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

Literature
1. du Vigneaud VE. Trail of research in sulfur chemistry and metabolism, and related fields. Ithaca, New York: Cornell University Press, 1932.
2. Kang SS, Wong PWK, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 1992;12:279-298.
3. 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.
4. 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.
5. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-881.
6. Montalescot G, Ankri A, Chadefaux-Vekemans B, Blacher J, Philippe F, Drobinski G, Benzidia R, Kamoun P, Thomas D. Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease. Int J Cardiol 1997;60:295-300.
7. Boers GH, Smals AG, Trijbels FJ, Leermakers AI, Kloppenborg PW. Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. J Clin Invest 1983;72:1971-1976.
8. Taylor LM Jr, DeFrang RD, Harris EJ Jr, Porter JM. The association of elevated plasma homocyst(e)ine with progression of symptomatic peripheral arterial disease. J Vasc Surg 1991;13:128-136.
9. Brattstrom LE, Hardebp E, Hultberg BL. Moderate homocysteinemia – a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke 1984;15:1012-1016.
10. Brattstrom L, Lindgren A, Israelsson B, Malinow MR, Norrving B, Upson B, Hamfelt A. Hyperhomocysteinaemia in stroke: prevalence, cause and relationships to type of stroke and stroke risk factors. Eur J Clin Invest 1992;22:214-221.
11. 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.
12. 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.
13. 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.
14. Block WD, Markovs ME, Steele BF. Effect of protein and of free L-methionine intake on amino acid excretion by human subjects. J Nutr 1965;86:256-264.
15. Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem 1990;1:228-237.
16. Bores GHJ, Smals AGH, Trijbels FJM, Fowler B, Bakkerem JAJM, Schoonderwaldt HC, Kleijer WJ, Kloppenborg PWC. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 1985:313:709-715.
17. 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.
18. Engbersen AMT, Franken DG, Bores GHJ, Steven EMB, Trijbels FJM, Blom HJ. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 1995;56:142-150.
19. Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PWF, Belanger AJ, O’Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH. Association between plasma homocysteine concentration and extracranial carotids-artery stenosis. N Eng J Med 1995;332:286-291.
20. Tsai MY, Yang F, Bignell M, Aras O, Hanson NQ. Relation between plasma homocysteine concentration, the 844ins68 variant of the cystathionine b-synthase gene, and pyridoxal-5''-phosphate concentration. Mol Genet Metab 1999;67:352-356.
21. Bostom AG, Jacques PF, Nadeau MR, Williams RR, Ellison RC, Selhub J. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis 1995;16:147-151.
22. Joosten E, van den Berg A, Riezler R, Naurath HJ, Lindenbaum J, Stabler SP, Allen RH. Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people. Am J Clin Nutr 1993;58:468-476.
23. Lussier-Cacan S, Xhignesse M, Piolot A, Selhub J, Davignon J, Genest J. Plasmatotal homocysteine in healthy subjects: sex-specific relation with biological traits. Am J Clin Nutr 1996;64:587-593.
24. Saw SM, Yuan JM, Ong CN, Arakawa K, Lee HP, Coetzee GA, Yu MC. Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentration in middle-aged and older Chinese men and women in Singapore. Am J Cin Nutr 2001;73:232-239.
25. Morris MS, Jacques PF, Rosenberg IH, Selhub J, Browman BA, Gunter EW, Wright JD, Johnson CL. Serum total homocysteine concentration is related to self-reported heart attack or stroke history among men and women in the NHANES Ш. J Nutr 2000;130:3073-3076.
26. Anderson JL, King GJ, Thomson J, Todd M, Bair TL, Muhlestein JB Carlquist JF. A mutation in the methylenetetrahydrofolate reductase gene is not associated with increase risk for coronary artery disease or myocardial infarction. J Am Coll Cardiol 1997;30:1206-1211.
27. Markus HS, Ali N, Swaminathan R, Sankaralingam A, Molloy J, Powell J. A common polymorphism in the methylenetetrahydrofolate reductase gene, homocysteine, and ischemic cerebrovascular disease. Stroke 1997;28:1739-1743.
28. Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y. Genetic polymorphism of 5,10- methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation 1997;95:2032-2036.
29. 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.
30. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996;27:517-527.
