Gallagher P M, Meleady R, Shields D C, Tan K S, McMaster D, Rozen R, Evans A, Graham I M, Whitehead A S
Department of Genetics, Trinity College, Dublin 2, Ireland.
Circulation. 1996 Nov 1;94(9):2154-8. doi: 10.1161/01.cir.94.9.2154.
Plasma homocysteine levels are modulated by nutritional and genetic factors, among which is the enzyme methylenetetrahydrofolate reductase (MTHFR). A common defective (thermolabile) variant of this enzyme is causally associated with elevated plasma homocysteine, itself an independent risk factor for coronary heart disease.
To examine the hypothesis that the allele (T) that codes for the thermolabile defect increases the risk of coronary heart disease, we studied 111 patients with clinical and objective investigational evidence of coronary heart disease and 105 control subjects. The frequencies of the thermolabile defect (T) in patients and control subjects were measured, and the prevalence of elevated plasma total homocysteine according to genotype was assessed. The frequency of the defective allele was higher in patients than in control subjects with an OR of 1.6 (95% CI, 1.1 to 2.4; P = .02). The OR in the coronary heart disease group for the homozygous TT genotype was 2.9 (95% CI, 1.2 to 7.2; P = .02); 17% of patients and 7% of control subjects had the TT genotype. Plasma total homocysteine levels were significantly associated with disease status, a relationship that matched the strength of the association between disease and homozygous inheritance of the defective enzyme.
Homozygotes for the defective allele (T) are at increased risk of premature coronary heart disease. MTHFR, which modulates basal plasma homocysteine concentration, is folate dependent, and dietary supplementation or fortification with folic acid may reduce plasma homocysteine levels and consequent coronary risk in a significant proportion of the general population.
血浆同型半胱氨酸水平受营养和遗传因素调节，其中包括亚甲基四氢叶酸还原酶（MTHFR）。该酶一种常见的缺陷（不耐热）变体与血浆同型半胱氨酸升高有因果关系，而血浆同型半胱氨酸升高本身就是冠心病的一个独立危险因素。
为检验编码不耐热缺陷的等位基因（T）会增加冠心病风险这一假说，我们研究了111例有冠心病临床及客观研究证据的患者和105名对照者。测量了患者和对照者中不耐热缺陷（T）的频率，并评估了根据基因型划分的血浆总同型半胱氨酸升高的患病率。患者中缺陷等位基因的频率高于对照者，比值比为1.6（95%可信区间，1.1至2.4；P = 0.02）。冠心病组中纯合子TT基因型的比值比为2.9（95%可信区间，1.2至7.2；P = 0.02）；17%的患者和7%的对照者有TT基因型。血浆总同型半胱氨酸水平与疾病状态显著相关，这种关系与疾病和缺陷酶纯合遗传之间关联的强度相符。
缺陷等位基因（T）的纯合子患早发性冠心病的风险增加。调节基础血浆同型半胱氨酸浓度的MTHFR是叶酸依赖性的，膳食补充或强化叶酸可能会降低很大一部分普通人群的血浆同型半胱氨酸水平及随之而来的冠心病风险。
