Berg K
Institute of Medical Genetics, University of Oslo, Norway.
Acta Genet Med Gemellol (Roma). 1990;39(1):15-24. doi: 10.1017/s0001566000005559.
Present attempts to identify genes contributing to coronary heart disease (CHD) risk focus on "candidate genes". With respect to CHD this could be any gene whose protein product is directly or indirectly involved in atherogenesis, thrombogenesis or thrombolysis/fibrinolysis. Genes that exhibit associations with absolute risk factor levels may be referred to as "level genes" to distinguish them from "variability genes", which are genes involved in establishing the framework within which environmental influences may cause risk factor variation. In a series of persons recruited from the Norwegian Twin Panel, confirmatory evidence for level gene effect with respect to apolipoprotein B (apoB) concentration was found with an XbaI polymorphism in DNA at the apoB locus corresponding to residue 2,488 in the mature protein. Evidence for variability gene effect with respect to apoB as well as body mass index emerged with DNA variants in the 3' part of the apoB gene. Level gene effect with respect to apolipoprotein A-I (apoA-I) and high density lipoprotein (HDL) cholesterol as well apparent variability gene effect with respect to total and LDL cholesterol were detected with a DNA polymorphism at the cholesteryl ester transfer protein (CETP) locus. The first example of interaction between normal genes in determining risk factor level was uncovered in analysis of the apolipoprotein E (apoE) polymorphism and a restriction fragment length polymorphism (RFLP) at the low density lipoprotein receptor (LDLR) locus. An LDLR gene identified by presence of a PvuII restriction site eliminated completely the well known effect of the apoE4 allele on cholesterol level. Finally, in families where high Lp(a) lipoprotein level (a well established risk factor for CHD) segregated as a Mendelian trait, very close linkage with an RFLP at the plasminogen locus was established and DNA variation at the LPA locus reflecting varying numbers of a structure homologous to the "kringle IV" region of plasminogen was uncovered.
目前，旨在识别与冠心病（CHD）风险相关基因的研究主要聚焦于“候选基因”。就冠心病而言，这类基因的蛋白质产物直接或间接参与动脉粥样硬化、血栓形成或血栓溶解/纤维蛋白溶解过程。与绝对风险因素水平存在关联的基因可被称为“水平基因”，以区别于“变异性基因”，变异性基因参与构建环境影响可能导致风险因素变化的框架。在从挪威双胞胎队列招募的一系列个体中，发现载脂蛋白B（apoB）浓度的水平基因效应的验证性证据，该效应与apoB基因座处对应于成熟蛋白中第2488位残基的DNA中的XbaI多态性有关。apoB基因3'端的DNA变异出现了apoB以及体重指数的变异性基因效应的证据。在胆固醇酯转运蛋白（CETP）基因座处的DNA多态性检测到了载脂蛋白A-I（apoA-I）和高密度脂蛋白（HDL）胆固醇的水平基因效应以及总胆固醇和低密度脂蛋白（LDL）胆固醇的明显变异性基因效应。在对载脂蛋白E（apoE）多态性和低密度脂蛋白受体（LDLR）基因座处的限制性片段长度多态性（RFLP）进行分析时，发现了正常基因在决定风险因素水平方面相互作用的首个实例。通过存在PvuII限制性位点鉴定出的LDLR基因完全消除了apoE4等位基因对胆固醇水平的众所周知的影响。最后，在高脂蛋白（a）水平（一种已明确的冠心病风险因素）作为孟德尔性状分离的家族中，确定了与纤溶酶原基因座处的RFLP非常紧密的连锁关系，并发现LPA基因座处的DNA变异反映了与纤溶酶原“kringle IV”区域同源结构数量的变化。
