Gemmati D, Previati M, Serino M L, Moratelli S, Guerra S, Capitani S, Forini E, Ballerini G, Scapoli G L
Centre for the Study of Haemostasis and Thrombosis Institute of Human Anatomy, the University of Ferrara, Ferrara, Italy.
Arterioscler Thromb Vasc Biol. 1999 Jul;19(7):1761-7. doi: 10.1161/01.atv.19.7.1761.
Several studies have indicated that mild to moderate hyperhomocystinemia is a common cause of arterial occlusive disease. Whether hyperhomocystinemia per se is an independent risk factor for vein thromboembolism (VTE) is still somewhat controversial. Both genetic and nutritional factors influence plasma homocysteine levels. Therefore, we evaluated plasma total homocysteine (tHcy), folate, and vitamin B12 levels and established, by polymerase chain reaction, the presence of the C677T mutation (A223V) in the methylenetetrahydrofolate reductase (MTHFR) gene in 220 cases with VTE without well-established prothrombotic defects. As a control group, 220 healthy subjects from the same geographic area as the cases were investigated. Hyperhomocystinemia was defined as a plasma tHcy level above the 95th percentile in the controls (18.05 micromol/L). Hyperhomocystinemia was found in 16% of cases (odds ratio=3.59; P<0.001); deficiencies of folate (<2.47 ng/mL) or vitamin B12 (<165 pg/mL), defined as values below the 5th percentile in controls, were found in 17.7% (P<0.001) and 12.3% (P=0.015) of cases, respectively. The homozygous condition for the MTHFR mutation (VV) was present in 28.2% of cases and 17.7% of controls (odds ratio=1.82; P=0.013). Comparing only the idiopathic forms of VTE (n=80/220; 36.3%) with normal controls, individuals with hyperhomocystinemia, or individuals homozygous for MTHFR mutation increased the odds ratios to 4.03 (P=0.005) and 2.11 (P=0.018), respectively. No statistically significant difference was observed in the MTHFR genotype distribution of cases and controls with hyperhomocystinemia (P=0.386); however, the normal MTHFR genotype (AA) appeared in control subjects only when tHcy levels were below the 80th percentile (10.57 micromol/L) of the distribution, whereas in case patients, it was present at the highest tHcy levels. A strong association between mutated homozygosity (VV), low folate levels, and hyperhomocystinemia was found in both groups. We conclude that in patients with VTE who do not have coexisting prothrombotic defects, hyperhomocystinemia increases the risk of developing idiopathic and venous thrombosis; the homozygous condition for the MTHFR mutation confers a moderate risk but, together with low folate levels, it is the main determinant of mild hyperhomocystinemia in normal and thromboembolic populations.
多项研究表明，轻至中度高同型半胱氨酸血症是动脉闭塞性疾病的常见病因。高同型半胱氨酸血症本身是否为静脉血栓栓塞（VTE）的独立危险因素仍存在一定争议。遗传因素和营养因素均会影响血浆同型半胱氨酸水平。因此，我们评估了220例无明确血栓形成前缺陷的VTE患者的血浆总同型半胱氨酸（tHcy）、叶酸和维生素B12水平，并通过聚合酶链反应确定亚甲基四氢叶酸还原酶（MTHFR）基因中C677T突变（A223V）的存在情况。作为对照组，我们调查了与病例来自同一地理区域的220名健康受试者。高同型半胱氨酸血症定义为血浆tHcy水平高于对照组第95百分位数（18.05微摩尔/升）。16%的病例存在高同型半胱氨酸血症（优势比=3.59；P<0.001）；叶酸缺乏（<2.47纳克/毫升）或维生素B12缺乏（<165皮克/毫升），定义为低于对照组第5百分位数的值，分别在17.7%（P<0.001）和12.3%（P=0.015）的病例中发现。MTHFR突变的纯合状态（VV）在28.2%的病例和17.7%的对照组中存在（优势比=1.82；P=0.013）。仅将VTE的特发性形式（n=80/220；36.3%）与正常对照组进行比较时，高同型半胱氨酸血症患者或MTHFR突变纯合个体的优势比分别增加至4.03（P=0.005）和2.11（P=0.018）。在高同型半胱氨酸血症的病例和对照组中，未观察到MTHFR基因型分布的统计学显著差异（P=0.386）；然而，正常MTHFR基因型（AA）仅在tHcy水平低于分布的第80百分位数（10.57微摩尔/升）时出现在对照受试者中，而在病例患者中，它出现在最高tHcy水平时。在两组中均发现突变纯合性（VV）、低叶酸水平和高同型半胱氨酸血症之间存在强关联。我们得出结论，在没有并存血栓形成前缺陷的VTE患者中，高同型半胱氨酸血症会增加发生特发性和静脉血栓形成的风险；MTHFR突变的纯合状态带来中度风险，但与低叶酸水平一起，它是正常人群和血栓栓塞人群轻度高同型半胱氨酸血症的主要决定因素。
