冠心病患者同型半胱氨酸代谢相关酶基因突变的研究及高同型半胱氨酸血症治疗的初步探讨
摘要
冠心病患者同型半胱氨酸代谢相关酶基因突变的研究及高同型半胱氨酸血症治疗的初步探讨
冠心病是一种多因素疾病，传统危险因素包括吸烟、高血压、高脂血症、糖尿病等，近年来发现高同型半胱氨酸血症(Hyperhomocysteinemia)可能是动脉粥样硬化和冠心病的一个重要危险因素。同型半胱氨酸可促进内皮细胞损伤；刺激血管平滑肌细胞增生和迁移；促进血小板粘附和聚集，激活各种血栓调节因子和凝血因子，并使机体纤溶活性下降；促进氧化低密度脂蛋白的形成，促进脂质沉积于动脉壁等。
同型半胱氨酸(Homocysteine，Hcy)在体内的代谢途径主要有两条，一是经胱硫醚缩合酶(Cystathionine β-synthase，CBS)作用与丝氨酸缩合为胱硫醚，以维生素B_6为辅因子；二是经甲硫氨酸合成酶(Methionine Synthase，MS)催化再甲基化为甲硫氨酸，甲基供体来源于5-甲基四氢叶酸，后者由5,10-甲烯四氢叶酸在其还原酶(Methylenetetrahydrofolate Reductase，MTHFR)作用下生成，需维生素B_(12)为辅因子。高同型半胱氨酸血症是由于代谢过程发生障碍所致，包括遗传即关键酶MTHFR、CBS、MS基因变异和环境营养即叶酸、维生素B_6、B_(12)缺乏两种因素。
血浆同型半胱氨酸水平在不同地域、不同人种间有所差异，我国人的情况尚缺乏了解。本课题进行了以下研究：
1．测定了冠心病患者血浆同型半胱氨酸水平，结果明显高于正常对照组(主要为北方汉族人)，不同年龄段、不同性别的患者组和正常组均有显著差异，患者组高同型半胱氨酸血症者占47.5％，正常对照组中占20.6％。并且
Mutation Study of Homocysteine Metabolism-related Enzyme Genes and Treatment of Hyperhomocystememia in Patients with
Coronary Heart Disease
The conventional risk factors for coronary heart disease (CHD) include smoking, hypertension, hyperlipidemia and diabetes mellitus. In recent years, hyperhomocysteinemia has received greater attention as a possible important risk factor for atherosclerosis and coronary artery disease. Homocysteine (Hcy) may cause endothelial cell injury, promote proliferation and migration of vascular smooth muscle cells, increase adhesiveness and aggregation of platelets, activate many factors involved in the clotting cascade and reduce antithrombin activity. It may lead to increase susceptibility of low density lipoprotein to oxidation that makes them more atherogenic.
Hcy is an intermediate during the metabolism of methionine. Then Hcy enters either the transsulfuration pathway or the remethylation cycle. In the former pathway, the vitamin B_6-dependent Cystathionine P-synthase (CBS) binds homocysteine to serine to form cystathionine. In the latter pathway, Hcy requires vitamin B_(12)-dependent Methionine Synthase (MS) to form methionine . Methylcobalamin and methyltetrahydrofolate serve as cofactor and cosubstrate for this enzyme. Methylenetetrahydrofolate Reductase (MTHFR) is also an essential enzyme in this cycle. The causes of hyperhomocysteinemia are multifactorial. Genetic factors include low activities of MTHFR, CBS and MS due to gene
冠心病是一种多因素疾病，传统危险因素包括吸烟、高血压、高脂血症、糖尿病等，近年来发现高同型半胱氨酸血症(Hyperhomocysteinemia)可能是动脉粥样硬化和冠心病的一个重要危险因素。同型半胱氨酸可促进内皮细胞损伤；刺激血管平滑肌细胞增生和迁移；促进血小板粘附和聚集，激活各种血栓调节因子和凝血因子，并使机体纤溶活性下降；促进氧化低密度脂蛋白的形成，促进脂质沉积于动脉壁等。
同型半胱氨酸(Homocysteine，Hcy)在体内的代谢途径主要有两条，一是经胱硫醚缩合酶(Cystathionine β-synthase，CBS)作用与丝氨酸缩合为胱硫醚，以维生素B_6为辅因子；二是经甲硫氨酸合成酶(Methionine Synthase，MS)催化再甲基化为甲硫氨酸，甲基供体来源于5-甲基四氢叶酸，后者由5,10-甲烯四氢叶酸在其还原酶(Methylenetetrahydrofolate Reductase，MTHFR)作用下生成，需维生素B_(12)为辅因子。高同型半胱氨酸血症是由于代谢过程发生障碍所致，包括遗传即关键酶MTHFR、CBS、MS基因变异和环境营养即叶酸、维生素B_6、B_(12)缺乏两种因素。
血浆同型半胱氨酸水平在不同地域、不同人种间有所差异，我国人的情况尚缺乏了解。本课题进行了以下研究：
1．测定了冠心病患者血浆同型半胱氨酸水平，结果明显高于正常对照组(主要为北方汉族人)，不同年龄段、不同性别的患者组和正常组均有显著差异，患者组高同型半胱氨酸血症者占47.5％，正常对照组中占20.6％。并且
Mutation Study of Homocysteine Metabolism-related Enzyme Genes and Treatment of Hyperhomocystememia in Patients with
Coronary Heart Disease
The conventional risk factors for coronary heart disease (CHD) include smoking, hypertension, hyperlipidemia and diabetes mellitus. In recent years, hyperhomocysteinemia has received greater attention as a possible important risk factor for atherosclerosis and coronary artery disease. Homocysteine (Hcy) may cause endothelial cell injury, promote proliferation and migration of vascular smooth muscle cells, increase adhesiveness and aggregation of platelets, activate many factors involved in the clotting cascade and reduce antithrombin activity. It may lead to increase susceptibility of low density lipoprotein to oxidation that makes them more atherogenic.
Hcy is an intermediate during the metabolism of methionine. Then Hcy enters either the transsulfuration pathway or the remethylation cycle. In the former pathway, the vitamin B_6-dependent Cystathionine P-synthase (CBS) binds homocysteine to serine to form cystathionine. In the latter pathway, Hcy requires vitamin B_(12)-dependent Methionine Synthase (MS) to form methionine . Methylcobalamin and methyltetrahydrofolate serve as cofactor and cosubstrate for this enzyme. Methylenetetrahydrofolate Reductase (MTHFR) is also an essential enzyme in this cycle. The causes of hyperhomocysteinemia are multifactorial. Genetic factors include low activities of MTHFR, CBS and MS due to gene
引文
1. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease—enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997; 17: 2074-20812. Ueland per M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med.1989;114:473-501
3. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157:2299-2308
4. Gallagher PM, Meleady R, Shields DC, et al. Homocysteine and risk of premature coronary heart disease. Circulation. 1996;94:2154-2158
5. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. JACC. 1996;27:517-527
6. Woo KS, Chook P, Young RP, Sanderson JE. New risk factor for coronary disease in Asia. Intern J Cardiology. 1997;62 Suppl 1:S39-S42
7. Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, Ji J, Otto JM,Taylor LM. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem.1994;40:873-881
8. Refsum H, Helland S, Ueland PM. Radioenzymic determination of homocysteine in plasma and urine. Clin Chem. 1985;31:624-628
9. McCully KS, Ragsdale BD. Production of arteriosclerosis by homocysteinemia.Am J Pathology. 1970;61:1-8
10. McCully KS. Vascular pathology of homocysteine: implications for the pathogenesis of arteriosclerosis. Am J Pathology. 1969;56:111-121
11. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet.1996;58:17-20
12. Evans, et al. Homocysteine and Cardiovascular disease in MRFTT study.Arterioscler Thromb Vasu Biol. 1997; 17:1946-1952
13. Evans RW, Shaten BJ, Hempel JD, et al. Homocysteine and risk of cardiovascular disease in the multiple risk factor intervention trial. Arterioscler Thromb Vasc Biol. 1997;17:1947-1953
14. Stehouwer CD, et al. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol. 1998;18:1895-1901
15. Kang SS, Wong PWK, Cook HY, Norusis M, Messer JV. Protein-bound homocysteine, a possible risk factor for coronary artery disease. J Clin Invest.1986,77:1482-148616. Stampfer J, Malinow MR, Wiilett WC, et al. Prospective study of plasma homocysteine and risk of myocardial infartion in US physicians. JAMA. 1992; 268: 877-881
17. Boushey CJ, Beresford SAA, Omenn GS, Motuisky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA. 1995; 274: 1049-1067
18. Arnesen E, Refsum H, Bonaa K, et al. Serum total homocysteine and coronary heart disease. Intern J Epidemiology. 1995; 24: 704-709
19. Gupta A, Moustapha A, Jacorsen DW, et al. High homocysteine, low folate, and low vitamin B_6 concentration. Transplantation. 1998; 65: 544-550
20. Fermo I, Vigano'D'Angeto S, Paroni R, et al. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med. 1995; 123: 747-753
21．黄其擎，惠汝太，张春玲，等．高压液相层析法测定血浆同型半胱氨酸及其初步应用．世界医学杂志．1999；3：50-52
22．汤佩麟，王毓明，李明珍，等．血浆高半胱氨酸水平和冠心病的关系．中国循环杂志．1997；12：324-326
23. Ueland per M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989; 114: 473-501
24. Boers GH, Smals AG, Trijbels FJ. et al. Unique efficiency of methionine metabolism in premenopausal woman may protect against vascular disease in the reproductive years. J Clin Invest. 1983; 72: 1971-1976
