Nakai K, Itoh C, Nakai K, Habano W, Gurwitz D
Laboratory Medicine, Iwate Medical University, Morioka, Japan.
Am J Cardiovasc Drugs. 2001;1(5):353-61. doi: 10.2165/00129784-200101050-00005.
The lesions of coronary atherosclerosis represent the result of a complex, multicellular, inflammatory-healing response in the coronary arterial wall. In vivo and in vitro cellular and molecular studies have suggested a role for tissue homocysteine in endothelial cell injury and adverse extra-cellular matrix remodeling. Gene polymorphisms in relation with numerous risk factors might increase the incidence of coronary artery disease (CAD). In this review we have focused on the correlations between plasma homocysteine levels, the incidence of cardiovascular disease and the cytosine-to-thymidine substitution at nucleotide 677 (C677T) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, coding for a key enzyme in methionine-homocysteine metabolism. The role of the C677T MTHFR gene polymorphism in the causation of CAD is controversial. We reviewed 12 recent case-control studies comprising 5370 genotyped patients with CAD and 4961 genotyped participants without CAD. There was no significant difference between those with and without CAD in the frequency of the C677T polymorphism (34.9 vs 33.6%). The frequency of homozygous C677T polymorphism in these groups was 10.9 versus 12.8%, respectively, although there were some ethnic differences in the C677T MTHFR polymorphism. In the analysis of the 12 studies, the odds ratio of CAD associated with the TT genotype (homozygous C677T polymorphism) was 1.18. Only slightly higher plasma homocysteine levels were observed in participants with the val/val (TT) genotype (14.4+/-2.9 micro mol/L in TT genotype vs 11.1+/-1.9 and 11.9+/-2 micro mol/L in CC and CT genotype, respectively). In addition, the relation between homocysteine increase after methionine loading and MTHFR genotypes is also controversial. However, hyperhomocysteinemia because of the C677T MTHFR allele may be corrected with oral folic acid therapy. Further investigations on the relationships between MTHFR genotypes and the incidence of CAD should be based on larger samples, paying attention to the differences between various ethnic populations. Individual therapeutic strategies based on single nucleotide polymorphism may become increasingly important for preventive treatment against polygenic CAD.
冠状动脉粥样硬化病变是冠状动脉壁内复杂的多细胞炎症修复反应的结果。体内和体外细胞及分子研究表明，组织同型半胱氨酸在内皮细胞损伤和不良细胞外基质重塑中起作用。与众多危险因素相关的基因多态性可能会增加冠状动脉疾病（CAD）的发病率。在本综述中，我们重点关注了血浆同型半胱氨酸水平、心血管疾病发病率与5,10-亚甲基四氢叶酸还原酶（MTHFR）基因第677位核苷酸（C677T）胞嘧啶到胸腺嘧啶的替换之间的相关性，该基因编码甲硫氨酸-同型半胱氨酸代谢中的关键酶。C677T MTHFR基因多态性在CAD病因中的作用存在争议。我们回顾了12项近期的病例对照研究，包括5370例经基因分型的CAD患者和4961例经基因分型的非CAD参与者。C677T多态性的频率在CAD患者和非CAD患者之间没有显著差异（34.9%对33.6%）。这些组中纯合C677T多态性的频率分别为10.9%和12.8%，尽管C677T MTHFR多态性存在一些种族差异。在对这12项研究的分析中，与TT基因型（纯合C677T多态性）相关的CAD优势比为1.18。仅在val/val（TT）基因型的参与者中观察到略高的血浆同型半胱氨酸水平（TT基因型为14.4±2.9微摩尔/升，而CC和CT基因型分别为11.1±1.9和11.9±2微摩尔/升）。此外，甲硫氨酸负荷后同型半胱氨酸增加与MTHFR基因型之间的关系也存在争议。然而，因C677T MTHFR等位基因导致的高同型半胱氨酸血症可用口服叶酸治疗纠正。关于MTHFR基因型与CAD发病率之间关系的进一步研究应基于更大的样本，注意不同种族人群之间的差异。基于单核苷酸多态性的个体化治疗策略对于多基因CAD的预防性治疗可能变得越来越重要。
