Kadziela Jacek, Janas Jadwiga, Dzielińska Zofia, Szperl Małgorzata, Gaździk Danuta, Chotkowska Ewa, Piotrowski Walerian, Ruzyłło Witold
1st Department of Coronary Artery Disease, National Institute of Cardiology, Warsaw, Poland.
Kardiol Pol. 2003 Jul;59(7):17-26; discussion 26.
The C677T mutation in methylenetetrahydrofolate reductase (MTHFR) gene is one of the causes of an elevated homocysteine plasma concentration and is probably one of the atherosclerotic risk factors.
To assess the relationship between the presence of the MTHFR gene mutation, plasma homocysteine concentration and the risk of coronary artery disease (CAD).
The study group consisted of 120 consecutive patients (78% were male, mean age 59.2+/-9.6 years) with angiographically confirmed CAD and 106 healthy volunteers (76% were male, mean age 47.4+ or -6.0 years). The MTHFR gene mutation was detected based on the polymerase chain reaction and digestion with restrictive endonuclease HinfI. Total homocysteine plasma concentration was measured using HPLC. Folic acid and vitamin B12 plasma levels were assessed using the chemiluminescence method. Hyperhomocysteinemia was defined as homocysteine concentration > or =90 percentile of the control group which was > or =12.4 micro mol/L.
The incidence of the mutation of allele T and the genotype TT was similar in patients and controls (51.7% vs 56.6%, and 9.2% vs 10.4%, NS, respectively). The folic acid and vitamin B12 levels were not related to the MTHFR genotype (folic acid: 8.1 ng/L in homozygotes TT vs 8.6 in heterozygotes CT and 8.3 in homozygotes CC; and vitamin B12: 273 pg/L vs 303.3 vs 314.3, respectively). Although homozygotes TT had significantly higher homocysteine concentration than heterozygotes and homozygotes CT or CC (15.4 vs 11.0 vs 11.2 micro mol/L, p<0.001), the odds ratio for CAD in genotype TT was 0.87 (95% CI 0.5-2.1, NS). The odds ratio in subjects with at least one mutated T allele was 0.82 (95%CI 0.5-1.4, NS). Homocysteine plasma concentration was significantly higher in patients with CAD than controls (12.8+/-5.1 vs 10.0+/-5.0 micro mol/L, p<0.001) and correlated significantly with folic acid (r= -0.28, p=0.0001), vitamin B12 (r= -0.19, p<0.005), age (r=0.35, p=0.0001) and creatinine (r=0.26, p=0.0001). The odds ratio for CAD in subjects with hyperhomocysteinemia was 7.1 (95%CI 3.4-14.9, p=0.001) and was 2.6 (95%CI 1.6-4.1, p=0.0001) with a homocysteine increase of 5 micro mol/L. Multivariate analysis showed that hyperhomocysteinemia was an independent risk factor of CAD (OR 2.7, 95%CI 1-7.2, p<0.05). Conclusions. Hyperhomocysteinemia rather than a mutation in the methylenetetrahydrofolate reductase gene, is an independent risk factor of coronary artery disease.
亚甲基四氢叶酸还原酶（MTHFR）基因的C677T突变是血浆同型半胱氨酸浓度升高的原因之一，可能是动脉粥样硬化的危险因素之一。
评估MTHFR基因突变的存在、血浆同型半胱氨酸浓度与冠状动脉疾病（CAD）风险之间的关系。
研究组由120例经血管造影证实患有CAD的连续患者（78%为男性，平均年龄59.2±9.6岁）和106名健康志愿者（76%为男性，平均年龄47.4±6.0岁）组成。基于聚合酶链反应和限制性内切酶HinfI消化检测MTHFR基因突变。使用高效液相色谱法测量血浆总同型半胱氨酸浓度。使用化学发光法评估叶酸和维生素B12的血浆水平。高同型半胱氨酸血症定义为同型半胱氨酸浓度≥对照组第90百分位数，即≥12.4μmol/L。
患者和对照组中T等位基因突变和TT基因型的发生率相似（分别为51.7%对56.6%，9.2%对10.4%，无统计学差异）。叶酸和维生素B12水平与MTHFR基因型无关（叶酸：TT纯合子中为8.1ng/L，CT杂合子中为8.6，CC纯合子中为8.3；维生素B12：分别为273pg/L对303.3对314.3）。尽管TT纯合子的同型半胱氨酸浓度显著高于CT杂合子和CC纯合子（15.4对11.0对11.2μmol/L，p<0.001），但TT基因型患CAD的优势比为0.87（95%CI 0.5 - 2.1，无统计学差异）。至少有一个突变T等位基因的受试者的优势比为0.82（95%CI 0.5 - 1.4，无统计学差异）。CAD患者的血浆同型半胱氨酸浓度显著高于对照组（12.8±5.1对10.0±5.0μmol/L，p<0.001），且与叶酸（r = -0.28，p = 0.0001）、维生素B12（r = -0.19，p<0.005）、年龄（r = 0.35，p = 0.0001）和肌酐（r = 0.26，p = 0.0001）显著相关。高同型半胱氨酸血症患者患CAD的优势比为7.1（95%CI 3.4 - 14.9，p = 0.001），同型半胱氨酸每增加5μmol/L，优势比为2.6（95%CI 1.6 - 4.1，p = 0.0001）。多变量分析显示，高同型半胱氨酸血症是CAD的独立危险因素（OR 2.7，95%CI 1 - 7.2，p<0.05）。结论。高同型半胱氨酸血症而非亚甲基四氢叶酸还原酶基因突变是冠状动脉疾病的独立危险因素。