31. Booth GL, Wang EEL. Preventive health care, 2000 update: Screening and management of hyperhomocysteinemia for prevention of coronary artery disease events. The Canadian Task Force on Preventive health care. CAMJ 2000;163:21-29.
32. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693-2698.
33. Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ. Folate and vitamin B-6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:359-364.
34. Brouwer IA, Van Dussedorp M, Thomas CA, Duran M, Hautrast JG, Eskes TK, Steegers-Theunissen RP. Low-dose folic acid supplementation decrease plasma homocysteine concentration: a randomized trial. Am J Clin Nutr 1999;69:99-104.
35. Ubbink JB. The role of vitamins in the pathogenesis and treatment of hyperhomocyst(e)inaemia. J Inherit Metab Dis 1997;20:316-325.
36. Herbert V. Making sense of laboratory tests of folate status: folate requirements to sustain normality. Am J Hematology 1987;26:199-207.
37. 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.
38. Ovesen L, Boeing H, the EFCOSUM group. The use of biomarkers in multicentric studies with particular consideration of iodine, sodium, iron, folate and vitamin D. Eur J Clin Nutr 2002;56(suppl 2):s12-17.
39. Stites TE, Bailey LB, Scott KC, Toth JP, Fisher WP, Gregory JF 3rd. Kinetic modeling of folate metabolism through use of chronic administration of deuterium-labeled folic acid in men. Am J Clin Nutr 1997;65:53-60.
40. Wu A, Chanarin I, Slavin G, Levi AJ. Folate deficiency in the alcoholic – its relationship to clinical and hematolofical abnormalities, liver disease and folate stores. Br J Haematol 1975;29:469-478.
41. Bailey L. Folate status assessment. J Nutr 1990;120:1508-1511.
42. Ueland PM, Refsum H, Stabler SP, Malinow MR, Anderson A, Allen RH. Total homocysteine in plasma or serum: methods and clinical implications. Clin Chem 1993;39:1764-1769.
43. Choumenkovitch SF, Jacques PF, Nadeau MR, Wilson PWF, Rosenberg IH, Selhub J. Folic acid fortification increases red blood cell folate concentrations in the Framingham study. J Nutr 2001;131:3277-3280.
44. Allen R, Stabler S, Savage D, Lindenbaum J. Diagnosis of cobalamin deficiency I: usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 1990;34:90-98.
45. Rasmussen K, Møller J, Lyngbak M, Pedersen AM, Dybkjaer L. Age- and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. Clin Chem 1996;42:630-636.
46. Shultz TD, Hansen CM. Plasma homocysteine change with vitamin B-6 depletion and repletion in young women. Nutr Res 1998;18:975-978.
47. Robinson K, Mayer EL, Miller DP, Green R, van Lente F, Gupta A, Kottke-Marchant K, Savon 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.
48. Brattström L, Israelsson B, Norrving B, Bergqvist D, Thörne 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.
49. Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology. Arterioscler Thromb 1993;13:1253-1260.
50. Siri PW, Verhoef P, Kok FJ. Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis. J Am Coll Nutr 1998;17:435-441.
51. 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. Clin Chim Acta 1999;280:101-111.
52. 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.
53. Giraud DW, Driskell JA, Setiawan B. Plasma homocysteine concentrations of Indonesian children with inadequate and adequate vitamin B-6 status. Nutr Res 2001;21:961-966.
54. Ross R. Atherosclerosis: an inflammatory disease. Am Heart J 1999;138:S419-420.
55. Kullo IJ, Gau GT, Tajik AJ. Novel risk factors for atheroisclerosis. Mayo Clin Proc 2000;75:369-380.
56. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998;279:1477-1482.
57. Friso S, Jacques PF, Wilson PWF, Rosenberg IH, Selhub J. Low circulating vitamin B6 is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation 2001;103:2788–2791.
58. Louw JA, Werbeck A, Louw ME, Kotze TJ, Cooper R, Labadarios D. Blood vitamin concentrations during the acute-phase response. Crit Care Med 1992;20:934-941.
59. Galloway P, McMillan DC, Sattar N. Effect of the inflammatory response on trace element and vitamin status. Ann Clin Biochem 2000;37:289-297.
60. Talwar D, Quasim T, McMillan DC, Kinsella J, Williamson C, O''Reilly DS. Pyridoxal phosphate decreases in plasma but not erythrocytes during systemic inflammatory response. Clin Chem 2003;49:515-518.
