.,Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia.New Engl.J.Med.1986;314:671-677.
[78]A.Rees,J.Stocks,C.C.Shoulders,et al.DNA polymorphism adjacent to human apoprotein A-I gene:relation to hypertriglyceridaemia.Lancet.1983;1:444-446.
[79] J.M. Ordovas, F. Civeira, Jr J. Genest, et al. Restriction fragment length polymorphisms of the apolipoprotein A-Ⅰ, C-Ⅲ, A-Ⅳ gene locus. Relationships with lipids, apolipoproteins, and premature coronary artery disease. Atherosclerosis. 1991; 87:75-86.
[80] H. Paul-Hayase, M. Rosseneu, D. Robinson, et al. Polymorphisms in the apolipoprotein (apo) AⅡ-CⅢ-AⅣ gene cluster: detection of genetic variation determining plasma apo AⅠ, apo CⅢ and apo AⅣ concentrations. Hum. Genet. 1992; 88:439-446.
[81] A.M. Kessling, R. Taylor, A. Temple, et al. A PvuⅡ polymorphism in the 5' flanking region of the apolipoprotein A-Ⅳ gene: its use to study genetic variation determining serum lipid and apolipoprotein concentration. Hum. Genet. 1988; 78:237-239.
[82] A.M. Kessling, B. Horsthemke, S.E. Humphries, et al. A study of DNA polymorphisms around the human apolipoprotein AⅠ gene in hyperlipidemic and normal individuals. Clin. Genet. 1985; 28:296-306.
[83] J. Song, J.W. Park, H. Park, et al. Linkage disequilibrium of the apo AⅠ-CⅢ-AⅣ gene cluster and their relationship to plasma triglyceride, apolipoprotein AⅠ and CⅢ levels in Koreans. Mol. Cells. 1997; 8:12-18.
[84] Li WW, Dammerman MM, Smith JD, et al. Common genetic variation in the promoter of the human apo CⅢ gene abolishes regulation by insulin and may contribute to hypertriglyceridemia. J Clin Invest. 1995; 96:2601-2605.
[85] Ito Y, Azrolan N, O'Connell A, Walsh A, et al. Hypertriglyceridemia as a result of human apo CⅢ gene expression in transgenic mice. Science. 1990; 249:790-793.
[86] Dallongeville J, Meirhaeghe A, Cottel D, et al. Gender related association between genetic variations of APOC-Ⅲ gene and lipid and lipoprotein variables in northern France. Atherosclerosis. 2000; 150:149-157.
[87] Hegele RA, Connelly PW, Hanley AJ, et al. Common genomic variation in the APOC3 promoter associated with variation in plasma lipoproteins. Arterioscler Thromb Vasc Biol. 1997; 17:2753-2758.
[88] Waterworth DM, Talmud PJ, Bujac SR, et al. Contribution of apolipoprotein C-Ⅲ gene variants to determination of triglyceride levels and interaction with smoking in middle-aged men.Arterioscler Thromb Vasc Biol.2000;20:2663-2669.
[89]Pollex RL,Ban MR,Young TK,et al.Association between the -455T>C promoter polymorphism of the APOC3 gene and the metabolic syndrome in a multi-ethnic sample.BMC Med Genet.2007;8:80.
[90]Surguchov AP,Page GP,Smith L,et al.Polymorphic markers in apolipoprotein C-Ⅲ gene flanking regions and hypertfiglyc-fidemia.Arterioscler qhromb Vasc Biol.1996;16:941-947.
[91]刘合妮,李雪毪,张思仲.等APOC3基因SstI单核苷酸多态性与冠心病、Ⅱ型糖尿病合并高甘油三酯血症的关联性研究.遗传学报.2005,32:11-18.
[92]郭阳,郑东明,刘晓梅等.低密度脂蛋白受体基因NcoI、APOC-Ⅲ基因SacI多态性与动脉粥样硬化脑梗死.中国现代医学杂志,2006.16:641-644.
[93]Talmud PJ,Ye S,Humphries SE.Polymorphism in the promoter region of the apolipoprotein A I gene associated with diferences in apolipoprotein AI levels:the European Atherosclerosis Research Study.Genet Epidemiol.1994;11:265-280.
[94]Sadaf Siddiqui S,Lestringant GO,et al.Apolipoprotein AI promoter variant in blood presstwe determination Clin Genet.2002.61:314-316.
[95]邹阳春,胡大一,杨新春等.国人载脂蛋白A1基因多态性与血脂水平及冠心病的关系中国动脉硬化杂志,2003,11:345-348.
[96]王绿娅,顾云,吴桂贤等.脑梗死患者载脂蛋白基因多态性分布的病例对照研究.中华流行病学杂志,2000,21:22-25.
[97]Flood C,Gustafsson M,Pitas RE,et al.Molecular mechanism for changes in proteoglycan binding on compositional changes of the core and the surface of low-density lipoprotein-containing human apolipoprotein B100.Arterioscler Thromb Vasc Biol.2004;24(3):564-570.
[98]Kallel A,Jemaa R,Feki M,et al.XbaI polymorphism of apolipoprotein B gene in a Tunisian population:Alleles frequencies and relationship with plasma lipid parameters.Ann Biol Clin,2007;65:265-270.
[99]Scartezini M,Zago MA,Chautard-Freire-Maia E.A.,et al.The X-X-/E+E+ genotype of the XbaI/EcoRI polymorphisms of the apolipoprotein B gene as a marker of coronary artery disease in a Brazilian sample. Braz J Med Biol Res. 2003; 36: 369-375.