25. Montalescot G, et al. Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease. Int J Cardiol. 1997; 60: 295-300.
26. Malinow MR, et al. Plasma homocyst(e)ine levels and graded risk for myocardial infarction: findings in two populations at contrasting risk for coronary heart disease. Atherosclerosis. 1996; 126: 27-341. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157: 2299-23082. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. JACC. 1996; 27: 517-527
3. Goyette P, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nature Genet. 1994; 7: 195-200
4. Frosst P, Blom H J, Goyette MP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics. 1995; 10: 111-113
5. Schmitz C, Lindpaintner K, Verhoef P, Gaziano JM, Buring J. Genetic polymorphism of methylenetetrahydrofolate reductase and myocardial infartion. Circulation. 1996; 94: 1812-1814
6. Goyette P, ChristensenB, Rosenblatt DS, et al. Severe and mild mutations in cis for the methylenetetrahydrofolate reductase(MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet. 1996; 59: 1268-1275
7. Kang SS, Wong PWK, Bock HGO, Horwitz A, Grix A. Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Hum Genet. 1991; 48: 546-551
8. Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase(MTHFR). Thrombosis and Haemostasis. 1997; 78: 523-526
9. Weisberg H, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase(MTHFR) associated with decreased enzyme activity. Molecular Genetics and Metabolism. 1998; 64: 169-172
10. Arruda VR, Siqueira LH, Goncalves MS, et al. Prevalence of the mutation C677→T in the methylenetetrahydrofolate reductase gene among distinct groups in Brazil. Am J Med Genet. 1998; 78: 332-335
11. Matthews RG, Sheppard C, Goulding C. Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology. Eur J Pediatr. 1998; 157: S54-S59
12．朱慧萍．5，10-亚甲基四氢叶酸还原酶(MTHFR)基因与神经管畸形关系的研究．北京医科大学学位研究生论文(博士学位)1997年，12-17，35-37．
13. Wilcken DEL, Wang XL, Sim AS, McCredie M Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase(MTHFR) C677T mutation. Arterioscler Thromb Vasu Biol. 1996; 16: 878-88214 Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins. Circulation. 1998;98:204-210
15. Verhoef P, et al. A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among U.S. men. J Am Coll Cardiol. 1998;32:353-359.
16. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41
17. Morita HM, Taguchi J, Kurihara H, et al. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation. 1997;95:2032-2036
18. van Bockxmeer FM, Mamotte CDS, Vasikaran S, Taylor RR.Methylenetetrahydrofolate reductase gene and coronary artery disease.Circulation. 1997;95:21-23
19. Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infartion in US physicians. Circulation. 1996;94:2410-2416
20. Jacques PF, Bostom AG, Williams RR, Et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7-9
21. Samani NJ.Methylenetetrahydrofolate reductase mutation and coronary artery disease. Circulation. 1998;98:2932-2933
22 Gallagher PM, et al. Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation. Circulation. 1996;94:2154-2158
23 Kang SS, Wong PW, Bock HG, Horwitz A, Grix A. Intermediate hyperhomocysteinemia resulting from compound heterozygous of methylenetetrahydrofolate reductase mutations. Am J Hum Genet.1991;48:546-5511. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157: 2299-2308
2. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. JACC. 1996; 27: 517-527
3. Ueland per M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989; 114: 473-501
4. McCully KS. Vascular pathology of homocysteine: implications for the pathogenesis of arteriosclerosis. Am J Pathology. 1969; 56: 111-121
5. Tsai MY, Garg U, Key NS, et al. Molecular and biochemical approaches in the identification of heterozygous for homocystinuria. Atherosclerosis. 1996; 122: 69-77
6．曾溢滔主编．蛋白质和核酸遗传病．1981年，上海科学技术出版社
7. Wicken DEL, Reddy S, Gupta VJ. Homocysteinemia, ischemia heart disease,??and the carrier state for homocystinuria. Metabolism, 1983;32:363-370
8. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet.1996;58:17-20
9. Sebastio G, Sperandeo MP, Panico M, et al. The molecular basis of homocystinuria due to cystathionine β-synthase deficiency in Italian families, and report of four novel mutations. Am J Hum Genet. 1995;56:1324-1333
10 Tsai MY, Bigell M, Schwichtenberg K, Hanson NQ. High prevalence of a mutation in the cystathionine β-synthase gene. Am J Hum Genet.1996;59:1262-1267
11. Kluijtmans LAJ, Blom HJ, Boers GHJ, et al. Two novel missense mutations in the cystathionine β-synthase gene in homocystinuric patients. Hum Genet.1995;96:249-250
12. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41
13. Tsai MY, Hanson NQ, Schwichtenberg K, et al. Amplification refractory mutation system to identify mutations in cystathionine β-synthase deficiency.Clinical Chemistry. 1995;41:1775-1777
14. Shih VE, Fringer JM, Mandell R, et al. A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet.1995;57:34-39
1. Watkins D, Rosenblatt DS. Functional methionine synthase deficiency(cblE and cblG): clinical and biochemical heterogeneity. Am J Med Gen. 1989; 34: 427-434
2. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M, Eydoux P, Rosenblatt DS, Rozen R, Gravel RA. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Human Mol Gen. 1996; 5: 1867-1874
3. Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD. Cloning, mapping and RNA analysis of the human methionine synthasr gene. Human Mol genetics. 1996; 5: 1851-1858
4. Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, Shane B. Human methionine synthase—cDNA cloning, gene localization, and expression. J BioChem. 1997; 272: 3628-3634
5. Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC, Banerjee R. Defects in human methionine synthase in cbIG patients. Human Mol genetics. 1996; 5: 1859-1865
6. Jarrett JT, Amaratunga M, Drennan CL, Scholten JD, Sands RH, Ludwig ML, Matthews R. Mutations in the B 12-binding region of methionine synthase: how the protein controls methylcobalamin reactivity. Biochemistry. 1996; 35: 2464-??2475
7. Gulddberg P, Henriksen KF, Gutter F, et al. Molecular analysis of phenylketonuria in Fenmark: 99% of the mutations detected by denaturing gradient gel electrophoresis. Genomics. 1993; 17: 141
8. Delwart EL, Shaper EG, Louwagie J, et al. Genetic relationships determined by a DNA heteroduplex mobility assay: analysis of HIV-1 genes. Science. 1993; 82: 7575
9. Orita M, Iwahana H, Knazawa H, et al. Detection of polymorphisms of human DNA by gel electrophoresis as single strand conformation polymorphisms. Pro Natl Acad Sci. 1989; 86: 2766
10. Chrambach A, Rodbard R. Polyacrylamide gel electrophoresis. Science. 1971; 172: 440
11. Gaidano G, Ballerini P, Gong JZ, et al. Proc Natl Acad Sci USA. 1991; 88: 5413
12．赵蔚明，司静懿，于修平。PCR-SSCP分析技术及其在肿瘤学研究中的应用。国外医学肿瘤学分册 1995；22：133
13. van der Put NMJ, van der Molen EF, Kluijtmans LAJ, Heil SG, Trejbels JMF, Eskes TKAB, Oppenraaij-Emmerzaal DV, Bamerjee R, Blom HJ. Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteine in neural-tube defects and vascular disease. Q J Med. 1997; 90: 511-5171. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease—enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997; 17: 2074-2081
2. Rosenouist TH, Ratashak SA, Selhub J. Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci USA. 1996; 93: 15227-15232
3. Harker LA, Ross R, Slichteb SJ, Scott CR. Homocysteine-induced arteriosclerosis—the role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976; 58: 731-741
4. Malinow MR, Nieto F J, Kruger WD, Duell PB, Hess DL, Gluckman RA, Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. The Effects of folic acid supplementation on plasma total homocysteine are modulated by multiVitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997; 17: 1157-1162
5. Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infartion in US physicians. Circulation. 1996; 94: 2410-2416
6. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157: 2299-2308
7. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary??atherosclerosis. JACC. 1996;27:517-527
8. Woo KS, Chook P, Young RP, Sanderson JE. New risk factor for coronary disease in Asia. Intern J Cardiology. 1997;62 Suppl 1:S39-S42
9. Dalery K, et al. Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate. Am J Cardiol. 1995;75:1107-1111
10. Kluller LH, Evans RW. Homocysteine, vitamins, and cardiovascular disease.Circulation. 1998;98:196-199
11. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet.1996;58:17-20
12. Kang SS, Wong PWK. Genetic and nongenetic factors for moderate hyperhomocysteinemia. Atherosclerosis. 1996;119:135-138
13. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B-12,vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia.Am J Clin Nutr.1993;57:47-53
14 Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, Ji J,Otto JM,Taylor LM. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem.1994;40:873-881
