臺灣博碩士論文加值系統

高同半胱胺酸已被證實是冠狀動脈疾病的獨立危險因子。B-維生素（葉酸、維生素B-6、維生素B-12）缺乏是造成高同半胱胺酸血症的主要原因。雖然禁食及甲硫胺酸負荷後的同半胱胺酸濃度不盡然具有相關性，但若不評估甲硫胺酸負荷後同半胱胺酸濃度，將有高比例的高同半胱胺酸血症會被遺漏。除了高同半胱胺酸血症會增加冠狀動脈疾病的危險性外，低維生素B-6營養狀況也可能因與發炎反應有顯著相關，進而增加冠狀動脈疾病的危險性。本研究目的是：1) 評估哪一個B-維生素營養指標（血清葉酸、紅血球葉酸、血清維生素B-12、血漿磷酸比哆醛）可作為評估台灣年輕族群禁食同半胱胺酸濃度的最可依賴之指標；2) 研究B-維生素及五甲基四氫葉酸還原酶677C→T基因多型性對禁食及甲硫胺酸負荷後的同半胱胺酸濃度的影響；3) 探討血漿磷酸比哆醛是否為發炎反應的獨立或非獨立的影響因子進而影響冠狀動脈疾病的危險性。
冠狀動脈疾病受試病人是經心導管檢查確認至少有一條冠狀動脈狹窄程度>70%（n = 184）；對照組（n = 516）為具有正常血液生化值的健康受試者。另外根據198位健康受試者的75百分位的禁食及甲硫胺酸負荷後同半胱胺酸濃度為切點，分別分派至高同半胱胺酸血症組（禁食高同半胱胺酸濃度 ³ 12.2 mmol/L，n = 51）；甲硫胺酸負荷後同半胱胺酸血症組（禁食高同半胱胺酸濃度< 12.2 mmol/L但甲硫胺酸負荷後同半胱胺酸濃度³ 25.6 mmol/L，n = 29）；正常同半胱胺酸組（禁食高同半胱胺酸濃度< 12.2 mmol/L且甲硫胺酸負荷後同半胱胺酸濃度< 25.6 mmol/L，n = 118）。130位健康年輕受試者則依禁食同半胱胺酸濃度分派至高同半胱胺酸血症組（³ 14.9 mmol/L）（HHcy, n = 13），臨界高同半胱胺酸血症組（fasting homocysteine, 14.9 – 10.2 mmol/L）（BHcy, n = 52），或是正常同半胱胺酸組（fasting homocysteine < 10.2 mmol/L）（NHcy, n = 65）。所有受試者皆測量其身高、體重、血壓、基因多型性、血漿禁食及甲硫胺酸負荷後同半胱胺酸、血清葉酸、紅血球葉酸、血清維生素B-12、血漿磷酸比哆醛、高敏感度C-反應蛋白及血脂質濃度。
在調整干擾因子後，血清葉酸濃度顯著影響血漿禁食同半胱胺酸濃度（b = -0.21, P < 0.05）。進一步調整其他兩個B-維生素對同半胱胺酸的可能影響後，仍只有高血清葉酸濃度顯著降低禁食同半胱胺酸濃度（OR, 0.73, CI, 0.56 – 0.95）。相較其他B-維生素指標，血清葉酸有顯著較高的接受者操作區線下面積（AUC）以預測高同半胱胺酸血症（AUC, 0.81）及臨界高同半胱胺酸血症（AUC, 0.77）的危險。但血清葉酸濃度沒有顯著影響甲硫胺酸負荷後同半胱胺酸濃度及五甲基四氫葉酸還原酶677C→T基因多型性。在高同半胱胺酸血症組及pool組的禁食及甲硫胺酸負荷後同半胱胺酸成顯著相關性（P < 0.01）。甲硫胺酸負荷後同半胱胺酸與血清葉酸（P = 0.302）、維生素B-12（P = 0.465）、血漿磷酸比哆醛（P = 0.996）及五甲基四氫葉酸還原酶677C→T基因多型性 (P = 0.136) 之間並無顯著交互作用去影響同半胱胺酸濃度。只有對照組的血漿磷酸比哆醛顯著影響高敏感度C-反應蛋白（b = -0.001, P = 0.03）。低血漿磷酸比哆醛（OR, 2.39）及高的高敏感度C-反應蛋白（OR, 3.37）濃度對冠狀動脈疾病危險性的影響強度是相似的。雖然低血漿磷酸比哆醛合併低的高敏感度C-反應蛋白濃度（OR, 2.34），或是高血漿磷酸比哆醛合併高的高敏感度C-反應蛋白濃度（OR, 3.61）都顯著增加冠狀動脈疾病危險性；但是低血漿磷酸比哆醛合併高的高敏感度C-反應蛋白濃度對增加冠狀動脈疾病危險性（OR, 4.35）有更顯著的影響。
血清葉酸濃度可做為預測台灣年輕族群禁食同半胱胺酸血症的可靠指標。如果同時評估甲硫胺酸負荷後同半胱胺酸濃度則有大約三分之ㄧ（36.3%）的高同半胱胺酸血症會被遺漏。因此建議即使受試者有正常的禁食同半胱胺酸濃度，仍應進一步評估其甲硫胺酸負荷後同半胱胺酸濃度。雖然血漿磷酸比哆醛及高敏感度C-反應蛋白顯著獨立影響冠狀動脈疾病危險性，但若低血漿磷酸比哆醛合併高的高敏感度C-反應蛋白，對冠狀動脈疾病危險性的影響將更加顯著。