[100] Boekholdt SM, Peters RJ, Fountoulaki K, et al. Molecular variation at the apolipoprotein B gene locus in relation to lipids and cardiovascular disease: a systematic meta-analysis. Hum Genet. 2003; 113:417-425.
[101] Frossard PM, Obineche EN, Lestringant GG. Association of an apolipoprotein B gene marker with essential hypertension. Hypertension 1999; 33:1052-1056.
[102] Kallel A, Ben Ali S, Sediri Y, et al. Association of the insertion/deletion gene polymorphism of the apolipoprotein B signal peptide with myocardial infarction in Tunisian patients. Clin Chem Lab Med. 2008; 46:1097-1101.
[103] Hu ZY, Zhang L, Yang QD. Effect of apoB polymorphism on plasma lipid levels and cerebral hemorrhage in Changsha Han Chinese. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2008; 33(6):494-9.
[104] Gardemann A, Ohly D, Fink M, et al. Association of the insertion/deletion gene polymorphism of the apolipoprotein B signal peptide with myocardial infarction. Atherosclerosis. 1998; 141(1):167-75.
[105] Cavalli SA, Hirata MH, Salazar LA, et al. Apolipoprotein B gene polymorphisms: prevalence and impact on serum lipid concentrations in hypercholesterolemic individuals from Brazil. Clin Chim Acta. 2000; 302(1-2):189-203.
[106] Jemaa R, Mebazaa A, Fumeron F. Polymorphism insertion/deletion of apolipoprotein B gene: effect on lipid levels in obese patients. Ann Biol Clin (Paris). 2004; 62(2): 183-188.
[107] Jemaa R, Mebazaa A, Fumeron F. Apolipoprotein B signal peptide polymorphism and plasma LDL-cholesterol response to low-calorie diet. Int J Obes Relat Metab Disord. 2004; 28:902-905.
[108] M.L. Choong, E.S.C. Koay, M.C. Khaw, et al. Apolipoprotein B 5'-Ins/Del and 3'-VNTR Polymorphisms in Chinese, Malay and Indian Singaporeans. Hum Hered. 1999;49:31-40
[109] Boekholdt SM, Peters RJ, Fountoulaki K, et al. Molecular variation at the apolipoprotein B gene locus in relation to lipids and cardiovascular disease: a systematic meta-analysis. Hum Genet. 2003; 113(5):417-425.
[110] Rebhi L, Omezzine A, Kchok K, et al. 5' ins/del and 3' VNTR polymorphisms in the apolipoprotein B gene in relation to lipids and coronary artery disease. Clin Chem Lab Med. 2008; 46:329-334.
[111] Chiodini BD, Barlera S, Franzosi MG, et al. APOB gene polymorphisms and coronary artery disease: a meta-analysis. Atherosclerosis. 2003; 167(2): 355-366.
[112] Kallel A, Ben Ali S, Sediri Y, et al. Association of the insertion/deletion gene polymorphism of the apolipoprotein B signal peptide with myocardial infarction in Tunisian patients. Clin Chem Lab Med. 2008; 46:1097-1101.
[113] Gardemann A, Ohly D, Fink M, et al. Association of the insertion/deletion gene polymorphism of the apolipoprotein B signal peptide with myocardial infarction. Atherosclerosis. 1998; 141:167-175.
[114] Chatterton JE, Schlapfer P, Butler E, et al. Identification of apolipoprotein B100 polymorphisms that affect low-density lipoprotein metabolism: description of a new approach involving monoclonal antibodies and dynamic light scattering. Biochemistry. 1995; 34:9571-9580.
[115] Liljedahl U, Lind L, Kurland L, et al. Single nucleotide polymorphisms in the apolipoprotein B and low density lipoprotein receptor genes affect response to antihypertensive treatment. BMC Cardiovasc Disord. 2004; 4:16.
[116] Huang AQ, Hu YH, Xu B, et al. Association and linkage analysis between the S447X polymorphism of LPL gene and serum lipids, blood pressures in twins. Beijing Da Xue Xue Bao. 2005; 37:585-590.
[117] Yang W, Huang J, Ge D, et al. Lipoprotein lipase gene is in linkage with blood pressure phenotypes in Chinese pedigrees. Hum Genet. 2004; 115:8-12.
[118] Liu A, Lee L, Zhan S, et al. The S447X polymorphism of the lipoprotein lipase gene is associated with lipoprotein lipid and blood pressure levels in Chinese patients with essential hypertension. J Hypertens. 2004; 22:1503-1509.
[119] Li B, Ge D, Wang Y, et al. Lipoprotein lipase gene polymorphisms and blood pressure levels in the Northern Chinese Han population. Hypertens Res. 2004; 27:373-378.
[120] Du JK, Huang QY, Li SH, et al. Association of Hind RFLP in lipoprotein lipase gene with type 2 diabetes. Yi Chuan. 2007; 29:929-933.
[121] Jemaa R, Tuzet S, Portos C, Betoulle D, Apfelbaum M, Fumeron F. Lipoprotein lipase gene polymorphisms: associations with hypertrigly- ceridemia and body mass index in obese people. Int J Obes Relat Metab Disord. 1995; 19:270-274.
[122] Yamada Y, Matsuo H, Segawa T, et al. Assessment of genetic risk for myocardial infarction. Thromb Haemost. 2006; 96:220-227.
[123] Gambino R, Scaglione L, Alemanno N, et al. Human lipoprotein lipase HindⅢ polymorphism in young patients with myocardial infarction. Metabolism. 1999; 48:1157-1161.