61. Huang YC, Chang HH, Huang SC, Cheng CS, Lee BJ, Cheng SY, Su KH. Plasma Pyridoxal 5’-phosphate is a significant indicator of immune responses in the mechanically ventilated critically ill. Nutr 2005;21:779-785.
62. Rinehart JF, Greenberg LD. Arteriosclerotic lesions in pyridoxine-deficient monkeys. Am J Pathol 1949;25:481-491.
63. Ellis JM, McCully KS. Prevention of myocardial infarction by vitamin B6. Res Commun Mol Pathol Pharm 1995;89:208-220.
64. Murray JC, Frazer DR, Levene CI. The effect of pyridoxine deficiency on lysyl oxidase activity in the chick. Exp Mol Path 1978;28:301-308.
65. McCully KS. Homocysteine theory of arteriosclerosis – Development and current status. Ath Rev 1983;11:157-246.
66. Cunnane SC, Manku MS, Horrobin DF. Accumulation of linoleic acid and g-linolenic acid in tissue lipids of pyridoxine-deficient rats. J Nutr 1984;114:1754-1761.
67. Packham MA, Lam SCT, Mustard JF. Vitamin B6 as an antithromnotic agent. Lancet 1981;10:809-810.
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.
7. Wu A, Chanarin I, Slavin G, Levi AJ. Folate deficiency in the alcoholic – its relationship to clinical and hematolofical abnormalities, liver disease and folate stores. Br J Haematol 1975;29:469-478.
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.
14. Hankey GJ, Eikelboom JW, Ho WK, van Bockxmeer FM. Clinical usefulness of plasma homocysteine in vascular disease. Med J Aust 2004;181:314-318.
15. Arauz A, Hoyos L, Cantu C, Jara A, Martinez L, Garcia I, Fernandez Mde L, Alonso E. Mild hyperhomocysteinemia and low folate concentrations as risk factors for cervical arterial dissection. Cerebrovasc Dis 2007;24:210-214.
16. Dierkes J, Jeckel S, Ambrosch A, Westphal S, Luley C, Boeing H. Factors Explaining the Difference of Total Homocysteine Between Men and Women in the European Investigation Into Cancer and Nutrition Potsdam Study. Metabolism 2001;50:640-645.
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.
20. Michalis LK, Pappas K, Tweddel A, Kolaitis N, Katsouras CS, Loukas S, Goudevenos J, Bourantas K, Sideris DA. Relatively low red cell folate levels and acute coronary syndromes. Coron Artery Dis 2001;12:665-668.
21. Jacques RF, Sulsky SI, Sadowski JA, Phillips JCC, Rush D, Willett WC. Comparison of micronutrient intake measured by a dietary questionnaire and biochemical indicators of micronutrient status. Am J Clin Nutr 1993;57:182-189.
22. Caudill MA, Le T, Monnie SA, Esfahani ST, Cogger EA. Folate status in women of childbearing age residing in Southern California after folic acid fortification. J Am Coll Nutr 2001;20(suppl 2):129-134.
23. Choumenkovitch SF, Jacques PF, Nadeau MR, Wilson PWF, Rosenberg IH, Selhub J. Folic acid fortification increases red blood cell folate concentrations in the Framingham study. J Nutr 2001;131:3277-3280.
24. Dietrick M, Brown CJP, Block G. The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States. J Am Coll Nutr 2005;24:266-274.
25. Ganji V, Kafai MR. Trends in serum folate, RBC folate, and circulating total homocysteine concentrations in the United States: analysis of data from National Health and Nutrition Examination Surveys, 1988-1994, 1990-2000, and 2001-2002. J Nutr 2006;136:153-158.
26. Bain BJ, Wickramasinghe SN, Broom GN, Litwinczuk RA, Sims J. Assessment of the value of a competitive protein binding radioassay of folic acid in the detection of folic acid deficiency. J Clin Pathol 1984;37:888-894.
27. Dawson DW, Fish DI, Frew ID, Roome T, Tilston I. Laboratory diagnosis of megaloblastic anaemia: current methods assessed by external quality assurance trials. J Clin Pathol 1987;40:393-397.