15 Robinson K, Arheart K, Refsum H, Brattstrom L, Boers G, Ueland P, Rubba P,Palma-Reis R, Meleady R, Daly L, Witteman J, Graham I. Low circulating folate and vitamin B_6 concentrations — risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation. 1998;97:437-443
16. Ubbink JB, et al.Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem. 1995;41:1033-1037
17. Omenn GS, Beresford SAA, Motulsky AG. Preventing coronary heart disease---B vitamins and homocysteine. Circulation. 1998;97:421-424
18. Malinow MR, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med. 1998;338:1009-1015
19. Ward M,Mcnulty H, Mcpartlin J, Strain JJ, Weir DG, Scott JM. Plasma homocysteine, a risk factor for cardiovascalar disease, is lowed by physiological doses of folic acid. Q J Med. 1997;90:519-524
20. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Willians RR. Higher plasma homocysteine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vasc Biol.1995,15:1314-1320
21. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins Circulation. 1998;98:204-210
22. Jacques PF, Bostom AG, Williams RR, Et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations Circulation. 1996;93:7-9
23. Siri PW, et al. Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis. J Am Coll Nutr.1998;17:435-441
24. Robinson K, et al. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830
25. Bostom AG, et al. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis. 1995;116:147-151
1. McCully KS, Ragsdale BD. Production of arteriosclerosis by homocysteinemia. Am J Pathology. 1970; 61: 1-8
2. McCully KS. Vascular pathology of homocysteine: implications for the pathogenesis of arteriosclerosis. Am J Pathology. 1969; 56: 111-121
3. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157: 2299-2308
4. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary??atherosclerosis. JACC. 1996; 27: 517-527
5. Woo KS, Chook P, Young RP, Sanderson JE. New risk factor for coronary disease in Asia. Intern J Cardiology. 1997; 62 Suppl 1: S39-S42
6. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991; 324: 1149-1155
7. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998; 338: 1043-1052
8. Kang SS, Wong PWK. Genetic and nongenetic factors for moderate hyperhomocysteinemia. Atherosclerosis. 1996; 119: 135-138
9. Ueland per M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989; 114: 473-501
10. Boers GH. Hyperhomocysteinemia as a risk factor for arterial and venous disease. A review of evidence and relevance. Thromb Haemost. 1997; 78: 520-522
11. Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurence, cofactor therapy, and enzymology. Arterioscler Thromb. 1993; 13: 1253-1260
12. Ubbink JB, Vermank WJH, van der Merwe A, Beeker PJ. The effect of blood sample aging and food consumption on plasma total homocysteine levels. Clin Chim Acta. 1992; 207: 119-128
13. Refsum H, Helland S, Ueland PM. Radioenzymic determination of homocysteine in plasma and urine. Clin Chem. 1985; 31: 624-628
14. Franken DG, Boers GHJ, Blom HJ, Cruysberg JRM, Trijbels FJM, Hamel BCJ. Prevalence of familial mild hyperhomocysteinemia. Atherosclerosis. 1996; 125: 71-80
15．黄其擎，惠汝太，张春玲，等．高压液相层析法测定血浆同型半胱氨酸及其初步应用．世界医学杂志．1999；3：50-52
16. Jacobsen DW, Gatautis V J, Green R, Robinson K, Savon SR, Secic M, Ji J, Otto JM, Taylor LM. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem. 1994; 40: 873-881
17. Stabler SP, et al. Quantitation of total homocysteine, total cysteine, and methionine in normal serum and urine using capillary gas chromatography-??mass spectrometry. Anal Biochem. 1987; 162: 185-196
18. Gupta A, Moustapha A, Jacorsen DW, et al. High homocysteine, low folate, and low vitamin B_6 concentration. Transplantation. 1998; 65: 544-550
19. Fermo I, Vigano'D'Angeto S, Paroni R, et al. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med. 1995; 123: 747-753
20. Ubbink JB, Vermank H, Delport R, van der Merve A, Becker PJ, Potgieter H. Effective homocysteine metabolism may protect South African blacks against coronary heart disease. Am J Clin Nutr. 1995; 62: 802-808
21．汤佩麟，王毓明，李明珍，等．血浆高半胱氨酸水平和冠心病的关系．中国循环杂志．1997；12：324-326
22. Boers G, Smals AG, Trijbels FJ, et al. Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. J Clin Invest. 1983; 72: 1971-1976
23. Kang SS, Wong PWK, Cook HY, Norusis M, Messer JV. Protein-bound homocysteine, a possible risk factor for coronary artery disease. J Clin Invest. 1986; 77: 1482-1486
24. Nygard O, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA. 1995; 274: 1526-1533Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Willians RR. Higher plasma homocysteine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vase Biol. 1995; 15: 1314-1320
25. Durand P, Prost M, Blache D. Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity. Arterioscler Thromb Vase Biol. 1997; 17: 1939-1946
26. Nygard O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile: the Hordaland Homocysteine Study. JAMA. 1995; 274: 1526-1533
27. Vychytil A, Sunder-Plassmann G, Horl WH, Et al. Major determinants of hyperhomocysteinemia in peritoneal dialysis patients. Kidney Int. 1998; 53: 1775-1782
28. ChauveauP, Chadefaux B, Coude M, et al. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Intern. 1993; 43: S72-
29. Bostom AG, Selhub J, Rosenberg IH. et al. Excess prevalence of fasting and??postmethionine-loading hyperhomocysteinemia in stable renal transplant recipients. Arterioscler Thromb Vasc Biol. 1997; 17:1894-1900
30. Tsai MY, Garg U, Key NS, et al. Molecular and biochemical approaches in the identification of heterozygous for homocystinuria. Atherosclerosis.1996;122:69-77
31. 曾溢滔主编.蛋白质和核酸遗传病. 1981年,上海科学技术出版社
32. Sebastio G, Sperandeo MP, Panico M, et al. The molecular basis of homocystinuria due to cystathionine P-synthase deficiency in Italian families,and report of four novel mutations. Am J Hum Genet. 1995;56:1324-1333
33. Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thrombosis and Haemostasis.1997;78:523-526
34. Goyette P, Frosst P, Rosenblatt D, Rozen R. Seven novel mutation in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet. 1995;56:1052-1059
35. Wilcken DEL, Wang XL, Sim AS, McCredie M. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Arterioscler Thromb Vasu Biol. 1996; 16:878-882
36. Frosst P, Blom HJ, Goyette MP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.Nature Genetics. 1995;10:111-113
37. Tsai MY, Bigell M, Schwichtenberg K, Hanson NQ. High prevalence of a mutation in the cystathionine p-synthase gene. Am J Hum Genet.1996;59:1262-1267
38. Kluijtmans LAJ, Blom HJ, Boers GHJ, et al. Two novel missense mutations in the cystathionine P-synthase gene in homocystinuric patients. Hum Genet.1995;96:249-250
39. Sebastio G, Sperandeo MP, Panico M, et al. The molecular basis of homocystinuria due to cystathionine p-synthase deficiency in Italian families,and report of four novel mutations. Am J Hum Genet. 1995;56:1324-1333
40. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M,Eydoux P, Rosenblatt DS, Rozen R, Gravel RA. Human methionine synthase:cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Human Mol Gen.1996;5:1867-1874
41. Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD. Cloning,mapping and RNA analysis of the human methionine synthasr gene. Human Mol genetics. 1996;5:1851-1858
42. van der Put NMJ, van der Molen EF, Kluijtmans LAJ, Heil SG, Trejbels JMF,Eskes TKAB, Oppenraaij-Emmerzaal DV, Bamerjee R, Blom HJ. Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteine in neural-tube defects and vascular disease. Q J Med.1997;90:511-517
43. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B-12,vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia.Am J Clin Nutr.1993;57:47-53
44. Robinson K, Arheart K, Refsum H, Brattstrom L, Boers G, Ueland P, Rubba P,Palma-Reis R, Meleady R, Daly L, Witteman J, Graham I. Low circulating folate and vitamin B_6 concentrations — risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation. 1998;97:437-443
45. Omenn GS, Beresford SAA, Motulsky AG. Preventing coronary heart disease---B vitamins and homocysteine. Circulation. 1998;97:421-424
46 Kluller LH, Evans RW. Homocysteine, vitamins, and cardiovascular disease.Circulation. 1998,98:196-199
47. Evans, et al. Homocysteine and Cardiovascular disease in MRFTT study.Arterioscler Thromb Vasu Biol. 1997;17:1946-1952
48 Evans RW, Shaten BJ, Hempel JD, et al. Homocysteine and risk of cardiovascular disease in the multiple risk factor intervention trial. Arterioscler Thromb Vasc Biol. 1997;17:1947-1953
49 Israelsson B, Brattstrom LE, Gultberg BL. Homocysteine and myocardial infartcion. Atherosclerosis. 1988;227-233
50. Arnesen E, Refsum H, Bonaa K, et al. Serum total homocysteine and coronary heart disease. Intern J Epidemiology. 1995;24:704-709
51. Robinsin K, Mayer EL, Miller DP, et al. Hyperhomocysteinemia and low pyridoxal phosphate, common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830
52. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins. Circulation. 1998;98:204-210