[124] Zhao SP, Tong QG, Xiao ZJ, et al. The lipoprotein lipase Ser447Ter mutation and risk of stroke in the Chinese. Clin Chim Acta. 2003; 330:161-164.
[125] 林惠琼,李吕力,刘晓春,等.HindⅢ基因多态性与脑出血的关. 2006; 28:1860-1862.
[126] Hitsumoto T, Yoshinaga K, Aoyagi K, et al. Associationbetween preheparin serum lipoprotein lipase mass and acute myocardial infarction in Japanese men. J Atheroscler Thromb. 2002; 9:163-169.
[127] Hitsumoto T, Yoshinaga K, Noike H, et al. Clinical significance of preheparin serum lipoprotein lipase mass in coronary vasospasm. Jpn Circ J. 2001; 65(6):539-44.
[128] Tsutsumi K. Lipoprotein lipase and atherosclerosis. Curr Vasc Pharmacol. 20 03; 1:11-17.
[129] Wang SH, Cui HB, Wang DQ, et al. Geographical characteristics of single nucleotide polymorphism of candidate genes associated with coronary artery disease in Chinese Han population. Zhonghua Xin Xue Guan Bing Za Zhi 2008; 36:24-29.
[130] Zhang R, Liu Y, Yang LC, et al. Study on lipoprotein lipase gene Hind Ⅲ polymorphism in Chinese type Ⅱb hyperlipoproteinemia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2003; 20:539-541.
[131] Du JK, Huang QY, Li SH, et al. Association of Hind RFLP in lipoprotein lipase gene with type 2 diabetes. Yi Chuan. 2007; 29:929-933.
[132] Jemaa R, Tuzet S, Portos C, et al. Lipoprotein lipase gene polymorphisms: associations with hypertriglyceridemia and body mass index in obese people. Int J Obes Relat Metab Disord. 1995; 19:270-274.
[133] Socquard E, Durlach A, Clavel C, et al. Association of HindⅢ and PvuⅡ genetic polymorphisms of lipoprotein lipase with lipid metabolism and macrovascular events in type 2 diabetic patients. Diabetes Metab. 2006; 32:262-269.
[134] Shimo-Nakanishi Y, Urabe T, Hattori N, et al. Polymorphism of the lipoprotein lipase gene and risk of atherothrombotic cerebral infarction in the Japanese. Stroke. 2001; 3 2(7):1481-1486.
[135] Parfenov MG, Nikolaeva TY, Sudomoina MA, et al. Polymorphism of apolipoprotein E (APOE) and lipoprotein lipase (LPL) genes and ischaemic stroke in individuals of Yakut ethnicity. J Neurol Sci. 2007; 255:42-49.
[136] Laios E, Drogari E. Analysis of LDLR mutations in familial hypercholesterolemia patients in Greece by use of the NanoChip microelectronic array technology. Clin Chim Acta. 2006; 374:93-99.
[137] Vladimirova-Kitova LG, Deneva TI, Angelova E, et al. Role of some biomarkers of atherogenic risk in the screening for molecular defects in the low density lipoprotein receptor in severe hypercholesterolemia. Folia Med (Plovdiv). 2008; 50:14-22.
[138] Polisecki E, Muallem H, Maeda N, et al. Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER. Atherosclerosis. 2008; 200:109-114.
[139] Crawford DC, Nord AS, Badzioch MD, et al. A common VLDLR polymorphism interacts with APOE genotype in the prediction of carotid artery disease risk. J Lipid Res. 2008; 49:588-596.
[140] Pedersen JC, Berg K. Normal DNA polymorphism at the low density lipoprotein receptor (LDLR) locus associated with serum cholesterol level. Clin Genet. 1988; 34:306-312.
[141] Schuster H, Humphries S, Rauh G, et al. Association of DNA-haplotypes in the human LDL-receptor gene with normal serum cholesterol levels. Clin Genet. 1990; 38:401-409.
[142] Poledne R, Pisa Z, Berg K. Normal genetic variation at the low density lipoprotein receptor (LDLR) locus influences cholesterol levels in children. Clin Genet. 1993; 43:122-126.
[143] Salazar LA, Hirata MH, Giannini SD, et al. Seven DNA polymorphisms at the candidate genes of atherosclerosis in Brazilian women with angiographically documented coronary artery disease. Clin Chim Acta. 2000; 300:139-149.
[144] YI Ann, MI Kamboh, CE Aston, et al. Role of common genetic polymorphisms in the LDL receptor gene in affecting plasma cholesterol levels in the general population. Arteriosclerosis, Thrombosis, and Vascular Biology. 1994; 14: 663-670.
[145] Hansen PS, Defesche JC, Kastelein JJ, et al. Phenotypic variation in patients heterozygous for familial defective apolipoprotein B (FDB) in three European countries. Arterioscler Thromb Vasc Biol. 1997; 17:741-747.
[146] Mattevi VS, Coimbra CE, Jr., Santos RV, et al. Association of the low-density lipoprotein receptor gene with obesity in Native American populations. Hum Genet. 2000; 106:546-552.
[147] Hoppe C, Klitz W, Cheng S, et al. Gene interactions and stroke risk in children with sickle cell anemia. Blood. 2004; 103:2391-2396.
[148] Boright AP et al. Association and linkage of LDLR gene variation with variation in plasma low density lipoprotein cholesterol. J Hum Genet. 1998; 43: 153-159.
[149] Fu Y, Katsuya T, Higaki J, et al. A common mutation of low-density lipoprotein receptor gene is associated with essential hypertension among Japanese. J Hum Hypertens. 2001; 15:125-130.
[150] Cunningham D, Danley DE, Geoghegan KF, et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Naf Struct Mol Biol 2007; 14:413-419.
