Hanson N Q, Aras O, Yang F, Tsai M Y
Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455-0392, USA.
Clin Chem. 2001 Apr;47(4):661-6.
Moderately increased plasma concentrations of total homocysteine (tHcy) have been shown to be an important risk factor for vascular diseases. Two common polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, the thermolabile C677T and a more recently reported A1298C polymorphism, may contribute to hyperhomocysteinemia.
Using PCR and restriction fragment length polymorphism analysis, we studied the prevalence of the C677T and A1298C MTHFR genotypes and the combined effect of these polymorphisms on plasma tHcy concentrations, as measured by HPLC with fluorometric detection, both fasting and post-methionine load (PML), in 1238 individuals.
The prevalences of the C677T and A1298C genotypes did not differ significantly in 772 individuals with documented coronary artery disease (CAD), 137 individuals with deep-vein thrombosis (DVT), and 329 individuals without documented vascular disease. Individuals homozygous for the 677T allele had significantly increased fasting tHcy, particularly in the presence of low folate, compared with individuals homozygous for the wild-type allele. Neither the 1298AC nor the 1298CC genotype was associated with significantly increased fasting or PML tHcy concentrations irrespective of serum folate. Of the nine combined MTHFR genotypes, six were present in >10% of the population. Of these, the difference in mean fasting tHcy reached statistical significance (P<0.005) only in individuals with the 677TT/1298AA genotype compared with individuals with the wild-type 677CC/1298AA genotype. Differences in mean fasting tHcy did not reach statistical significance in individuals heterozygous for both MTHFR variants. We detected two 677CT/1298CC and three 677TT/1298AC individuals; only one, an 677TT/1298AC individual, had increased tHcy (both fasting and PML). No individuals had the 677TT/1298CC genotype.
The prevalences of the C677T and A1298C polymorphisms did not differ among individuals with CAD, DVT, or those without documented vascular disease. In contrast to the C677T polymorphism, the A1298C polymorphism is not associated with increased fasting tHcy. Although the two polymorphisms usually exist in trans configuration, crossover may occur rarely to form recombinant chromosomes.
血浆总同型半胱氨酸（tHcy）浓度适度升高已被证明是血管疾病的重要危险因素。亚甲基四氢叶酸还原酶（MTHFR）基因的两种常见多态性，即不耐热的C677T和最近报道的A1298C多态性，可能导致高同型半胱氨酸血症。
我们采用聚合酶链反应（PCR）和限制性片段长度多态性分析，研究了1238例个体中C677T和A1298C MTHFR基因型的患病率，以及这些多态性对血浆tHcy浓度的联合影响，血浆tHcy浓度通过高效液相色谱法（HPLC）荧光检测测定，包括空腹和蛋氨酸负荷后（PML）。
在772例有冠状动脉疾病（CAD）记录的个体、137例有深静脉血栓形成（DVT）的个体和329例无血管疾病记录的个体中，C677T和A1298C基因型的患病率无显著差异。与野生型等位基因纯合个体相比，677T等位基因纯合个体的空腹tHcy显著升高，尤其是在叶酸水平较低的情况下。无论血清叶酸水平如何，1298AC或1298CC基因型均与空腹或PML时tHcy浓度显著升高无关。在9种组合的MTHFR基因型中，6种在人群中的出现频率>10%。其中，只有与野生型677CC/1298AA基因型个体相比，677TT/1298AA基因型个体的平均空腹tHcy差异达到统计学意义（P<0.005）。两种MTHFR变体均为杂合子的个体，其平均空腹tHcy差异未达到统计学意义。我们检测到2例677CT/1298CC和3例677TT/1298AC个体；只有1例677TT/1298AC个体的tHcy升高（空腹和PML时均升高）。没有个体具有677TT/1298CC基因型个体。
C677T和A1298C多态性的患病率在CAD、DVT个体或无血管疾病记录的个体之间无差异。与C677T多态性不同，A1298C多态性与空腹tHcy升高无关。虽然这两种多态性通常以反式构型存在，但可能很少发生交叉形成重组染色体。
