胱硫醚β-合成酶基因多型性與高同半胱胺酸血症及罹患冠狀動脈心臟病之關係

導致高同半胱酸血症的原因很多，其中參與同半胱胺酸代謝的轉硫作用中的胱硫醚 β-合成酶 (Cystathionine β-synthase, CBS) 基因缺損（如： CBS844ins68 突變基因）已經受到廣泛研究，但目前國內對於 CBS 844ins68 基因多型性與血漿同半胱胺酸及冠狀動脈心臟病關係之研究卻非常少。因此，本研究目的為： (1) 瞭解 CBS 844ins68 基因多型性的分佈狀況及與不同種族人口分佈狀況相比較； (2) 探討 CBS 844ins68 基因多型性與血漿同半胱胺酸、血漿磷酸比哆醛濃度之關係； (3) 探討 CBS 844ins68 基因多型性與罹患冠狀動脈心臟病之關係。實驗設計為病例—對照研究，由台中榮民總醫院心臟內科招募冠狀動脈心臟病病人作為病例組，共 186 位；另外由台中榮民總醫院體檢部門招募健康受試者為對照組，共 321 位。採集受試者空腹禁食至少 8 小時後的全血，進行同半胱胺酸、磷酸比哆醛、葉酸及維生素 B-12 的分析。由白血球衣萃取出之 DNA ，利用聚合酵素連鎖反應後經聚丙烯醯胺凝膠電泳確定 CBS 基因型。結果顯示 CBS 844ins68 為異型合子 (+/-) 之基因座頻率在病例組為 2.7% ；對照組為 0.3% 。CBS 844ins68 野生型 (-/-) 與 CBS 844ins68 異型合子 (+/-) 者在營養素攝取皆無差異性。但是，CBS 844ins68 野生型 (-/-) 的受試者血漿同半胱胺酸濃度與血漿磷酸比哆醛 (r = -0.165, p < 0.0001) 、血清葉酸 (r = -0.129, p = 0.00429) 與血清維生素 B-12 (r = -0.192, p < 0.0001) 濃度皆呈顯著負相關性。但 CBS 844ins68 異型合子 (+/-) 受試者的血漿同半胱胺酸濃度與磷酸比哆醛、血清葉酸與維生素 B-12 濃度無顯著相關性。以複迴歸分析，調整性別、磷酸比哆醛、葉酸、維生素 B-12 及其他相關危險因子後， CBS 844ins68 基因多型性與血漿同半胱胺酸、磷酸比哆醛及血清葉酸濃度皆無顯著關係。利用邏輯式迴歸分析，調整年齡、性別、磷酸比哆醛、葉酸及維生素 B-12 及其他相關危險因子後， CBS 844ins68 異型合子 (+/-) 基因型者罹患冠狀動脈心臟病的相對危險比 (Odd ratio, OR) 與 CBS 844ins68 同型合子 (-/-) 基因型者並無顯著差異 (OR = 4.8; 95 % CI, 0.15-160.62, p = 0.38) 。雖然病例組之受試者有較高的 CBS 844ins68 異型合子 (+/-) 基因座頻率，但此突變對禁食血漿同半胱胺酸濃度及冠狀動脈心臟病之相對危險比皆無顯著之關係。

關鍵字

胱硫醚 β-合成酶基因多型性；同半胱胺酸；冠狀動脈心臟病；相對危險比

並列摘要

Many factors are associated with the elevation of plasma homocysteine, of particular, is cystathionine　β-synthase (CBS) genetic defects in the transsulfuration of homocysteine metabolism. Recently, the relationship between CBS 844ins68 polymorphism with hyperhomocysteinemia and coronary artery disease (CAD) mortality have been paid much attention. However, few data has been reported in Taiwan. Therefore, the purposes of this study were: (1) to investigate and compare the distribution of CBS 844ins68 polymorphism and genotype and (+) allele frequency of CBS 844ins68 polymorphism in cardiovascular disease and health subjects in different ethnic population; (2) to determine the association between of CBS 844ins68 polymorphism with plasma homocysteine (Hcy), pyridoxal 5’-phosphate (PLP) concentrations; (3) to estimate the relation between CBS 844ins68 polymorphism and the odds ratio (OR) of CAD. This was a case-control study. CAD patients and healthy subjects were recruited from Taichung Veterans General Hospital and were assigned to either the case group (n = 186) or the control group (n = 321). Fasting blood (at least 8 hr) samples were drawn for the measurements of Hcy, PLP, folate, and vitamin B-12. Genomic DNA was extracted from buffy coat, and the CBS 844ins68 polymorphism was identified by using a polymorphism chain reaction assay. Results showed that the gene frequency of CBS844ins68 (+/-) is 2.7% and 0.3% in the case and control group, respectively. There were no differences between case and control groups in their dietary intakes. Plasma Hcy concentration was significantly negatively correlated with plasma PLP (r = -0.165, p < 0.0001), serum folate (r = -0.129, p = 0.00429) and serum vitamin B-12 (r = -0.192, p < 0.0001) concentrations in subjects with CBS 844ins68 wild type (-/-). However, plasma homocysteine concentration was not correlated with plasma PLP, serum folate and vitamin B-12 concentrations in subjects with CBS 844ins68 heterozygous (+/-). Plasma homocysteine, PLP and serum folate concentrations were not associated by the CBS 844ins68 polymorphism after adjusting with gender, PLP, folate, vitamin B-12 and other potential risk factors by using multiple linear regression. In addition, the CBS 844ins68 polymorphism had no association with the risk of CAD (OR = 4.8; 95 % CI, 0.15-160.62, p = 0.38). There was a higher frequency of CBS 844ins68 (+/-) in the case group; however, this mutation had no association with plasma homocysteine concentration and the risk of CAD.

並列關鍵字

cystathionine β-synthase ； polymorphisms ； homocysteine ； coronary artery disease ； odds ratio

參考文獻

徐憶驊。砷暴露地區居民同半胱胺酸代謝酵素基因多形性與頸動脈粥狀硬化之相關性研究。臺北醫學大學公共衛生研究所碩士論文。 2002 。

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Afman LA, Lievers KJ, Kluijtmans LA, Trijbels FJ, Blom HJ. Gene-gene interaction between the cystathionine beta-synthase 31 base pair variable number of tandem repeats and the methylenetetrahydrofolate reductase 677C > T polymorphism on homocysteine levels and risk for neural tube defects. Mol Genet Metab 2003; 78: 211-225.

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胱硫醚β-合成酶基因多型性與高同半胱胺酸血症及罹患冠狀動脈心臟病之關係

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