[151] Abboud S, Karhunen PJ, Lutjohann D, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke. PLoS ONE. 2007; 2:e1043.
[152] Anderson JL, Carlquist JF, Home BD, Hopkins PN. Progress in unraveling the genetics of coronary artery disease and myocardial infarction. Curr Atheroscler Rep. 2007; 9:179-186.
[153] Hsu LA, Teng MS, Ko YL, et al. The PCSK9 gene E670G polymorphism affects low-density lipoprotein cholesterol levels but is not a risk factor for coronary artery disease in ethnic Chinese in Taiwan. Clin Chem Lab Med. 2009; 47:154-158.
[154] Humphries SE, Whittall RA, Hubbart CS, et al. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet. 2006; 43:943-949.
[155] Maxwell K.N., Fisher E.A., Breslow J.L., et al. Over expression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Pcor NatlAcad Sci USA. 2005; 102 2069-2074.
[156] RashidS., CurtisD.E, GarutiR., et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Nalt Acad Sci USA. 2005; 102:5374-5379.
[157] Chen SN, Ballantyne CM, Gotto AM, Jr., et al. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J Am Coll Cardiol 2005; 45:1611-1619.
[158] Wilier, C.J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 2008; 40, 161-169.
[159] Kathiresan, S. et al. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N. Engl. J. Med. 2008; 358:2299-2300.
[160] Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 2008; 40: 189-197.
[161] Kathiresan S, Voight BF, Purcell S, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009; 41:334-341.
[1] CJL Murray and AD Lopez, Mortality by cause for eight regions of the world: global burden of disease study, Lancet. 1997; 349: 1269-12762
[2] CDA Wolfe, The impact of stroke, Br Med Bull. 2000; 56:275-286.
[3] Khan FA, Engstrom G, Jerntorp I, Pessah-Rasmussen H, Janzon L: Seasonal patterns of incidence and case fatality of stroke in Malmo,Sweden: the STROMA study. Neuroepidemiology. 2005; 24: 26-31.
[4] Anderson CS, Chakera TM, Stewart-Wynne EG, et al. Spectrum of primary intracerebral haemorrhage in Perth, Western Australia, 1989-90: incidence and outcome. J Neurol Neurosurg Psychiatry. 1994; 57: 936-940.
[5] Yang QD, Niu Q, Zhou YH, et al. Incidence of cerebral hemorrhage in the Changsha community. A prospective study from 1986 to 2000. Cerebrovasc Dis, 2004; 17(4): 303-313.
[6] S. Bak, et al., Genetic liability in stroke: a long-term follow-up study of Danish twins, Stroke. 2002; 33 (3) 769-774.
[7] Woo D, Sauerbeck LR, Kissela BM, et al. Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke. 2002; 33:1190-1196.
[8] Woo D, Sauerbeck L, Khoury J, et al. Familial aggregation of stroke and intracerebral hemorrhage. Stroke 2000; 31:316.
[9] Polychronopoulos P, Gioldasis G, Ellul J, et al. Family history of stroke in stroke types and subtypes. J Neurol Sci 2002; 195:117-22.
[10] Alberts MJ, McCarron MO, Hoffmann KL, et al. Familial clustering of intracerebral hemorrhage: A prospective study in North Carolina. Neuroepidemiology. 2002; 21:18-21.
[11] Brass LM, Isaacsohn JL, Merikangas AR. A study of twins and stroke. Stroke. 1992;23:221-3.
[12] Kato H, Suzuki H, Tajima S, et al. Angiotensin 2 stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens. 1991; 9:17-21.
[13] Farhy RD, Ho KL, Carretero OA, et al. Kinins mediate the antiproliferative effects of ramipril in rat carotid artery. Biochem Biophys Res Commun. 1992;182:283-288.
[14] Tiret L, Rigat B, Visvikis S, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992;51:197-205.
[15] Danser AHJ, Schalekamp MADH, Bax WA, et al. Angiotensin-converting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation. 1995; 92:1387-1388.
[16] Samani NJ, Thompson JR, O'Toole L, et al. A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. Circulation 1996;94:708-712.
[17] Sharma P. Meta-analysis of the ACE gene in ischemic stroke. J Neurol Neurosurg Psychiatry 1998;64:227-230.
[18] Mondry A, Loh M, Liu P, et al. Polymorphisms of the insertion / deletion ACE and M235T AGT genes and hypertension: surprising new findings and meta-analysis of data. BMC Nephrol. 2005 11;6(1):1.
[19] Wei X, Wang G, Jiang C, et al. Association between hypertensive cerebrovascular stroke and renin-angiotensin system gene polymorphism from Chinese cohort in Shanghai.Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2000;17(4):256-8.
[20] Nakata Y, Katsuya T, Rakugi H, et al.Polymorphism of angiotensin converting enzyme, angiotensinogen, and apolipoprotein E genes in a Japanese population with cerebrovascular disease. Am J Hypertens. 1997; 10:1391-5.
[21] Catto A, Carter AM, Barrett JH, et al. Angiotensin-converting enzyme insertion/deletion polymorphism and cerebrovascular disease. Stroke. 1996;27(3):435-40
[22] Slowik A, Turaj W, Dziedzic T, et al. DD genotype of ACE gene is a risk factor for intracerebral hemorrhage.Neurology.2004 27;63(2):359-23.
[23] Wang Y, Zhang W, Zhang Y, et al. VK0RC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection).Circulation. 2006; 113(12):1615-21.
[24] Anwar R, Miloszewki KJA. Factor ⅩⅢ deficiency. Br J Haematol. 1999; 107: 468-484.