28. Ueland PM, Refsum H, Stabler SP, Malinow MR, Anderson A, Allen RH. Total homocysteine in plasma or serum: methods and clinical implications. Clin Chem 1993;39:1764-1769.
29. Ovesen L, Boeing H, the EFCOSUM group. The use of biomarkers in multicentric studies with particular consideration of iodine, sodium, iron, folate and vitamin D. Eur J Clin Nutr 2002;56(suppl 2):s12-17.
30. Selhub J, Jacques PF, Dallal G, Choumenkovitch S, Rogers G. The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B12 status. Food Nutr Bulletin 2008;29:S67-73.
31. Jaffe JP, Schilling RF. Erythrocyte folate levels: a clinical study. Am J Hematol 1991;36:116-121.
32. Phekoo K, Williams Y, Schey SA, Andrews VE, Dudley JM, Hoffbrand AV. Folate assays: serum or red cell? J R Coll Physicians Lond 1997;31:291-5.
33. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 1990;34:99-107.
34. Bailey LB, Duhaney RL, Maneval DR, Kauwell GP, Quinlivan EP, Davis SR, Cuadras A, Hutson AD, Gregory JF 3rd. Vitamin B-12 status is inversely associated with plasma homocysteine in young women with C677T and/or A1298C methylenetetrahydrofolate reductase polymorphisms. J Nutr 2002;132:1872-1878.
35. 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.
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.
13. Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology. Arterioscler Thromb 1993;13:1253-1260.
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.
16. Bostom AG, Jacques PF, Nadeau MR, Williams RR, Ellison RC, Selhub J. 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.
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.
23. van den Berg M, de Jong SC, Devillé W, Rauwerda JA, Jakobs C, Pals G, Boers GH, Stehouwer CD. Variability of fasting and post-methionine plasma homocysteine levels in normo- and hyperhomocysteinemia individuals. Neth J Med 1999;55:29-38.
24. Dunkelgrun M, Hoeks SE, Schouten O, Feringa HHH, Welten GMJM, Vidakovic R, van Gestel YRBM, van Domburg RT, Goei D, de Jonge R, Lindemans J, Poldermans D. Methionine loading does not enhance the predictive value of homocysteine serum testing for all-cause mortality or major adverse cardiac events. Intern Med J 200939:13-18.
25. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99:178-182.
26. Durand P, Prost M, Loreau N, Lussier-Cacan S, Blache D. Impaired homocysteine metabolism and atherothrombotic disease. Lab Invest 2001;81:645–672.
27. Refsum H, Ueland PM, Nygrd O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31–62.
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.
33. Hart SR, Mangoni AA, Swift CG, Jackson SH. Effect of methionine loading on pulse wave analysis in elderly volunteers. Postgrad Med J 2006a;82:524-527.
34. Hart SR, Mangoni AA, Swift CG, Jackson SHD. Lack of significant effects of methionine loading on endothelial function in elderly volunteers. Heat Lung Circ 2006b;15:358-361
35. Qujeq D, Omran TS, Hosini L. Correlation between total homocysteine, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol in the serum of patients with myocardial infarction. Clin Biochem 2001;34:97-101.
36. Refsum H, Ueland PM. Recent data are not in conflict with homocysteine as a cardiovascular risk factor. Curr Opin Lipidol 1998;9:533-539.
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.
14. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135-1143.
15. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998;279:1477-1482.
16. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 2001;32:917-924.
17. Kullo IJ, Gau GT, Tajik AJ. Novel risk factors for atheroisclerosis. Mayo Clin Proc 2000;75:369-380.
18. Friso S, Jacques PF, Wilson PWF, Rosenberg IH, Selhub J. Low circulating vitamin B6 is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation 2001;103:2788-2791.
19. Chiang EP, Smith DE, Selhub J, Dallal G, Wang YC, Roubenoff R. Inflammation causes tissue-specific depletion of vitamin B6. Arthritis Res & Therapy 2005;7:R1254-1262.
20. Galloway P, McMillan DC, Sattar N. Effect of the inflammatory response on trace element and vitamin status. Ann Clin Biochem 2000;37:289-897.
21. Talwar D, Quasim T, McMillan DC, Kinsella J, Williamson C, O''Reilly DS. Pyridoxal phosphate decreases in plasma but not erythrocytes during systemic inflammatory response. Clin Chem 2003;49:515-518.
22. 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.