Hyperhomocysteinemia has been shown to be an independent risk factor of coronary artery disease (CAD). Deficiencies of B-vitamins (folate, vitamin B-6 and B-12) may account for most cases of hyperhomocysteinemia. Although fasting and post methionine loading (PML) homocysteine concentrations are not necessarily related, a high percentage of hyperhomocysteinemia cases would be missed if methionine loading was not performed. Other than through hyperhomocysteinemia to increase the risk of CAD, low vitamin B-6 status might be associated with inflammation for the risk of CAD. The purposes of this study were to: 1) assess which B-vitamin status indicator [serum folate, red blood cell (RBC) folate, serum vitamin B-12 or plasma pyridoxal 5’-phosphate (PLP)] is the most reliable indicator of fasting plasma homocysteine status in young Taiwanese adults; 2) study the influences of B-vitamins and genetic polymorphism (methylenetetrahydrofolate reductase 677C→T, MTHFR 677C→T) on fasting and PML homocysteine concentrations and the relationship between fasting and PML homocysteine and 3) investigate whether plasma pyridoxal 5’-phosphate (PLP) is dependent or independent on the inflammation marker to associate with the risk of CAD.
Patients were identified with cardiac catheterization as having at least 70% stenosis of one major coronary artery were assigned to the case group (n = 184). The control group (n = 516) was comprised of healthy individuals with normal blood biochemical values. One hundred and ninety-eight healthy subjects were divided into either fasting hyper-homocysteinemia (³ 12.2 mmol/L) (fasting hyper-hcy, n = 51), PML hyper-homocysteinemia (fasting homocysteine &lt; 12.2 mmol/L but PML homocysteine ³ 25.6 mmol/L) (PML hyper-hcy, n = 29), or normo-homocysteinemia (fasting homocysteine &lt; 12.2 mmol/L and PML homocysteine &lt; 25.6 mmol/L) (normo-hcy, n = 118) group based on elevated fasting and PML homocysteine levels of the 75th percentile of the population. One hundred and thirty healthy young adults were divided into either a hyper-homocysteinemia (³ 14.9 mmol/L) (HHcy, n = 13), borderline hyper-homocysteinemia (fasting homocysteine, 14.9 – 10.2 mmol/L) (BHcy, n = 52), or normo-homocysteinemia (fasting homocysteine &lt; 10.2 mmol/L) (NHcy, n = 65) group based on fasting homocysteine levels. All subjects’ height, weight, blood pressure, genetic polymorphisms, plasma fasting and PML homocysteine, serum folate, vitamin B-12, plasma PLP, high sensitivity C-reactive protein (hs-CRP) and lipid profiles were measured.
Fasting homocysteine was only significantly and inversely affected by serum folate (b = -0.21, P &lt; 0.05) concentration after adjusting for potential confounders. Only serum folate concentration remained to decrease the risk of fasting hyperhomocysteinemia (OR, 0.73, CI, 0.56 – 0.95) after the other B-vitamins were additionally adjusted. Serum folate also had the highest area under the receiver operating characteristic curve (AUC) to predict the risk of hyperhomocysteinemia (AUC, 0.81) and hyper-borderline- hyperhomocysteinemia (AUC, 0.77). PML homocysteine and MTHFR 677C→T genotype, was not significantly affected by serum folate concentration after adjusting for potential confounders. Fasting and PML homocysteine were highly associated in the fasting hyper-hcy and pooled groups (P &lt; 0.01) but not in the PML hyper-hcy and normo-hcy groups. PML homocysteine did not interact with either serum folate (P = 0.302), vitamin B-12 (P = 0.465), plasma PLP (P = 0.996) or MTHFR 677C→T genotype (P = 0.136) to affect fasting homocysteine concentration. Plasma PLP concentration was only negatively associated with hs-CRP level in the control group (b = -0.001, p = 0.03) but not in the CAD or pooled groups. The magnitude of the risk of CAD for low plasma PLP (OR, 2.39) and high hs-CRP (OR, 3.37) was very similar. Both low plasma PLP concentration combined with low hs-CRP level (OR, 2.34) and high plasma PLP concentration combined with high hs-CRP level (OR, 3.61) were independently associated with risk for CAD. However, the combined presence of low PLP and higher hs-CRP levels enhanced the risk of CAD and the magnitude was substantially greater (OR, 4.35).
Serum folate is a reliable indicator of fasting hyperhomocysteinemia in the young adult population. Approximately one third (36.3%) of hyperhomocysteinemia cases would be missed if methionine loading were not performed. Even though subjects may have a normal fasting homocysteine concentration, they need further screening for their PML homocysteine. Plasma PLP and hs-CRP are independently associated with an increased risk of CAD, the combined presence of low PLP and high hs-CRP enhanced the risk of CAD and the magnitude was almost double.