[25] Board PG, Losowsky MS, Miloszewski KJ: Factor ⅩⅢ:Inherited and acquired deficiency. Blood Rev 7:229-242,1993
[26] Kohler HP, Ariens RA, Whitaker P, et al: A common coding polymorphism in the FⅩⅢ A-subunit gene (FⅩⅢVal34Leu) affects cross-linking activity. Thromb Haemost 80:704, 1998
[27] Kangsadalampai S, Board PG. The Val34Leu polymorphism in the A subunit of coagulation factor ⅩⅢ contributes to the large normal range in activity and demonstrates that the activation peptide plays a role in catalytic activity. Blood 1998; 92:2766-2770.
[28] Anwar R, Gallivan L, Edmonds SD, et al. Genotype/phenotype correlations for coagulation factor ⅩⅢ: Specific normal polymorphisms are associated with high or low factor ⅩⅢ specific activity. Blood 1999; 93:897-905.
[29] Catto AJ, Kohler HE Coore J, et al: Association of a common polymorphism in the factor ⅩⅢ gene with venous thrombosis. Blood 1999;93:906-908.
[30] Gemmati D, Serino ML, Ongaro A, et al. A common mutation in the gene for coagulation factor ⅩⅢ-A (VAL34Leu): a risk factor for primary intracerebral hemorrhage is protective against atherothrombotic diseases. Am J Hematol. 2001;67(3):183-8.
[31] Franco RF, Pazin-Filho A, Tavella MH, et al. Factor ⅩⅢ va1341eu and the risk of myocardial infarction. Haematologica 2000;85:67-71.
[32] Atti(?)-Castro FA, Zago MA, Lavinha J, et al. Ethnic heterogeneity of the factor ⅩⅢ Val34Leu polymorphism. Thromb Haemost. 2000; 84(4):601-3.
[33] Catto AJ, Kohler HP, Barnnan S, et al. Factor ⅩⅢ Val 34 Leu: a novel association wit h primary int racerebral hemorrhage. Stroke. 1998; 29:813-816.
[34] Corral J, Iniesta JA, Gonzalez-Conejero R, et al. Factor ⅩⅢ Val34Leu polymorphism in primary intracerebral haemorrhage Hematol J. 2000;1(4):269-73.
[35] Endler G, Funk M, Haering D, et al. Is the factor ⅩⅢ 34Val/Leu polymorphism a protective factor for cerebrovascular disease? Br J Haematol. 2003; 120(2):310-4.
[36] Reiner AP, Schwartz SM, Frank MB, et al. Poly- rphisms of coagulation factor ⅩⅢ subunit A and risk of nonfatal hemorrhagic stroke in young white women. Stroke. 2001 ;32:2580-2587
[37] Imaizumi T, Stafforini DM, Yamada Y, et al. Platelet-activating factor: a mediator for clinicians. J Intern Med. 1995; 238:5-20.
[38] Braquet P, Spinnewyn B, Demerle C, et al. The role of platelet-activating factor in cerebral ischemic and related disorders. Ann NY Acad Sci. 1989; 559:296-312.
[39] Lindsberg PJ, Yue T-L, Frericks KU, et al. Evidence for platelet-activating factor as a novel mediator in experimental stroke in rabbits. Stroke. 1990;21:1452-1457.
[40] Stafforini DM , Satoh K, At kinson DL , et al . Platelet-activating factor acetylhydrolase deficiency. missense mutation near the active site of an antiinflammatory phospholipase. J Clin Invest. 1996; 97 (12) :2784-2791.
[41] Hiramoto M, Yoshida H, Imaizumi T, et al. A mutation in plasma platelet-activating factor acetylhydrolase (Val279-~Phe) is a genetic risk factor for stroke. Stroke 1997; 28:2417-2420.
[42] Yoshida H, Imaizumi T, Fujimoto K, et al. A mutation in plasma platelet-activating factor acetylhydrolase (Val279Phe) is a genetic risk factor for cerebral hemorrhage but not for hypertension. Thromb Haemost. 1998; 80(3):372-5.
[43] Mariani G, Lo Coco L, Bernardi F, et al. Molecular and clinical aspects of factor Ⅶ deficiency. Blood Coagul Fibrinolysis. 1998;9:83-88
[44] Doggen CJ, Manger Cats V, Bertina RM, et al. A genetic propensity to high factor Ⅶ is not associated with the risk of myocardial infarction in men. Thromb Haemost. 1998;80:281-285
[45] Martinelli N, Trabetti E, Pinotti M, et al.Combined effect of hemostatic gene polymorphisms and the risk of myocardial infarction in patients with advanced coronary atherosclerosis. PLoS ONE. 2008; 3(2): 1523.
[46] Girelli D, Russo C, Ferraresi P, et al. Polymorphisms in the factor Ⅶ gene and the risk of myocardial infarction in patients with coronary artery disease. N Engl J Med. 2000; 343:774-780.
[47] Corral J, Iniesta JA, Gonzalez-Conejero R, et al. Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage. Blood. 2001;97(10):2979-82.
[48] Greisenegger S, Weber M, Funk M, et al. Polymorphisms in the coagulation factor Ⅶ gene and risk of primary intracerebral hemorrhage. Eur J Neurol. 2007;14(10):1098-101.
[49] Corral J, Iniesta JA, Gonzalez-Conejero R, et al. Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage. Blood. 2001;97(10):2979-82.
[50] Navarro-Nunez L, Lozano ML, Rivera J, et al. The association of the betal-tubulin Q43P polymorphism with intracerebral hemorrhage in men. Haematologica. 2007;92(4):513-8
[51] Reiner AP, Kumar PN, Schwartz SM, et al. Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke. 2000;31(7):1628-33.