53. Montalescot G, et al. Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease. Int J Cardiol. 1997;60:295-300.
54. van den Berg M, Stehouwer SE, Rauwerda JA. Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease. Arterioscler Thromb Vasu Biol. 1996;16:165-171
55. Nygard O, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:230-236
56. von Eckardstein A, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:1632-1633
57. van Bockxmeer FM, Mamotte CDS, Vasikaran S, Taylor RR.Methylenetetrahydrofolate reductase gene and coronary artery disease.Circulation. 1997;95:21-23
58. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41
59. Harker LA, Ross R, Slichteb SJ, Scott CR. Homocysteine-induced arteriosclerosis---the role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976;58:731-741
60. Refsum H, Vollset SE, Nygard O, Ueland PM. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62
61. DeRose DJ, et al. Expanding and understanding risk factors for coronary heart disease. JAMA. 1997;278:636
62. Cheng TO. Homocysteinaemia and coronary atherosclerosis. Heart.1997;77:390-391
63. Mayer EL, et al. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27:517-527
64. Bellamy MF, McDowell LFW, Ramsey MW. et al. Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation. 1998;98:1848-1852
65. Lentz SR. Homocysteine and vascular dysfunction. Life Sciences. 1997;61:1205-1215
66. Dalton ML, Gadson PF, Wrenn RW, Rosenquist TH. Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smooth muscle cells. FASEB J. 1997; 11:703-711
67. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease---enhanced collagen production and accumulation by smooth musclecells. Arterioscler Thromb Vasc Biol. 1997; 17:2074-2081
68. Tsai JC, Wang H, Perrella MA, Yoshizumi M, Sibinga NES, Tan LC, Haber E,Chang THT, Schiegel R, Lee ME. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells. J Clin Invest. 1996;97:146-153
69. Tang L, Mamotte CDS, van Bockxmeer FM, Taylor RR. The effects of homocysteine on DNA synthesis in cultured human vascular smooth muscle.Atherosclerosis. 1998; 136:169-173
70. Durand P, Lussier-cacan S, Blache D. Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J.1997;11:1157-1168
71. Durand P, Prost M, Blache D. Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity. Arterioscler Thromb Vasc Biol.1997;17:1939-1946Ward M,Mcnulty H, Mcpartlin J, Strain JJ, Weir DG, Scott JM. Plasma homocysteine, a risk factor for cardiovascalar disease, is lowed by physiological doses of folic acid. Q J Med. 1997;90:519-524
72. Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA,Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. The Effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997;17:1157-1162
73. Jacques PF, Bostom AG, Williams RR, Et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7-9
74. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet.1996;58:17-20
75. Siri PW, et al. Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis. J Am Coll Nutr.1998;17:435-441
76. Malinow MR, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med. 1998;338:1009-1015
77. Hopkins PN, et al. Higher plasma homocyst(e)ine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease.Arterioscler Thromb Vase Biol. 1995; 15:1314-1320
78. Omenn GS, et al.Preventing coronary heart disease: B vitamins and homocysteine. Circulation. 1998;97:421-424
79. Ubbink JB, et al.Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem. 1995;41:1033-1037
80. Dalery K, et al. Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate. Am J Cardiol. 1995;75:1107-1111
81. Donner MG, et al. Plasma total homocysteine levels in patients with early-onset coronary heart disease and a low cardiovascular risk profile. Metabolism.1998;47:273-279
82. Malinow MR, et al.Plasma homocyst(e)ine levels and graded risk for myocardial infarction: findings in two populations at contrasting risk for coronary heart disease. Atherosclerosis. 1996; 126:27-34
83. Robinson K, et al. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830
1. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary??artery disease. Arch Intern Med. 1997; 157: 2299-2308
2. Cheng TO. Hyperhomocysteinaemia. Postgrad Med J. 1997; 73: 606-607
3. Gallagher PM, et al. Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation. Circulation. 1996; 94: 2154-2158
4. Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurence, cofactor therapy, and enzymology. Arterioscler Thromb. 1993; 13: 1253-1260
5. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. JACC. 1996; 27: 517-527
6. Woo KS, Chook P, Young RP, Sanderson JE. New risk factor for coronary disease in Asia. Intern J Cardiology. 1997; 62 Suppl 1: S39-S42
7. Kang SS, Wong PWK. Genetic and nongenetic factors for moderate hyperhomocysteinemia. Athero sclerosis. 1996; 119: 135-138
8. Matthews RG, Sheppard C, Goulding C. Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology. Eur J Pediatr. 1998; 157: S54-S59
9. Kang SS, Wong PWK, Bock HGO, Horwitz A, Grix A. Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Hum Genet. 1991; 48: 546-551
10. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet. 1996; 58: 17-20
11．朱慧萍．5，10-亚甲基四氢叶酸还原酶(MTHFR)基因与神经管畸形关系的研究．北京医科大学学位研究生论文(博士学位)1997年，12-17，35-37．
12. Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase(MTHFR). Thrombosis and Haemostasis. 1997; 78: 523-526
13. Malik NM, et al. Methylenetetrahydrofolate reductase polymorphism(C-677T) and coronary artery disease. Clin Sci(Colch). 1998; 95: 311-315
14. Goyette P, ChristensenB, Rosenblatt DS, et al. Severe and mild mutations in cis for the methylenetetrahydrofolate reductase(MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet. 1996; 59: 1268-127515 Goyette P, Frosst P, Rosenblatt D, Rozen R. Seven novel mutation in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet. 1995;56:1052-1059
16. Weisberg H, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Molecular Genetics and Metabolism. 1998;64:169-172
17. Frosst P, Blom HJ, Goyette MP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics. 1995;10:111-113
18. Samani NJ.Methylenetetrahydrofolate reductase mutation and coronary artery disease. Circulation. 1998;98:2932-2933
19. Arruda VR, Siqueira LH, Goncalves MS, et al. Prevalence of the mutation C677→T in the methylenetetrahydrofolate reductase gene among distinct groups in Brazil. Am J Med Genet. 1998;78:332-335
20. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia. a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41
21. Jacques PF, Bostom AG, Williams RR, Et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7-9
22. Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infartion in US physicians. Circulation. 1996;94:2410-2416
23. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins. Circulation. 1998;98:204-210
24. Wilcken DEL, Wang XL, Sim AS, McCredie M. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Arterioscler Thromb Vasu Biol. 1996; 16:878-882
25 Schmitz C, Lindpaintner K, Verhoef P, Gaziano JM, Buring J. Genetic polymorphism of methylenetetrahydrofolate reductase and myocardial infartion. Circulation. 1996;94:1812-1814
26. Morita HM, Taguchi J, Kurihara H, et al. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation. 1997;95:2032-2036
27. van Bockxmeer FM, Mamotte CDS, Vasikaran S, Taylor RR. Methylenetetrahydrofolate reductase gene and coronary artery disease. Circulation. 1997;95:21-23
28. Verhoef P, et al. A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among U.S. men. J Am Coll Cardiol. 1998;32:353-359.