Contents

Chinese Abstract ---------------------------------------------------------------------------------------- 6
English Abstract ---------------------------------------------------------------------------------------- 9
Literature Review ------------------------------------------------------------------------------------- 12
Purposes ------------------------------------------------------------------------------------------------ 26

PART 1
Serum not red blood cell folate is strongly associated with hyperhomocysteinemia in healthy young adults ------------------------------------------------------------------------------------------- 28
Abstract ----------------------------------------------------------------------------------------------29
Introduction----------------------------------------------------------------------------------------- 30
Methods --------------------------------------------------------------------------------------------- 31
Results ------------------------------------------------------------------------ ---------------------- 33
Discussion ------------------------------------------------------------------------------------------ 35
References ------------------------------------------------------------------------------------------ 39
Tables ------------------------------------------------------------------------------------------------ 44

PART 2
B-vitamins, homocysteine and gene polymorphism in adults with fasting or post methionine loading hyperhomocysteinemia --------------------------------------------------------------------- 49
Abstract --------------------------------------------------------------------------------------------- 50
Introduction ----------------------------------------------------------------------------------------- 52
Methods --------------------------------------------------------------------------------------------- 53
Results ----------------------------------------------------------------------------------------------- 55
Discussion ------------------------------------------------------------------------------------------ 58
References ------------------------------------------------------------------------------------------ 62
Tables ------------------------------------------------------------------------------------------------ 67

PART 3
Plasma pyridoxal 5’-phosphate and high sensitivity C-reactive protein are independently associated with the increased risk of coronary artery disease ---------------------------------- 72
Abstract ------------------------------------------------------------------------------------------ 73
Introduction ------------------------------------------------------------------------------------- 74
Methods ------------------------------------------------------------------------------------------ 75
Results -------------------------------------------------------------------------------------------- 77
Discussion --------------------------------------------------------------------------------------- 78
References --------------------------------------------------------------------------------------- 82
Tables --------------------------------------------------------------------------------------------- 87

Conclusions ------------------------------------------------------------------------------------------- 90