[52] Iniesta JA, Corral J, Gonzalez-Conejero R, et al. Polymorphisms of platelet adhesive receptors: do they play a role in primary intracerebral hemorrhage? Cerebrovasc Dis. 2003;15(l-2):51-5.
[53] Li Z, Sun L, Zhang H, et al. Multicenter Case-Control Study in China.Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke, but methylenetetrahydrofolate reductase gene C677T polymorphism was a risk factor for thrombotic stroke: a Multicenter Case-Control Study in China. Stroke. 2003;34(9):2085-90.
[54] K. Toyoda, T.Uwatoko, T. Shimada, N., et al. Recurrent small-artery disease in hyperhomocysteinemia: widowers'stroke syndrome? Intern. Med. 2004; 43:869-872.
[55] Dikmen M, Ozbabalik D, Gunes HV, et al. Acute stroke in relation to homocysteine and methylenetetrahydrofolate reductase gene polymorphisms. Acta Neurol Scand. 2006;113(5):307-14
[56] Sazci A, Ergul E, Tuncer N, et al. Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C.Brain Res Bull. 2006;71(l-3):45-50.
[57] Fang X, Namba H, Akamine S, et al. Methylenetetrahydrofolate reductase gene polymorphisms in patients with cerebral hemorrhage. Neurol Res. 2005; 27(1):73-6.
[58] 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 Clin Invest 1998; 102:1369-1376.
[59] Flex A, Gaetani E, Papaleo P, et al. Proinflammatory genetic profiles in subjects with history of ischemic stroke. Stroke 2004; 35:2270-2275.
[60] Greisenegger S, Endler G, Haering D, et al. The (-174) G/C polymorphism in the interleukin-6 gene is associated with the severity of acute cerebrovascular events. Thromb Res 2003; 110:181-186.
[61] Strand M, Soderstrom I, Wiklund PG, et al. Polymorphisms at the osteoprotegerin and interleukin-6 genes in relation to first-ever stroke .Cerebrovasc Dis. 2007; 24(5):418-25.
[62] Yamada Y, Metoki N, Yoshida H, et al. Genetic risk for ischemic and hemorrhagic stroke. Arterioscler Thromb Vasc Biol. 2006; 26(8): 1920-5.
[63] Burman D, Mente A, Hegele RA, et al. Relationship of the ApoE polymorphism to plasma lipid traits among South Asians, Chinese, and Europeans living in Canada.Atherosclerosis. 2009; 203:192-200.
[64] Masemola ML, Alberts M, Urdal P. Apolipoprotein E genotypes and their relation to lipid levels in a rural South African population. Scand J Public Health Suppl. 2007; 69:60-5.
[65] Sima A, Iordan A, Stancu C. Apolipoprotein E polymorphism-a risk factor for metabolic syndrome.Clin Chem Lab Med. 2007;45(9):1149-53.
[66] Graner M, Kahri J, Varpula M, et al. Apolipoprotein E polymorphism is associated with both carotid and coronary atherosclerosis in patients with coronary artery disease.Nutr Metab Cardiovasc Dis. 2008;18(4):271-7.
[67] Pezzini A, Grassi M, Del Zotto E, et al. Synergistic effect of apolipoprotein E polymorphisms and cigarette smoking on risk of ischemic stroke in young adults.Stroke. 2004; 35(2):438-42.
[68] Kolovou GD, Daskalova DCh, Hatzivassiliou M, et al. The epsilon 2 and 4 alleles of apolipoprotein E and ischemic vascular events in the Greek population-implications for the interpretation of similar studies.Angiology. 2003;54(l):51-8
[69] McCarron MO, Delong D, Alberts MJ. APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta- analysis.Neurology. 1999;53(6):1308-11.
[70] Kokubo Y, Chowdhury AH, Date C, et al. Age-dependent association of apolipoprotein E genotypes with stroke subtypes in a Japanese rural population. Stroke. 2000;31(6): 1299-306.
[71] Alberts MJ,Graffagnino C,Mclenny C,et al.Apolipoprotein E polymorphism and and survival from intracerebral haemorrhage. Lancet. 1995;346(8974):575.
[72] Woo D, Kaushal R, Chakraborty R, et al.Association of apolipoprotein E4 and haplotypes of the apolipoprotein E gene with lobar intracerebral hemorrhage. Stroke. 2005;36(9):1874-9..
[73] Tzourio C, Arima H, Harrap S, et al. APOE genotype, ethnicity, and the risk of cerebral hemorrhage.Neurology. 2008;70(16):1322-8
[74] Sudlow C, Martinez Gonzalez NA, et al. Dose apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls. Stroke. 2006;37(2):364-70.
[75] Martinez-Gonzalez NA, Sudlow CL. Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage.J Neurol Neurosurg Psychiatry. 2006;77(l2): 1329-35
[76] McCarron MO, Weir CJ, Muir KW, et al. Effect of apolipoprotein E genotype on in-hospital mortality following intracerebral haemorrhage. Acta Neurol Scand. 2003;107(2): 106-9.
[77] O'Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage.N Engl J Med. 2000;342(4):240-5
[78] Polz, E. & Kostner, G.M. The binding of P2-glycoprotein Ⅰ to human serum lipoproteins: Distribution among density fractions. FEBS Lett 1979; 102, 183- 186.
[79] Schousboe, I. β_2-glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway. Blood. 1985;66,1086- 1091.
