Boerma M, Forsberg L, Van Zeijl L, Morgenstern R, De Faire U, Lemne C, Erlinge D, Thulin T, Hong Y, Cotgreave I A
Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
J Intern Med. 1999 Aug;246(2):211-8. doi: 10.1046/j.1365-2796.1999.00564.x.
Atherosclerosis is a multifactorial disease, in part characterized by chronic inflammatory changes in the vessel wall and loss of normal physical and biochemical interactions between endothelial cells and smooth muscle cells. Previous studies [Hu J., Cotgreave IA. J Clin Invest; 99: 1-5] have provided molecular links between inflammation and myoendothelial communication via gap junctions, suggesting that these structures may be important in the development of the atherosclerotic vessel phenotype. In order to strengthen this premise, the aim of the present work was to probe for structural polymorphisms in connexin 37, a gap junctional protein uniquely expressed in endothelial cells, and to assess for potential genotypic segregation in individuals displaying atherosclerotic plaque.
Computer-based comparisons of Expressed Sequence Tags (ESTs) predicted a polymorphism in the human gap junctional protein connexin 37 (cx37). The C1019-T mutation results in a proline to serine shift at codon 319 (cx371-cx372). A Restriction Fragment Length Polymorphism (RFLP) assay, involving the insertion of a novel Drd I cleavage site in the proline variant revealed a statistically significant over-representation of the cx37*1 allele in association with atherosclerotic plaque-bearing individuals (Odds-ratio for the homozygote = 2.38, Chi2 = 7.693, P = 0.006), in comparison to individuals lacking plaque, irrespective of a history of hypertension.
These data suggest that the C1019-T polymorphism in cx37 may provide 'single gene marker', which could be useful in assessing atherosclerotic plaque development, particularly in cardiovascular risk groups such as those with borderline hypertension.
动脉粥样硬化是一种多因素疾病，部分特征为血管壁的慢性炎症变化以及内皮细胞与平滑肌细胞之间正常物理和生化相互作用的丧失。先前的研究[Hu J., Cotgreave IA. 《临床研究杂志》；99: 1 - 5]已通过间隙连接提供了炎症与肌内皮通讯之间的分子联系，表明这些结构可能在动脉粥样硬化血管表型的发展中起重要作用。为了强化这一前提，本研究的目的是探究连接蛋白37（一种在内皮细胞中独特表达的间隙连接蛋白）的结构多态性，并评估显示有动脉粥样硬化斑块的个体中潜在的基因型分离情况。
基于计算机的表达序列标签（EST）比较预测人类间隙连接蛋白连接蛋白37（cx37）存在多态性。C1019 - T突变导致第319位密码子处脯氨酸向丝氨酸的转变（cx371 - cx372）。一种限制性片段长度多态性（RFLP）检测方法，涉及在脯氨酸变体中插入一个新的Drd I切割位点，结果显示与无斑块个体相比，cx37*1等位基因在有动脉粥样硬化斑块个体中具有统计学上显著的过度表达（纯合子的优势比 = 2.38，卡方 = 7.693，P = 0.006），无论其有无高血压病史。
这些数据表明cx37中的C1019 - T多态性可能提供一个“单基因标记”，这对于评估动脉粥样硬化斑块的发展可能有用，特别是在心血管风险人群中，如临界高血压患者。