23. 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. Clinica Chemica Acta 1999;280:101-111.
24. Dominici R, Luraschi P, Franzini C. Measurement of C-reactive protein: two high sensitivity methods compared. J Clin Lab Anal 2004;18:280-284.
25. Leklem JE. Vitamin B6: a status report. J Nutr 1990; 120:1503-1507.
26. Food and Nutrition Board – Institute of Medicine. Dietary Reference Intakes. Thiamin, Riboflavin, Niacin, Vitamin B-6, Folate, Vitamin B-12, Pantothenic acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998.
27. Lui A, Lumeng L, Aronoff GR, Li TK. Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: metabolic balance studies in humans. J Lab Clin Med 1985;106:491-497.
28. Friso S, Girelli D, Martinelli N, Olivieri O, Lotto V, Bozzini C, Pizzolo F, Faccini G, Beltrame F, Corrocher R. Low plasma vitamin B-6 concentrations and modulation of coronary artery disease risk. Am J Clin Nutr 2004;79:992-998.
29. Kelly PJ, Kistler JP, Shih VE, Mandell R, Atassi N, Barron M, Lee H, Silveira S, Furie KL. Inflammation, homocysteine, and vitamin B6 status after ischemic stroke. Stroke 2004;35:12-15.
30. Folsom AR, Desvarieux M, Nieto FJ, Boland LL, Ballantyne CM, Chambless LE. B vitamin status and inflammatory markers. Atheroscleroisis 2003;169:169-174.
31. Huang YC, Chang HH, Huang SC, Cheng CH, LeeBJ, Cheng SY, Su KH. Plasma pyridoxal 5’-phosphate is a significant indicator of immune responses in the mechanically ventilated critically ill. Nutr 2005;21:779-785.
32. Gray A, McMillan DC, Wilson C, Williamson C, O’Reilly D St.J, Talwar D. The relationship between plasma and red cell concentrations of vitamins thiamine diphosphate, flavin adenine dinucleotide and pyridoxal 5-phospahte following elective knee arthroplasty. Clin Nutr 2004;23:1080-1083.
33. Quasim T, McMillan DC, Talwar D, Vasilaki A, O’Reilly D St.J, Kinsella J. The relationship between plasma and red cell B-vitamin concentrations in critically-ill patients. Clin Nur 2005;24:956-960.
34. Dierkes J, Weikert C, Klipstein-Grobusch K, Westphal S, Luley C, Möhlig M, Spranger J, Boeing H. Plasma pyridoxal 5’-phosphate and future risk of myocardial infarction in the European Prospective Investigation into Cancer and Nutrition Potsdam cohort. Am J Clin Nutr 2007;86:214-220.
35. Harripersad R, Burger FJ. The effect of a subnormal dose of vitamin B6 on plasma lipid in the rat. Internat J Vit Nutr Res 1997;67:95-101.
36. Pregnolato P, Maranesi M, Marchetti M, Barzanti V, Bergami R, Tolomelli B. Interaction among dietary vitamin B6, proteins and lipids: effects on liver lipids in rats. Internat J Vit Nutr Res 1994;64:263-269.
37. Lin PT, Cheng CH, Liaw YP, Lee BJ, Lee TW, Huang YC. Low pyridoxal 5’-phosphate is associated with increased risk of coronary artery disease. Nutr 2006;22:1146-1151
38. Binder CJ, Chang M-K, Shaw PX, Miller YI, Hartvigsen K, Dewan A, Witztum JL. Innate and acquired immunity in atherogenesis. Nat Med 2002;23:535-541.
39. Greaves DR, Channon KM. Inflammation and immune responses in atherosclerosis. Trends Immunol 2002;8:1257-1262.
40. Talbott MC, Miller LT, Kerkvliet NI. Pyridoxine supplementation: effect on lymphocyte responses in elderly persons. Am J Clin Nutr 1987;46:659-664.
41. Folkers K, Morita M, McRee J Jr. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem & Biophys Res Commun 1993;193:88-92.
42. Meydani SN, Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elderly adults. Am J Clin Nutr 1991;53:1275-1280.
43. Cheng CH, Huang YC, Chang SJ, Lee BJ, Lin KL. Vitamin B6 supplementation improves immune responses in critically ill patients. Eur J Clin Nutr 2006;60:1207-1213.