[80] Schousboe, I. & Rasnussen, M.S. The effect of pVglycoprotein I on the dextran sulfate and sulfatide activation of the contact system (Hageman factor system) in the blood coagulation. Int. J. Biochem. 1988; 20, 787- 792.
[81] Jones, J.V., James, H., Tan, M.H. et al. Anti-phospholipid antibodies required β_2-glycoprotein Ⅰ (apolipoprotein H) as cofactor. J. Rhematol. 1992; 19, 1397- 1402.
[82] Mehdi, H., Aston, C.E., Sanghera, D.K., et al. Genetic variation in the apolipoprotein H (β_2-glycoprotein I) gene affects plasma apolipoprotein H concentrations. Hum. Genet. 1999;105, 63-71.
[83] Mehdi H, Manzi S, Desai P, et al. A functional polymorphism at the transcriptional initiation site in beta2-glycoprotein Ⅰ (apolipoprotein H) associated with reduced gene expression and lower plasma levels of beta2-glycoprotein I..Eur J Biochem. 2003;270(2):230-8.
[84] Xia J, Yang QD, Yang QM, et al. Apolipoprotein H gene polymorphisms and risk of primary cerebral hemorrhage in a Chinese population.Cerebrovasc Dis. 2004;17(2-3):197-203.
[85] Brazier L, Tiret L, Luc G, et al. Sequence polymorphisms in the apolipoprotein(a) gene and their association with lipoprotein(a) levels and myocardial infarction: the ECTIM Study. Atherosclerosis. 1999; 144: 323-333.
[86] Misirli H, Somay G, Ozbal N, et al. Relation of lipid and lipoprotein(a) to ischaemic stroke. J Clin Neurosci. 2002; 9: 127-132
[87] Wityk RJ, Kittner SJ, Jenner JL, et al. Lipoprotein(a) and the risk of ischemic stroke in young women. Atherosclerosis. 2000; 150: 389-396.
[88] Glader CA, Stegmayr B, Boman J, et al. Chlamydia pneumoniae antibodies and high lipoprotein(a) levels do not predict ischemic cerebral infarctions: results from a nested case-control study in northern Sweden. Stroke. 1999; 30: 2013-2018.
[89] Ridker PM, Stampfer MJ, Hennekens CH. Plasma concentration of lipoprotein(a) and the risk of future stroke. JAMA. 1995; 273: 1269-1273.
[90] Sun L, Li Z, Zhang H, Ma A, et al. Pentanucleotide TTTTA Repeat Polymorphism of Apolipoprotein(a) Gene and Plasma Lipoprotein(a) Are Associated With Ischemic and Hemorrhagic Stroke in Chinese Stroke. 2003;34:1617-1622
[91] Scholz M, Kraft HG, Lingenhel A, et al. Genetic control of lipoprotein(a) concentrations is different in Africans and Caucasians. Eur J Hum Genet. 1999; 7:169-178
[92] Trommsdorff M, Kochl S, Lingenhel A, et al. A pentanucleotide repeat polymorphism in the 5' control region of the apolipoprotein(a) gene is associated with lipoprotein(a) plasma concentrations in Caucasians. J Clin Invest. 1995; 96: 150-157.
[93] Schuit SC, de Jong FH, Stolk L, et al. Estrogen receptor a gene polymorphisms are associated with estradiol levels in postmenopausal women. Eur J Endocrinol 2005;153:327-334.
[94] Schuit SC, Oei HH, Witteman JC, et al. Estrogen receptor a gene polymorphisms and risk of myocardial infarction. JAMA. 2004;291:2969-2977.
[95] Ellis JA, Infantino T, Harrap SB. Sex-dependent association of blood pressure with oestrogen receptor genes ERα and ERβ. J Hypertens 2004;22:1127-1131.
[96] Nordstrom P, Glader CA, Dahlen G, et al. Oestrogen receptor a gene polymorphism is related to aortic valve sclerosis in postmenopausal women.J Intern Med 2003;254:140-146.
[97]Herrington DM,Howard TD,Hawkins GA,et al.Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease.N Engl J Med.2002;346:967-974.
[98]Herrington DM,Howard TD,Brosnihan KB,et al.Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein.Circulation.2002;105:1879-1882.
[99]Shearman AM,Cooper JA,Kotwinski PJ,et al.Estrogen receptor alpha gene variation and the risk of stroke.Stroke.2005 Oct;36(10):2281-2.
[100]Kjaergaard AD,Ellervik C,Tybjaerg-Hansen A,et al.Estrogen receptor alpha polymorphism and risk of cardiovascular disease,cancer,and hip fracture.Circulation.2007;115:861-871.
[101]Bos MJ,Schuit SC,Koudstaal PJ,et al.Variation in the estrogen receptor alpha gene and risk of stroke:the Rotterdam Study.Stroke.2008;39(4):1324-6.
[102]Strand M,S(o|¨)derstr(o|¨)m I,Wiklund PG,et al.Estrogen receptor alpha gene polymorphisms and first-ever intracerebral hemorrhage.Cerebrovasc Dis.2007;24(6):500-8
[103]Travis J,Salvesen GS.Human plasma proteinase inhibitors.Annu Rev Biochem 1983;52:655-709.
[104]Kamboh MI,Sanghera DK,Fenrrell RE,et al.APOE~*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism.Nat Genet 1995;10:486-488.
[105]Obach V,Revilla M,Vila N,et al.a1-Antichymotrypsin polymorphism.A risk factor for hemorrhagic stroke in normotensive subjects.Stroke.2001;32:2588-2591.