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Part 1:
1. Selhub J, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr 1992;55:131-138.
2. Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R, Vermaak WJ. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest 1996;98:177-184.
3. Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH, Stabler SP, Reynolds RD, Kok FJ, Hennekens CH, Willett WC. Homocysteine metabolism and risk of myocardial infarction: relation with vitamin B6, B12, and folate. Am J Epidemiol 1996;143:845-859.
4. Lee BJ, Lin PT, Liaw YP, Chang SJ, Cheng CH, Huang YC. Homocysteine and risk of coronary artery disease: Folate is the important determinant of plasma homocysteine concentration. Nutr 2003;19:577-583.
5. Hao L, Ma J, Zhu J, Stampfer MJ, Tian Y, Willett WC, Li Z. High prevalence of hyperhomocysteinemia in Chinese adults is associated with low folate, vitamin B-12, and vitamin B-6 status. J Nutr 2007;137;407-413.
6. Chadefaux B, Cooper BA, Gilfix BM, Lue-Shing H, Carson W, Gavsie A, Rosenblatt DS. Homocysteine: relationship to serum cobalamin, serum folate, erythrocyte folate, and lobation of neutrophils. Clin Invest Med 1994;17:540-550.
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8. Bailey L. Folate status assessment. J Nutr 1990;120:1508-1511.
9. Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987;422:43-52.
10. Bates CJ, Pentieva KD, Matthews N, Macdonald A. A simple, sensitive and reproducible assay for pyridoxal 5’-phosphate and 4-pyridoxic acid in human plasma. Chin Chim Acta 1999;280;101-111.
11. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academy Press, Washington, DC. 2000
12. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-881.
13. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis RJ, Boers GH, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales Luis AC, Parrot-Rouland FM, Tan KS, Higgins I, Garcon D, Andria G. Plasma homocysteine as a risk factor for vascular disease. The European concerted action project. JAMA 1997;277:1775-1781.
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17. Drogan D, Klipstein-Grobusch K, Wans S, Luley C, Boeing H, Dierkes J. Plasma folate as marker of folate status in epidemiological studies: the European Investigation into Cancer and Nutrition (EPIC)-Potsdam study. Brit J Nutr 2004;92:489-496.
18. Golbahar J, Rezaian G, Fathi Z, Aminzadeh MA. Association of low red blood cell folate concentrations with coronary artery disease in Iranians: a matched case-control study. J Vasc Res 2005;42:325-330.
19. Stanisławska-Sachadyn A, Woodside JV, Brown KS, Young IS, Murray L, McNulty H, Strain JJ, Boreham CA, Scott JM, Whitehead AS, Mitchell LE. Evidence for sex differences in the determinants of homocysteine concentrations. Mol Genet Metab 2008;93:355-362.
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36. Miller JW, Ribaya-Mercado JD, Russell RM, Shepard DC, Morrow FD, Cochary EF, Sadowski JA, Gershoff SN, Selhub J. Effect of vitamin B-6 deficiency on fasting plasma homocysteine concentrations. Am J Clin Nutr 1992;55:1154-1160.
37. Chasan-Taber L, Selhub J, Rosenberg IH, Malinow MR, Terry P, Tishler PV, Willett W, Hennekens CH, Stampfer MJ. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996;15:136-143.
38. McKinley MC, McNulty H, McPartlin J, Strain JJ, Pentieva K, Ward M, Weir DG, Scott JM. Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete. Am J Clin Nutr 2001;73:759-764.
39. Chan SJ, Chang CN, Hsu JC, Lee YS, Shen CH. Homocysteine, vitamin B6, and lipid in cardiovascular disease. Nutr 2002;18:595-598.
40. Lee BJ, Huang MC, Chung LJ, Cheng CH, Lin KL, Su KH, Huang YC. Folic acid and vitamin B-12 are more effective than vitamin B-6 in lowering fasting plasma homocysteine concentration in patients with coronary artery disease. Eur J Clin Nutr 2004;58:481-487.
Part 2:
1. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-881.
2. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intake. JAMA 1995;274:1049-1057.
3. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis RJ, Boers GH, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht, JC, de Valk HW, Sales Luis AC, Parrot-Rouland FM, Tan, KS, Higgins I, Garcon D, Andria G. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775-1781.
4. Refsum H, Ueland PM. Recent data are not in conflict with homocysteine as a cardiovascular risk factor. Curr Opin Lipidol 1998;9:533-539.
5. van der Griend R, Haas FJLM, Duran M, Biesma DH, Th Meuwissen OJA, Banga JD. Methionine loading test is necessary for detection of hyperhomocysteinemia. J Lab Clin Med 1998;132:67-72.
6. Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, Malinow MR, Willett WC, Rozen R. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation 1996;94:2410–2416.
7. Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH, Stabler SP, Reynolds RD, Kok FJ, Hennekens CH, Willett WC. Homocysteine metabolism and risk of myocardial infarction: relation with vitamin B6, B12, and folate. Am J Epidemiol 1996;143:845-859.
8. Verhoef P, Kok FJ, Kluijtmans LA, Blom HJ, Refsum H, Ueland PM, Kruyssen DA. The 677C®T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease. Atherosclerosis 1997;132:105-113.