29. Dunn J, et al. Relation of a common mutation in methylenetetrahydrofolate reductase to plasma homocysteine and early onset coronary artery disease. Clin Biochem. 1998;31:95-100
30. Ou T, et al. Methylenetetrahydrofolate reductase and apolipoprotein E polymorphisms are independent risk factors for coronary heart disease in Japanese: a case-control study. Atherosclerosis. 1998; 137:23-28
31. Brattstrom L, Zhang Y, Hurtig M, et al. A common methylenetetrahydrofolate reductase gene mutation and longevity. Atherosclerosis. 1998;141:315-319
32. Tsai MY, Garg U, Key NS, et al. Molecular and biochemical approaches in the identification of heterozygous for homocystinuria. Atherosclerosis.1996;122:69-77
33. Wicken DEL, Reddy S, Gupta VJ. Homocysteinemia, ischemia heart disease, and the carrier state for homocystinuria. Metabolism, 1983;32:363-370
34. McCully KS. Vascular pathology of homocysteine: implications for the pathogenesis of arteriosclerosis. Am J Pathology. 1969;56:111-121
35. 曾溢滔主编.蛋白质和核酸. 1986年.上海科学技术出版社
36. Munke M, Kraus JP, Ohura T, Francke U. The gene for cystathionine β-synthase(CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17. Am J Hum Genet. 1988;42:550-559
37. Kluijmans LA, Boers GH, Trijbels FJ, van Lith-Zanders HM, van den Henvel LP, Blom HJ. A common 844INS68 insertion variant in the cystathionine beta-synthase gene. Biochem Mol Med. 1997;62:23-25
38. Tsai MY, Hanson NQ, Schwichtenberg K, et al. Amplification refractory mutation system to identify mutations in cystathionine β-synthase deficiency.Clinical Chemistry. 1995;41:1775-1777
39. Sebastio G, Sperandeo MP, Panico M, et al. The molecular basis of homocystinuria due to cystathionine β-synthase deficiency in Italian families, and report of four novel mutations. Am J Hum Genet 1995;56:1324-1333
40. Kluijtmans LAJ, Blom HJ, Boers GHJ, et al. Two novel missense mutations in the cystathionine P-synthase gene in homocystinuric patients. Hum Genet.1995;96:249-250
41. Shih VE, Fringer JM, Mandell R, et al. A missense mutation (I278T) in the cystathionine P-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet.1995;57:34-39
42. Ramsbottom D, Scott JM, Molloy A, et al. Are common mutations of cystathionine P-synthase involved in the aetiology of neural tube defects? Clin Genet. 1997;51:30-42
43. Tsai MY, Bigell M, Schwichtenberg K, Hanson NQ. High prevalence of a mutation in the cystathionine p-synthase gene. Am J Hum Genet.1996;59:1262-1267
44. Jarrett JT, Amaratunga M, Drennan CL, Scholten JD, Sands RH, Ludwig ML,Matthews R. Mutations in the B12-binding region of methionine synthase: how the protein controls methylcobalamin reactivity. Biochemistry. 1996;35:2464-2475
45. Watkins D, Rosenblatt DS. Functional methionine synthase deficiency(cblE and cblG): clinical and biochemical heterogeneity. Am J Med Gen.1989;34:427-434
46. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M,Eydoux P, Rosenblatt DS, Rozen R, Gravel RA. Human methionine synthase:cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Human Mol Gen.1996;5:1867-1874
47. Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD. Cloning, mapping and RNA analysis of the human methionine synthasr gene. Human Mol genetics. 1996;5:1851-1858
48. Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, Shane B. Human methionine synthase---cDNA cloning, gene localization, and expression. J Bio Chem. 1997;272:3628-3634
49. Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC, Banerjee R. Defects in human methionine synthase in cblG patients. Human Mol genetics.1996;5:1859-1865
50. van der Put NMJ, Thomas CMG, Eskes TKAB, et al. Altered folate and vitamin B_(12) metabolism in families with spina bifida offspring. Q J Med.1997;90:505-510
51. Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, Ji J,Otto JM,Taylor LM. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem. 1994;40:873-881
52. Robinson K, Arheart K, Refsum H, Brattstrom L, Boers G, Ueland P, Rubba P,Palma-Reis R, Meleady R, Daly L, Witteman J, Graham I. Low circulating folate and vitamin B_6 concentrations — risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation. 1998;97:437-443
53. Ueland per M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med.1989;114:473-501
54. Vychytil A, Sunder-Plassmann G, Horl WH, Et al. Major determinants of hyperhomocysteinemia in peritoneal dialysis patients. Kidney Int.1998;53:1775-1782
55. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B-12,vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia.Am J Clin Nutr. 1993;57:47-53
56. Ubbink JB, et al.Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem. 1995;41:1033-1037
57. Omenn GS, Beresford SAA, Motulsky AG. Preventing coronary heart disease--B vitamins and homocysteine. Circulation. 1998;97:421-424
58. Kluller LH, Evans RW. Homocysteine, vitamins, and cardiovascular disease.Circulation. 1998;98:196-199
59. Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA,Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. TheEffects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997;17:1157-1162
60. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Willians RR. Higher plasma homocysteine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vasc Biol.1995;15:1314-1320
61 Ward M,Mcnulty H, Mcpartlin J, Strain JJ, Weir DG, Scott JM. Plasmahomocysteine, a risk factor for cardiovascalar disease, is lowed by physiological doses of folic acid. Q J Med. 1997;90:519-524
62. RobinsinK, Mayer EL, Miller DP, et al. Hyperhomocysteinemia and low pyridoxal phosphate, common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830
63. Malinow MR, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med. 1998;338:1009-1015
3. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157:2299-2308
4. Gallagher PM, Meleady R, Shields DC, et al. Homocysteine and risk of premature coronary heart disease. Circulation. 1996;94:2154-2158
5. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. JACC. 1996;27:517-527
6. Woo KS, Chook P, Young RP, Sanderson JE. New risk factor for coronary disease in Asia. Intern J Cardiology. 1997;62 Suppl 1:S39-S42
7. Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, Ji J, Otto JM,Taylor LM. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem.1994;40:873-881
8. Refsum H, Helland S, Ueland PM. Radioenzymic determination of homocysteine in plasma and urine. Clin Chem. 1985;31:624-628
9. McCully KS, Ragsdale BD. Production of arteriosclerosis by homocysteinemia.Am J Pathology. 1970;61:1-8
10. McCully KS. Vascular pathology of homocysteine: implications for the pathogenesis of arteriosclerosis. Am J Pathology. 1969;56:111-121
11. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet.1996;58:17-20
12. Evans, et al. Homocysteine and Cardiovascular disease in MRFTT study.Arterioscler Thromb Vasu Biol. 1997; 17:1946-1952
13. Evans RW, Shaten BJ, Hempel JD, et al. Homocysteine and risk of cardiovascular disease in the multiple risk factor intervention trial. Arterioscler Thromb Vasc Biol. 1997;17:1947-1953
14. Stehouwer CD, et al. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol. 1998;18:1895-1901
15. Kang SS, Wong PWK, Cook HY, Norusis M, Messer JV. Protein-bound homocysteine, a possible risk factor for coronary artery disease. J Clin Invest.1986,77:1482-148616. Stampfer J, Malinow MR, Wiilett WC, et al. Prospective study of plasma homocysteine and risk of myocardial infartion in US physicians. JAMA. 1992; 268: 877-881
17. Boushey CJ, Beresford SAA, Omenn GS, Motuisky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. JAMA. 1995; 274: 1049-1067
18. Arnesen E, Refsum H, Bonaa K, et al. Serum total homocysteine and coronary heart disease. Intern J Epidemiology. 1995; 24: 704-709
19. Gupta A, Moustapha A, Jacorsen DW, et al. High homocysteine, low folate, and low vitamin B_6 concentration. Transplantation. 1998; 65: 544-550
20. Fermo I, Vigano'D'Angeto S, Paroni R, et al. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med. 1995; 123: 747-753
21．黄其擎，惠汝太，张春玲，等．高压液相层析法测定血浆同型半胱氨酸及其初步应用．世界医学杂志．1999；3：50-52
22．汤佩麟，王毓明，李明珍，等．血浆高半胱氨酸水平和冠心病的关系．中国循环杂志．1997；12：324-326
23. Ueland per M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989; 114: 473-501
24. Boers GH, Smals AG, Trijbels FJ. et al. Unique efficiency of methionine metabolism in premenopausal woman may protect against vascular disease in the reproductive years. J Clin Invest. 1983; 72: 1971-1976
25. Montalescot G, et al. Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease. Int J Cardiol. 1997; 60: 295-300.
26. Malinow MR, et al. Plasma homocyst(e)ine levels and graded risk for myocardial infarction: findings in two populations at contrasting risk for coronary heart disease. Atherosclerosis. 1996; 126: 27-341. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157: 2299-23082. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. JACC. 1996; 27: 517-527
3. Goyette P, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nature Genet. 1994; 7: 195-200
4. Frosst P, Blom H J, Goyette MP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics. 1995; 10: 111-113
5. Schmitz C, Lindpaintner K, Verhoef P, Gaziano JM, Buring J. Genetic polymorphism of methylenetetrahydrofolate reductase and myocardial infartion. Circulation. 1996; 94: 1812-1814
6. Goyette P, ChristensenB, Rosenblatt DS, et al. Severe and mild mutations in cis for the methylenetetrahydrofolate reductase(MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet. 1996; 59: 1268-1275
7. Kang SS, Wong PWK, Bock HGO, Horwitz A, Grix A. Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Hum Genet. 1991; 48: 546-551
8. Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase(MTHFR). Thrombosis and Haemostasis. 1997; 78: 523-526
9. Weisberg H, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase(MTHFR) associated with decreased enzyme activity. Molecular Genetics and Metabolism. 1998; 64: 169-172
10. Arruda VR, Siqueira LH, Goncalves MS, et al. Prevalence of the mutation C677→T in the methylenetetrahydrofolate reductase gene among distinct groups in Brazil. Am J Med Genet. 1998; 78: 332-335
11. Matthews RG, Sheppard C, Goulding C. Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology. Eur J Pediatr. 1998; 157: S54-S59
12．朱慧萍．5，10-亚甲基四氢叶酸还原酶(MTHFR)基因与神经管畸形关系的研究．北京医科大学学位研究生论文(博士学位)1997年，12-17，35-37．
13. Wilcken DEL, Wang XL, Sim AS, McCredie M Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase(MTHFR) C677T mutation. Arterioscler Thromb Vasu Biol. 1996; 16: 878-88214 Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins. Circulation. 1998;98:204-210
15. Verhoef P, et al. A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among U.S. men. J Am Coll Cardiol. 1998;32:353-359.
16. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41
17. Morita HM, Taguchi J, Kurihara H, et al. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation. 1997;95:2032-2036
18. van Bockxmeer FM, Mamotte CDS, Vasikaran S, Taylor RR.Methylenetetrahydrofolate reductase gene and coronary artery disease.Circulation. 1997;95:21-23
19. Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infartion in US physicians. Circulation. 1996;94:2410-2416
20. Jacques PF, Bostom AG, Williams RR, Et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7-9
21. Samani NJ.Methylenetetrahydrofolate reductase mutation and coronary artery disease. Circulation. 1998;98:2932-2933
22 Gallagher PM, et al. Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation. Circulation. 1996;94:2154-2158
23 Kang SS, Wong PW, Bock HG, Horwitz A, Grix A. Intermediate hyperhomocysteinemia resulting from compound heterozygous of methylenetetrahydrofolate reductase mutations. Am J Hum Genet.1991;48:546-5511. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157: 2299-2308
2. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. JACC. 1996; 27: 517-527
3. Ueland per M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989; 114: 473-501
4. McCully KS. Vascular pathology of homocysteine: implications for the pathogenesis of arteriosclerosis. Am J Pathology. 1969; 56: 111-121
5. Tsai MY, Garg U, Key NS, et al. Molecular and biochemical approaches in the identification of heterozygous for homocystinuria. Atherosclerosis. 1996; 122: 69-77
6．曾溢滔主编．蛋白质和核酸遗传病．1981年，上海科学技术出版社
7. Wicken DEL, Reddy S, Gupta VJ. Homocysteinemia, ischemia heart disease,??and the carrier state for homocystinuria. Metabolism, 1983;32:363-370
8. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet.1996;58:17-20
9. Sebastio G, Sperandeo MP, Panico M, et al. The molecular basis of homocystinuria due to cystathionine β-synthase deficiency in Italian families, and report of four novel mutations. Am J Hum Genet. 1995;56:1324-1333
10 Tsai MY, Bigell M, Schwichtenberg K, Hanson NQ. High prevalence of a mutation in the cystathionine β-synthase gene. Am J Hum Genet.1996;59:1262-1267
11. Kluijtmans LAJ, Blom HJ, Boers GHJ, et al. Two novel missense mutations in the cystathionine β-synthase gene in homocystinuric patients. Hum Genet.1995;96:249-250
12. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41
13. Tsai MY, Hanson NQ, Schwichtenberg K, et al. Amplification refractory mutation system to identify mutations in cystathionine β-synthase deficiency.Clinical Chemistry. 1995;41:1775-1777
14. Shih VE, Fringer JM, Mandell R, et al. A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet.1995;57:34-39
1. Watkins D, Rosenblatt DS. Functional methionine synthase deficiency(cblE and cblG): clinical and biochemical heterogeneity. Am J Med Gen. 1989; 34: 427-434
2. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M, Eydoux P, Rosenblatt DS, Rozen R, Gravel RA. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Human Mol Gen. 1996; 5: 1867-1874
3. Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD. Cloning, mapping and RNA analysis of the human methionine synthasr gene. Human Mol genetics. 1996; 5: 1851-1858
4. Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, Shane B. Human methionine synthase—cDNA cloning, gene localization, and expression. J BioChem. 1997; 272: 3628-3634
5. Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC, Banerjee R. Defects in human methionine synthase in cbIG patients. Human Mol genetics. 1996; 5: 1859-1865
6. Jarrett JT, Amaratunga M, Drennan CL, Scholten JD, Sands RH, Ludwig ML, Matthews R. Mutations in the B 12-binding region of methionine synthase: how the protein controls methylcobalamin reactivity. Biochemistry. 1996; 35: 2464-??2475
7. Gulddberg P, Henriksen KF, Gutter F, et al. Molecular analysis of phenylketonuria in Fenmark: 99% of the mutations detected by denaturing gradient gel electrophoresis. Genomics. 1993; 17: 141
8. Delwart EL, Shaper EG, Louwagie J, et al. Genetic relationships determined by a DNA heteroduplex mobility assay: analysis of HIV-1 genes. Science. 1993; 82: 7575
9. Orita M, Iwahana H, Knazawa H, et al. Detection of polymorphisms of human DNA by gel electrophoresis as single strand conformation polymorphisms. Pro Natl Acad Sci. 1989; 86: 2766
10. Chrambach A, Rodbard R. Polyacrylamide gel electrophoresis. Science. 1971; 172: 440
11. Gaidano G, Ballerini P, Gong JZ, et al. Proc Natl Acad Sci USA. 1991; 88: 5413
12．赵蔚明，司静懿，于修平。PCR-SSCP分析技术及其在肿瘤学研究中的应用。国外医学肿瘤学分册 1995；22：133
13. van der Put NMJ, van der Molen EF, Kluijtmans LAJ, Heil SG, Trejbels JMF, Eskes TKAB, Oppenraaij-Emmerzaal DV, Bamerjee R, Blom HJ. Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteine in neural-tube defects and vascular disease. Q J Med. 1997; 90: 511-5171. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease—enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997; 17: 2074-2081
2. Rosenouist TH, Ratashak SA, Selhub J. Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci USA. 1996; 93: 15227-15232
3. Harker LA, Ross R, Slichteb SJ, Scott CR. Homocysteine-induced arteriosclerosis—the role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976; 58: 731-741
4. Malinow MR, Nieto F J, Kruger WD, Duell PB, Hess DL, Gluckman RA, Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. The Effects of folic acid supplementation on plasma total homocysteine are modulated by multiVitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997; 17: 1157-1162
5. Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infartion in US physicians. Circulation. 1996; 94: 2410-2416
6. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157: 2299-2308
7. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary??atherosclerosis. JACC. 1996;27:517-527
8. Woo KS, Chook P, Young RP, Sanderson JE. New risk factor for coronary disease in Asia. Intern J Cardiology. 1997;62 Suppl 1:S39-S42
9. Dalery K, et al. Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate. Am J Cardiol. 1995;75:1107-1111
10. Kluller LH, Evans RW. Homocysteine, vitamins, and cardiovascular disease.Circulation. 1998;98:196-199
11. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet.1996;58:17-20
12. Kang SS, Wong PWK. Genetic and nongenetic factors for moderate hyperhomocysteinemia. Atherosclerosis. 1996;119:135-138
13. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B-12,vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia.Am J Clin Nutr.1993;57:47-53
14 Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, Ji J,Otto JM,Taylor LM. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem.1994;40:873-881
15 Robinson K, Arheart K, Refsum H, Brattstrom L, Boers G, Ueland P, Rubba P,Palma-Reis R, Meleady R, Daly L, Witteman J, Graham I. Low circulating folate and vitamin B_6 concentrations — risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation. 1998;97:437-443
16. Ubbink JB, et al.Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem. 1995;41:1033-1037
17. Omenn GS, Beresford SAA, Motulsky AG. Preventing coronary heart disease---B vitamins and homocysteine. Circulation. 1998;97:421-424
18. Malinow MR, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med. 1998;338:1009-1015
19. Ward M,Mcnulty H, Mcpartlin J, Strain JJ, Weir DG, Scott JM. Plasma homocysteine, a risk factor for cardiovascalar disease, is lowed by physiological doses of folic acid. Q J Med. 1997;90:519-524
20. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Willians RR. Higher plasma homocysteine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vasc Biol.1995,15:1314-1320
21. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins Circulation. 1998;98:204-210
22. Jacques PF, Bostom AG, Williams RR, Et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations Circulation. 1996;93:7-9
23. Siri PW, et al. Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis. J Am Coll Nutr.1998;17:435-441
24. Robinson K, et al. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830
25. Bostom AG, et al. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis. 1995;116:147-151
1. McCully KS, Ragsdale BD. Production of arteriosclerosis by homocysteinemia. Am J Pathology. 1970; 61: 1-8
2. McCully KS. Vascular pathology of homocysteine: implications for the pathogenesis of arteriosclerosis. Am J Pathology. 1969; 56: 111-121
3. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med. 1997; 157: 2299-2308
4. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary??atherosclerosis. JACC. 1996; 27: 517-527
5. Woo KS, Chook P, Young RP, Sanderson JE. New risk factor for coronary disease in Asia. Intern J Cardiology. 1997; 62 Suppl 1: S39-S42
6. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991; 324: 1149-1155
7. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998; 338: 1043-1052
8. Kang SS, Wong PWK. Genetic and nongenetic factors for moderate hyperhomocysteinemia. Atherosclerosis. 1996; 119: 135-138
9. Ueland per M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989; 114: 473-501
10. Boers GH. Hyperhomocysteinemia as a risk factor for arterial and venous disease. A review of evidence and relevance. Thromb Haemost. 1997; 78: 520-522
11. Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurence, cofactor therapy, and enzymology. Arterioscler Thromb. 1993; 13: 1253-1260
12. Ubbink JB, Vermank WJH, van der Merwe A, Beeker PJ. The effect of blood sample aging and food consumption on plasma total homocysteine levels. Clin Chim Acta. 1992; 207: 119-128
13. Refsum H, Helland S, Ueland PM. Radioenzymic determination of homocysteine in plasma and urine. Clin Chem. 1985; 31: 624-628