[106]Fu Y,Xie R,Wang Y,et al.Association between alpha-1-antichymotrypsin gene polymorphism and cerebral hemorrhage.Zhonghua Yi Xue Za Zhi.2002;82:915-917.
[107]Dardiotis E,Hadjigeorgiou GM,Dardioti M,et al.Alpha-1 antichymotrypsin gene signal peptide a/t polymorphism and primary intracerebral hemorrhage. EurNeurol. 2008;59(6):307-14.
[108]Pera J, Slowik A, Dziedzic T, Szczudlik A. SERPINA3 polymorphism is not associated with primary intracerebral hemorrhage in a Polish population. Stroke. 2006; 37(3):906-7.
[109] Alberts MJ, Davis JP, Graffagnino C, et al. Endoglin gene polymorphism as a risk factor for sporadic intracerebral hemorrhage.Ann Neurol. 1997;41(5):683-6.
[110]Pera J, Slowik A, Dziedzic T, et al. Glutathione peroxidase 1 C593T polymorphism is associated with lobar intracerebral hemorrhage.Cerebrovasc Dis. 2008;25(5):445-9.
[111] Yamada Y. Identification of genetic factors and development of genetic risk diagnosis systems for cardiovascular diseases and stroke. Circ J. 2006;70(10):1240-8.
[1]Kokubo Y,Chowdhury AH,Date C,et al.Age-dependent association of apolipoprotein E genotypes with stroke subtypes in a Japanese rural population.Stroke,2000,31(6):1299-1306.
[2]Banerjee I,Gupta V,Ganesh S,et al.Association of gene polymorphism with genetic susceptibility to stroke in Asian populations:a meta-analysis.J Hum Genet,2007,52(3):205-219.
[3]Sudlow C,Martinez Gonzalez NA,Kim J,et al.Dose apolipoprotein E genotype influence the risk of ischemic stroke,intracerebral hemorrhage,or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961cases and 17,965 controls.Stroke,2006,37(2):364-370.
[4]Martinez Gonzalez NA,Sudlow CL.Effects of apolipoprotein E genotype on outcome after ischaemic stroke,intracerebral haemorrhage and subarachnoid haemorrhage.J Neurol Neurosurg Psychiatry,2006,77(12):1329-1335.
[5]O'Donnell HC,Rosand J,Knudsen KA,et al.Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage.N Engl J Med,2000,342(4):240-245.
[6]Sun L,Li Z,Zhang H et al.Pentanucleotide TTTTA repeat polymorphism of apolipoprotein(a) gene and plasma lipoprotein(a) are associated with ischemic and hemorrhagic stroke in Chinese:a multicenter case-control study in China.stroke,2003,34(7):1617-1622.
[7]Xia J,Yang QD,Yang QM,et al.Apolipoprotein H gene polymorphisms and risk of primary cerebral hemorrhage in a Chinese population.Cerebrovasc Dis,2004,17(2-3):197-203.
[8]Gemmati D,Serino ML,Ongaro A,Tognazzo S,et al.A common mutation in the gene for coagulation factor ⅩⅢ-A(VAL34Leu):a risk factor for primary intracerebral hemorrhage is protective against atherothrombotic diseases.Am J Hematol,2001,67(3):183-188.
[9]李正仪,石少亭,陈崴.FⅩⅢA3种基因多态性与脑血管疾病的关系.中风 与神经疾病杂志,2005,22(2):100-103.
[10]Slowik A,Dziedzic T,Pera J.Coagulation factor ⅩⅢ VaI34Leu polymorphism in patients with small vessel disease or primary intracerebral hemorrhage.Cerebrovasc Dis,2005,19(3):165-170.
[11]Yoshida H,Imaizumi T,Fujimoto K,et al.A mutation in plasma platelet-activating factor acetylhydrolase(Va1279Phe)is a genetic risk factor for cerebral hemorrhage but not for hypertension.Thromb Haemost,1998,80(3):372-375.
[12]Turaj W,Dziedzic T,Haefele A.DD genotype of ACE gene is a risk factor for intracerebral hemorrhage.Neurology,2004,63(2):359-361.
[13]Alberts MJ.Stroke genetics update.Stroke,2003,34(2):342-344.
[14]徐希平,王朝曦,刘娜.Endoglin基因插入缺失多态性与脑出血的相关研究.中风与神经疾病杂志,2000,17(6):356-357.
[15]Li Z,Sun L,Zhang H,et al.Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke,but methylenetetrahydrofolate reductase gene C677T polymorphism was a risk factor for thrombotic stroke:a Multicenter Case-Control Study in China.Stroke.2003,34(9):2085-2090.
[16]Sazci A,Ergul E,Tuncer N,et al.Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke:Dual effect of MTHFR polymorphisms C677T and A1298C.Brain Res Bull,2006,71(1-3):45-50.
[17]Fang X,Namba H,Akamine S,etal.Methylenetetrahydrofolate reductase gene polymorphisms in patients with cerebral hemorrhage.Neurol Res,2005;27(1):73-76.
[18]Fu Y,Xie R,Wang Y,etal.Association between alpha-1-antichymotrypsin gene polymorphism and cerebral hemorrhage.Zhonghua Yi Xue Za Zhi,2002,82(13):915-917.
[19]Obach V,Revilla M,Vila N,et al.alpha(1)-polymorphism:a risk factor for hemorrhagic stroke in normotensive subjects.Stroke,2001,32(11):2588-2591.
[20]Dou XF,Zhang HY,Huang XH,etal.Alpha-adducin gene.G/W460polymorphism is associated with intracerebral hemorrhage in Chinese.Zhonghua Yi Xue Za Zhi,2004,84(3):186-188.