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  • 學位論文

維生素B-6、B-12、葉酸與高同半胱胺酸血症、發炎反應及冠狀動脈疾病之相關性

Vitamin B-6, B-12 and Folate in Relation to Hyperhomocysteinemia, Inflammation and Coronary Artery Disease

指導教授 : 蔡宗博

摘要


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。

並列摘要


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 < 12.2 mmol/L but PML homocysteine ³ 25.6 mmol/L) (PML hyper-hcy, n = 29), or normo-homocysteinemia (fasting homocysteine < 12.2 mmol/L and PML homocysteine < 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 < 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 < 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 < 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.

參考文獻


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