14. Franken DG, Boers GHJ, Blom HJ, Cruysberg JRM, Trijbels FJM, Hamel BCJ. Prevalence of familial mild hyperhomocysteinemia. Atherosclerosis. 1996; 125: 71-80
15．黄其擎，惠汝太，张春玲，等．高压液相层析法测定血浆同型半胱氨酸及其初步应用．世界医学杂志．1999；3：50-52
16. Jacobsen DW, Gatautis V J, Green R, Robinson K, Savon SR, Secic M, Ji J, Otto JM, Taylor LM. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem. 1994; 40: 873-881
17. Stabler SP, et al. Quantitation of total homocysteine, total cysteine, and methionine in normal serum and urine using capillary gas chromatography-??mass spectrometry. Anal Biochem. 1987; 162: 185-196
18. Gupta A, Moustapha A, Jacorsen DW, et al. High homocysteine, low folate, and low vitamin B_6 concentration. Transplantation. 1998; 65: 544-550
19. Fermo I, Vigano'D'Angeto S, Paroni R, et al. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med. 1995; 123: 747-753
20. Ubbink JB, Vermank H, Delport R, van der Merve A, Becker PJ, Potgieter H. Effective homocysteine metabolism may protect South African blacks against coronary heart disease. Am J Clin Nutr. 1995; 62: 802-808
21．汤佩麟，王毓明，李明珍，等．血浆高半胱氨酸水平和冠心病的关系．中国循环杂志．1997；12：324-326
22. Boers G, Smals AG, Trijbels FJ, et al. Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. J Clin Invest. 1983; 72: 1971-1976
23. Kang SS, Wong PWK, Cook HY, Norusis M, Messer JV. Protein-bound homocysteine, a possible risk factor for coronary artery disease. J Clin Invest. 1986; 77: 1482-1486
24. Nygard O, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA. 1995; 274: 1526-1533Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Willians RR. Higher plasma homocysteine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vase Biol. 1995; 15: 1314-1320
25. Durand P, Prost M, Blache D. Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity. Arterioscler Thromb Vase Biol. 1997; 17: 1939-1946
26. Nygard O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile: the Hordaland Homocysteine Study. JAMA. 1995; 274: 1526-1533
27. Vychytil A, Sunder-Plassmann G, Horl WH, Et al. Major determinants of hyperhomocysteinemia in peritoneal dialysis patients. Kidney Int. 1998; 53: 1775-1782
28. ChauveauP, Chadefaux B, Coude M, et al. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Intern. 1993; 43: S72-
29. Bostom AG, Selhub J, Rosenberg IH. et al. Excess prevalence of fasting and??postmethionine-loading hyperhomocysteinemia in stable renal transplant recipients. Arterioscler Thromb Vasc Biol. 1997; 17:1894-1900
30. Tsai MY, Garg U, Key NS, et al. Molecular and biochemical approaches in the identification of heterozygous for homocystinuria. Atherosclerosis.1996;122:69-77
31. 曾溢滔主编.蛋白质和核酸遗传病. 1981年,上海科学技术出版社
32. Sebastio G, Sperandeo MP, Panico M, et al. The molecular basis of homocystinuria due to cystathionine P-synthase deficiency in Italian families,and report of four novel mutations. Am J Hum Genet. 1995;56:1324-1333
33. Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thrombosis and Haemostasis.1997;78:523-526
34. Goyette P, Frosst P, Rosenblatt D, Rozen R. Seven novel mutation in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet. 1995;56:1052-1059
35. Wilcken DEL, Wang XL, Sim AS, McCredie M. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Arterioscler Thromb Vasu Biol. 1996; 16:878-882
36. Frosst P, Blom HJ, Goyette MP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.Nature Genetics. 1995;10:111-113
37. Tsai MY, Bigell M, Schwichtenberg K, Hanson NQ. High prevalence of a mutation in the cystathionine p-synthase gene. Am J Hum Genet.1996;59:1262-1267
38. Kluijtmans LAJ, Blom HJ, Boers GHJ, et al. Two novel missense mutations in the cystathionine P-synthase gene in homocystinuric patients. Hum Genet.1995;96:249-250
39. Sebastio G, Sperandeo MP, Panico M, et al. The molecular basis of homocystinuria due to cystathionine p-synthase deficiency in Italian families,and report of four novel mutations. Am J Hum Genet. 1995;56:1324-1333
40. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M,Eydoux P, Rosenblatt DS, Rozen R, Gravel RA. Human methionine synthase:cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Human Mol Gen.1996;5:1867-1874
41. Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD. Cloning,mapping and RNA analysis of the human methionine synthasr gene. Human Mol genetics. 1996;5:1851-1858
42. van der Put NMJ, van der Molen EF, Kluijtmans LAJ, Heil SG, Trejbels JMF,Eskes TKAB, Oppenraaij-Emmerzaal DV, Bamerjee R, Blom HJ. Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteine in neural-tube defects and vascular disease. Q J Med.1997;90:511-517
43. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B-12,vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia.Am J Clin Nutr.1993;57:47-53
44. Robinson K, Arheart K, Refsum H, Brattstrom L, Boers G, Ueland P, Rubba P,Palma-Reis R, Meleady R, Daly L, Witteman J, Graham I. Low circulating folate and vitamin B_6 concentrations — risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation. 1998;97:437-443
45. Omenn GS, Beresford SAA, Motulsky AG. Preventing coronary heart disease---B vitamins and homocysteine. Circulation. 1998;97:421-424
46 Kluller LH, Evans RW. Homocysteine, vitamins, and cardiovascular disease.Circulation. 1998,98:196-199
47. Evans, et al. Homocysteine and Cardiovascular disease in MRFTT study.Arterioscler Thromb Vasu Biol. 1997;17:1946-1952
48 Evans RW, Shaten BJ, Hempel JD, et al. Homocysteine and risk of cardiovascular disease in the multiple risk factor intervention trial. Arterioscler Thromb Vasc Biol. 1997;17:1947-1953
49 Israelsson B, Brattstrom LE, Gultberg BL. Homocysteine and myocardial infartcion. Atherosclerosis. 1988;227-233
50. Arnesen E, Refsum H, Bonaa K, et al. Serum total homocysteine and coronary heart disease. Intern J Epidemiology. 1995;24:704-709
51. Robinsin K, Mayer EL, Miller DP, et al. Hyperhomocysteinemia and low pyridoxal phosphate, common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830
52. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins. Circulation. 1998;98:204-210
53. Montalescot G, et al. Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease. Int J Cardiol. 1997;60:295-300.
54. van den Berg M, Stehouwer SE, Rauwerda JA. Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease. Arterioscler Thromb Vasu Biol. 1996;16:165-171
55. Nygard O, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:230-236
56. von Eckardstein A, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:1632-1633
57. van Bockxmeer FM, Mamotte CDS, Vasikaran S, Taylor RR.Methylenetetrahydrofolate reductase gene and coronary artery disease.Circulation. 1997;95:21-23
58. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41
59. Harker LA, Ross R, Slichteb SJ, Scott CR. Homocysteine-induced arteriosclerosis---the role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976;58:731-741
60. Refsum H, Vollset SE, Nygard O, Ueland PM. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62
61. DeRose DJ, et al. Expanding and understanding risk factors for coronary heart disease. JAMA. 1997;278:636
62. Cheng TO. Homocysteinaemia and coronary atherosclerosis. Heart.1997;77:390-391
63. Mayer EL, et al. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol. 1996;27:517-527
64. Bellamy MF, McDowell LFW, Ramsey MW. et al. Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation. 1998;98:1848-1852
65. Lentz SR. Homocysteine and vascular dysfunction. Life Sciences. 1997;61:1205-1215
66. Dalton ML, Gadson PF, Wrenn RW, Rosenquist TH. Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smooth muscle cells. FASEB J. 1997; 11:703-711
67. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease---enhanced collagen production and accumulation by smooth musclecells. Arterioscler Thromb Vasc Biol. 1997; 17:2074-2081
68. Tsai JC, Wang H, Perrella MA, Yoshizumi M, Sibinga NES, Tan LC, Haber E,Chang THT, Schiegel R, Lee ME. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells. J Clin Invest. 1996;97:146-153
69. Tang L, Mamotte CDS, van Bockxmeer FM, Taylor RR. The effects of homocysteine on DNA synthesis in cultured human vascular smooth muscle.Atherosclerosis. 1998; 136:169-173
70. Durand P, Lussier-cacan S, Blache D. Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J.1997;11:1157-1168
71. Durand P, Prost M, Blache D. Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity. Arterioscler Thromb Vasc Biol.1997;17:1939-1946Ward M,Mcnulty H, Mcpartlin J, Strain JJ, Weir DG, Scott JM. Plasma homocysteine, a risk factor for cardiovascalar disease, is lowed by physiological doses of folic acid. Q J Med. 1997;90:519-524
72. Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA,Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. The Effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997;17:1157-1162
73. Jacques PF, Bostom AG, Williams RR, Et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7-9
74. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet.1996;58:17-20
75. Siri PW, et al. Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis. J Am Coll Nutr.1998;17:435-441
76. Malinow MR, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med. 1998;338:1009-1015
77. Hopkins PN, et al. Higher plasma homocyst(e)ine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease.Arterioscler Thromb Vase Biol. 1995; 15:1314-1320
78. Omenn GS, et al.Preventing coronary heart disease: B vitamins and homocysteine. Circulation. 1998;97:421-424
79. Ubbink JB, et al.Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem. 1995;41:1033-1037
80. Dalery K, et al. Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate. Am J Cardiol. 1995;75:1107-1111
81. Donner MG, et al. Plasma total homocysteine levels in patients with early-onset coronary heart disease and a low cardiovascular risk profile. Metabolism.1998;47:273-279
