Polymorphisms of the human matrix Gla protein (MGP) gene, vascular calcification, and myocardial infarction
Polymorphisms of the human matrix Gla protein (MGP) gene, vascular calcification, and myocardial infarction
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DOI：
10.1161/01.atv.20.11.2386
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发表时间：
2000-11-01
影响因子：
8.7
通讯作者：
Cambien, F
中科院分区：
文献类型：
--
作者：
Herrmann, SM;Whatling, C;Cambien, F
基质Gla蛋白（MGP）是血管和软骨钙化的重要抑制剂，其在人类钙化的动脉粥样硬化斑块中强烈表达，并且可以调节斑块钙化和冠心病风险。利用遗传学方法，我们通过鉴定MCP基因的多态性并检测其与心肌梗死（MI）和斑块钙化的可能关联来探索这种可能性。在MGP基因的编码序列和5 '侧翼序列中鉴定出8种多态性。在ECTIM研究中招募的607名MI患者和667名对照受试者以及参加AXA研究的717名超声心动图评估动脉钙化和动脉粥样硬化的健康个体中研究了ALI多态性。在ECTIM研究中，等位基因和基因型在整个研究组的患者和对照组中的分布相似;仅在1个定义为MI低风险的受试者亚组中，MI患者中一致的A-7和Ala 83等位基因的频率高于对照组（P < 0.003）。在AXA研究中，股动脉粥样硬化患者中，相同的等位基因在斑块钙化存在时比不存在时更常见（P < 0.025）。其他MGP多态性与任何研究的临床表型无关。用等位基因启动子-报告基因构建体和DNA-蛋白质相互作用测定进行瞬时转染实验，以评估在相对于转录起始的位置-814、-138和-7处检测到的启动子变体的可能的体外功能。当与-138 T等位基因相比时，次要-138 C等位基因在大鼠血管平滑肌细胞中始终赋予-20%（P < 0.0001）的降低的启动子活性，在人成纤维细胞系中赋予-50%（P < 0.004）的降低的启动子活性，而其他多态性（包括-7）没有显示出体外功能性的证据。我们得出结论，MGP基因的A-7或Ala 83等位基因可能会增加斑块钙化和MI的风险;然而，观察到的关系很弱或仅限于患者亚组，因此需要确认。
The matrix Gla protein (MGP) is an important inhibitor of vessel and cartilage calcification that is strongly expressed in human calcified, atherosclerotic plaques and could modulate plaque calcification and coronary heart disease risk. Using a genetic approach, we explored this possibility by identifying polymorphisms of the MCP gene and testing their possible association with myocardial infarction (MI) and plaque calcification. Eight polymorphisms were identified in the coding and 5'-flanking sequences of the MGP gene. ALI polymorphisms were investigated in 607 patients with MI and 667 control subjects recruited into the ECTIM Study (Etude Cas-Temoins de l'Infarctus du Myocarde) and in 717 healthy individuals with echographically assessed arterial calcification and atherosclerosis who were participating in the AXA Study. In the ECTIM Study, alleles and genotypes were distributed similarly in patients and controls in the whole study group; in only 1 subgroup of subjects defined as being at low risk for MI were the concordant A-7 and Ala 83 alleles more frequent in patients with MI than in controls (P < 0.003). In the AXA Study among subjects with femoral atherosclerosis, the same alleles were more common in the presence than the absence of plaque calcification (P < 0.025). The other MGP polymorphisms were not associated with any investigated clinical phenotype. Transient transfection experiments with allelic promoter-reporter gene constructs and DNA-protein interaction assays were carried out to assess possible in vitro functionality of the promoter variants detected at positions -814, -138, and -7 relative to the start of transcription. When compared with the -138 T allele, the minor -138 C allele consistently conferred a reduced promoter activity of -20% (P < 0.0001) in rat vascular smooth muscle cells and of -50% (P < 0.004) in a human fibroblast cell Line, whereas the other polymorphisms, including -7, displayed no evidence of in vitro functionality. We conclude that the A-7 or Ala 83 alleles of the MGP gene may confer an increased risk of plaque calcification and MI; however, the observed relationships are weak or limited to subgroups of patients and therefore need confirmation.