9. Clarke R, Armitage J. Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements. Semin Thromb Hemost 2000;26:341-348.
10. Lee BJ, Lin PT, Liaw YP, Chang SJ, Cheng CH, Huang YC. Homocysteine and risk of coronary artery disease: Folate is the important determinant of plasma homocysteine concentration. Nutr 2003;19:577-583.
11. Lee BJ, Huang MC, Chung LJ, Cheng CH, Lin KL, Su KH, Huang YC. Folic acid and vitamin B-12 are more effective than vitamin B-6 in lowering fasting plasma homocysteine concentration in patients with coronary artery disease. Eur J Clin Nutr 2004;58:481-487.
12. Brattström L, Israelsson B, Norrving B, Bergqvist D, Thorne J, Hultberg B, Hamfelt A. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. Atherosclerosis 1990;81:51-60.
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14. Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R, Vermaak WJ. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest 1996;98:177-184.
15. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149-1155.
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17. Tsai MY, Welge BG, Hanson NQ, Bignell MK, Vessey J, Schwichtenberg K, Yang F, Bullemer FE, Rasmussen R, Graham KJ. Genetic causes of mild hyperhomocysteinemia in patients with premature occlusive coronary artery diseases. Atherosclerosis 1999;143:163-170.
18. Marcucci R, Giusti B, Betti I, Evangelisti L, Fedi S, Sodi A, Cappelli S, Menchini U, Abbate R, Prisco D. Genetic determinants of fasting and post-methionine hyperhomocysteinemia in patients with retinal vein occlusion. Thromb Res 2003;11:7-12.
19. Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987;422:43-52.
20. Bates CJ, Pentieva KD, Matthews N, Macdonald A. A simple, sensitive and reproducible assay for pyridoxal 5’-phosphate and 4-pyridoxic acid in human plasma. Chin Chim Acta 1999;280:101-111.
21. Zhang G, Dai C. Gene polymorphism of homocysteine metabolism-related enzymes in Chinese patients with occlusive coronary artery or cerebral vascular disease. Thromb Res 2001;104:187-195.
22. Giusti B, Camacho-Vanegas O, Attanosio M, Comeglio P, Gori AM, Brunelli T, Prisco D, Gensini GF, Abbate R, Pepe G. Microheterogeneity in the distribution of the 844ins68 in the cystathionine β-synthase gene in Italy. Thromb Res 1999;94:249-254.
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28. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693–2698.
29. Selhub J, Miller JW. Hypothesis ― the pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr 1992;55:131-138.
30. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R, Potgieter HC. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927-1933.
31. Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH, Stabler SP. Homocysteine metabolism and risk of myocardial infarction: relation with vitamin B6, B12, and folate. Am J Epidemiol 1996;143:845-859.
32. Miller JW, Nadeau MR, Smith D, Selhub J. Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr 1994;59:1033-1039.
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Part 3:
1. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens GH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-881.
2. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of fasting plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-1057.
3. Rydlewicz A, Simpson JA, Taylor RJ, Bond CM, Golden MHN. The effect of folic acid supplementation on fasting plasma homocysteine in an elderly population. Q J Med 2002;95:27-35.
4. Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB. Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. Int J Epidemiol 2002;31:59-70.
5. Bautista LE, Arenas IA, Penuela A, Martinez LX. Total plasma homocysteine level and risk of cardiovascular disease: a meta-analysis of prospective cohort studies. J Clin Epidemiol 2002;55:882-887.
6. Serfontein WJ, Ubbink JB, de Villiers LS, Rapley CH, Becker PJ. Plasma pyridoxal-5-phosphate level as risk index for coronary artery disease. Atherosclerosis 1985;55:357-361.
7. Robinson K, Mayer EL, Miller DP, Green R, van Lente F, Gupta A, Kottke-Marchant K, Saon SR, Selhub J, Nissen SE. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation 1995;92:2825-2830.
8. Chan SJ, Chang CN, Hsu JC, Lee YS, Shen CH. Homocysteine, vitamin B6, and lipid in cardiovascular disease. Nutr 2002;18:595-598.
9. Lee BJ, Huang MC, Chung LJ, Cheng CH, Su KH, Huang YC. Folic acid and vitamin B-12 are more effective than vitamin B-6 in lowering fasting plasma homocysteine concentration in patients with coronary artery disease. Eur J Clin Nutr 2004;58:481-487.
10. Brattström L, Israelsson B, Norrving B, Bergqvist D, Thorne J, Hultberg B, Hamfelt A. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. Atherosclerosis 1990;81:51-60.
11. Miller JW, Ribaya-Mercado JD, Russell RM, Shepard DC, Morrow FD, Cochary EF, Sadowski JA, Gershoff SN, Selhun J. Effect of vitamin B-6 deficiency on fasting plasma homocysteine concentrations. Am J Clin Nutr 1992;55:1154-1160.
12. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ, Delport R, Potgieter HC. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927-1933.
13. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999;340:115-26.
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