82. Malinow MR, et al.Plasma homocyst(e)ine levels and graded risk for myocardial infarction: findings in two populations at contrasting risk for coronary heart disease. Atherosclerosis. 1996; 126:27-34
83. Robinson K, et al. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830
1. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary??artery disease. Arch Intern Med. 1997; 157: 2299-2308
2. Cheng TO. Hyperhomocysteinaemia. Postgrad Med J. 1997; 73: 606-607
3. Gallagher PM, et al. Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation. Circulation. 1996; 94: 2154-2158
4. Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurence, cofactor therapy, and enzymology. Arterioscler Thromb. 1993; 13: 1253-1260
5. Mayer EM, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. JACC. 1996; 27: 517-527
6. Woo KS, Chook P, Young RP, Sanderson JE. New risk factor for coronary disease in Asia. Intern J Cardiology. 1997; 62 Suppl 1: S39-S42
7. Kang SS, Wong PWK. Genetic and nongenetic factors for moderate hyperhomocysteinemia. Athero sclerosis. 1996; 119: 135-138
8. Matthews RG, Sheppard C, Goulding C. Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology. Eur J Pediatr. 1998; 157: S54-S59
9. Kang SS, Wong PWK, Bock HGO, Horwitz A, Grix A. Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations. Am J Hum Genet. 1991; 48: 546-551
10. Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet. 1996; 58: 17-20
11．朱慧萍．5，10-亚甲基四氢叶酸还原酶(MTHFR)基因与神经管畸形关系的研究．北京医科大学学位研究生论文(博士学位)1997年，12-17，35-37．
12. Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase(MTHFR). Thrombosis and Haemostasis. 1997; 78: 523-526
13. Malik NM, et al. Methylenetetrahydrofolate reductase polymorphism(C-677T) and coronary artery disease. Clin Sci(Colch). 1998; 95: 311-315
14. Goyette P, ChristensenB, Rosenblatt DS, et al. Severe and mild mutations in cis for the methylenetetrahydrofolate reductase(MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet. 1996; 59: 1268-127515 Goyette P, Frosst P, Rosenblatt D, Rozen R. Seven novel mutation in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet. 1995;56:1052-1059
16. Weisberg H, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Molecular Genetics and Metabolism. 1998;64:169-172
17. Frosst P, Blom HJ, Goyette MP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics. 1995;10:111-113
18. Samani NJ.Methylenetetrahydrofolate reductase mutation and coronary artery disease. Circulation. 1998;98:2932-2933
19. Arruda VR, Siqueira LH, Goncalves MS, et al. Prevalence of the mutation C677→T in the methylenetetrahydrofolate reductase gene among distinct groups in Brazil. Am J Med Genet. 1998;78:332-335
20. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia. a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41
21. Jacques PF, Bostom AG, Williams RR, Et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7-9
22. Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infartion in US physicians. Circulation. 1996;94:2410-2416
23. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins. Circulation. 1998;98:204-210
24. Wilcken DEL, Wang XL, Sim AS, McCredie M. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Arterioscler Thromb Vasu Biol. 1996; 16:878-882
25 Schmitz C, Lindpaintner K, Verhoef P, Gaziano JM, Buring J. Genetic polymorphism of methylenetetrahydrofolate reductase and myocardial infartion. Circulation. 1996;94:1812-1814
26. Morita HM, Taguchi J, Kurihara H, et al. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation. 1997;95:2032-2036
27. van Bockxmeer FM, Mamotte CDS, Vasikaran S, Taylor RR. Methylenetetrahydrofolate reductase gene and coronary artery disease. Circulation. 1997;95:21-23
28. Verhoef P, et al. A common mutation in the methylenetetrahydrofolate reductase gene and risk of coronary heart disease: results among U.S. men. J Am Coll Cardiol. 1998;32:353-359.
29. Dunn J, et al. Relation of a common mutation in methylenetetrahydrofolate reductase to plasma homocysteine and early onset coronary artery disease. Clin Biochem. 1998;31:95-100
30. Ou T, et al. Methylenetetrahydrofolate reductase and apolipoprotein E polymorphisms are independent risk factors for coronary heart disease in Japanese: a case-control study. Atherosclerosis. 1998; 137:23-28
31. Brattstrom L, Zhang Y, Hurtig M, et al. A common methylenetetrahydrofolate reductase gene mutation and longevity. Atherosclerosis. 1998;141:315-319
32. Tsai MY, Garg U, Key NS, et al. Molecular and biochemical approaches in the identification of heterozygous for homocystinuria. Atherosclerosis.1996;122:69-77
33. Wicken DEL, Reddy S, Gupta VJ. Homocysteinemia, ischemia heart disease, and the carrier state for homocystinuria. Metabolism, 1983;32:363-370
34. McCully KS. Vascular pathology of homocysteine: implications for the pathogenesis of arteriosclerosis. Am J Pathology. 1969;56:111-121
35. 曾溢滔主编.蛋白质和核酸. 1986年.上海科学技术出版社
36. Munke M, Kraus JP, Ohura T, Francke U. The gene for cystathionine β-synthase(CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17. Am J Hum Genet. 1988;42:550-559
37. Kluijmans LA, Boers GH, Trijbels FJ, van Lith-Zanders HM, van den Henvel LP, Blom HJ. A common 844INS68 insertion variant in the cystathionine beta-synthase gene. Biochem Mol Med. 1997;62:23-25
38. Tsai MY, Hanson NQ, Schwichtenberg K, et al. Amplification refractory mutation system to identify mutations in cystathionine β-synthase deficiency.Clinical Chemistry. 1995;41:1775-1777
39. Sebastio G, Sperandeo MP, Panico M, et al. The molecular basis of homocystinuria due to cystathionine β-synthase deficiency in Italian families, and report of four novel mutations. Am J Hum Genet 1995;56:1324-1333
40. Kluijtmans LAJ, Blom HJ, Boers GHJ, et al. Two novel missense mutations in the cystathionine P-synthase gene in homocystinuric patients. Hum Genet.1995;96:249-250
41. Shih VE, Fringer JM, Mandell R, et al. A missense mutation (I278T) in the cystathionine P-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet.1995;57:34-39
42. Ramsbottom D, Scott JM, Molloy A, et al. Are common mutations of cystathionine P-synthase involved in the aetiology of neural tube defects? Clin Genet. 1997;51:30-42
43. Tsai MY, Bigell M, Schwichtenberg K, Hanson NQ. High prevalence of a mutation in the cystathionine p-synthase gene. Am J Hum Genet.1996;59:1262-1267
44. Jarrett JT, Amaratunga M, Drennan CL, Scholten JD, Sands RH, Ludwig ML,Matthews R. Mutations in the B12-binding region of methionine synthase: how the protein controls methylcobalamin reactivity. Biochemistry. 1996;35:2464-2475
45. Watkins D, Rosenblatt DS. Functional methionine synthase deficiency(cblE and cblG): clinical and biochemical heterogeneity. Am J Med Gen.1989;34:427-434
46. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M,Eydoux P, Rosenblatt DS, Rozen R, Gravel RA. Human methionine synthase:cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Human Mol Gen.1996;5:1867-1874
47. Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD. Cloning, mapping and RNA analysis of the human methionine synthasr gene. Human Mol genetics. 1996;5:1851-1858
48. Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, Shane B. Human methionine synthase---cDNA cloning, gene localization, and expression. J Bio Chem. 1997;272:3628-3634
49. Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC, Banerjee R. Defects in human methionine synthase in cblG patients. Human Mol genetics.1996;5:1859-1865
50. van der Put NMJ, Thomas CMG, Eskes TKAB, et al. Altered folate and vitamin B_(12) metabolism in families with spina bifida offspring. Q J Med.1997;90:505-510
51. Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, Ji J,Otto JM,Taylor LM. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem. 1994;40:873-881
52. Robinson K, Arheart K, Refsum H, Brattstrom L, Boers G, Ueland P, Rubba P,Palma-Reis R, Meleady R, Daly L, Witteman J, Graham I. Low circulating folate and vitamin B_6 concentrations — risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation. 1998;97:437-443
53. Ueland per M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med.1989;114:473-501
54. Vychytil A, Sunder-Plassmann G, Horl WH, Et al. Major determinants of hyperhomocysteinemia in peritoneal dialysis patients. Kidney Int.1998;53:1775-1782
55. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B-12,vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia.Am J Clin Nutr. 1993;57:47-53
56. Ubbink JB, et al.Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem. 1995;41:1033-1037
57. Omenn GS, Beresford SAA, Motulsky AG. Preventing coronary heart disease--B vitamins and homocysteine. Circulation. 1998;97:421-424
58. Kluller LH, Evans RW. Homocysteine, vitamins, and cardiovascular disease.Circulation. 1998;98:196-199
59. Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA,Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. TheEffects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997;17:1157-1162
60. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Willians RR. Higher plasma homocysteine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease. Arterioscler Thromb Vasc Biol.1995;15:1314-1320
61 Ward M,Mcnulty H, Mcpartlin J, Strain JJ, Weir DG, Scott JM. Plasmahomocysteine, a risk factor for cardiovascalar disease, is lowed by physiological doses of folic acid. Q J Med. 1997;90:519-524
62. RobinsinK, Mayer EL, Miller DP, et al. Hyperhomocysteinemia and low pyridoxal phosphate, common and independent reversible risk factors for coronary artery disease. Circulation. 1995;92:2825-2830
63. Malinow MR, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med. 1998;338:1009-1015