Kruger W D, Evans A A, Wang L, Malinow M R, Duell P B, Anderson P H, Block P C, Hess D L, Graf E E, Upson B
Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA.
Mol Genet Metab. 2000 May;70(1):53-60. doi: 10.1006/mgme.2000.2993.
Elevated total plasma homocysteine (tHcy) is an established risk factor for the development of vascular disease and neural tube defects. Total homocysteine levels can be lowered by folic acid supplements but individual response is highly variable. In this case-control study, involving 142 coronary artery disease (CAD) patients and 102 controls, we have typed six genetic polymorphisms in three homocysteine metabolizing genes and examined their relationship to the incidence of CAD, tHcy levels, and lowering of tHcy levels in response to folic acid supplementation. We found that two single nucleotide polymorphisms in the cystathionine beta synthase (CBS) gene, 699C --> T and 1080T --> C, are associated with decreased risk of CAD and increased responsiveness to the tHcy lowering effects of folic acid. Individuals homozygous for 699T were significantly underrepresented in CAD patients as compared to controls (4.9% vs 17.3%, P = 0.0015), as were individuals homozygous for the 1080C (29.6% vs 44.2%, P = 0.018). Additionally, 699T and 1080C homozygous individuals were the most responsive to folate supplementation. 699T homozygotes lowered tHcy levels 13.6% on average, compared to 4.8% lowering in 699C homozygotes (P = 0.009), while 1080C homozygotes lowered 12.9% compared to just 2.7% for 1080T homozygotes (P = 0.005). The two polymorphisms in CBS are third codon changes and would not be predicted to affect the underlying protein. However, there is strong linkage disequilibrium between these two positions, suggesting that they may also be linked to other as yet unidentified polymorphisms within the CBS gene. These observations suggest that specific CBS alleles are a risk factor for the development of vascular disease and that genetic information could be predictive of individual response to folic acid supplementation.
血浆总同型半胱氨酸（tHcy）水平升高是血管疾病和神经管缺陷发生的既定风险因素。补充叶酸可降低总同型半胱氨酸水平，但个体反应差异很大。在这项病例对照研究中，我们纳入了142例冠状动脉疾病（CAD）患者和102例对照，对三个同型半胱氨酸代谢基因中的六个基因多态性进行了分型，并研究了它们与CAD发病率、tHcy水平以及叶酸补充后tHcy水平降低之间的关系。我们发现，胱硫醚β合酶（CBS）基因中的两个单核苷酸多态性，即699C→T和1080T→C，与CAD风险降低以及对叶酸降低tHcy水平的反应性增加有关。与对照组相比，CAD患者中699T纯合子个体的比例显著偏低（4.9%对17.3%，P = 0.0015），1080C纯合子个体也是如此（29.6%对44.2%，P = 0.018）。此外，699T和1080C纯合子个体对叶酸补充的反应最为敏感。699T纯合子平均降低tHcy水平13.6%，而699C纯合子降低4.8%（P = 0.009）；1080C纯合子降低12.9%，而1080T纯合子仅降低2.7%（P = 0.005）。CBS基因中的这两个多态性是第三位密码子的变化，预计不会影响基础蛋白质。然而，这两个位置之间存在很强的连锁不平衡，表明它们可能也与CBS基因内其他尚未确定的多态性相关。这些观察结果表明，特定的CBS等位基因是血管疾病发生的风险因素，并且基因信息可以预测个体对叶酸补充的反应。
