Magnusson Patrik K E, Boman Marcus, de Faire Ulf, Perola Markus, Peltonen Leena, Pedersen Nancy L
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Eur J Hum Genet. 2008 Sep;16(9):1103-10. doi: 10.1038/ejhg.2008.50. Epub 2008 Mar 5.
The effect of genetic variants underlying atherosclerosis is thought to be mediated through intermediate phenotypes such as serum cholesterol levels. Localization of quantitative trait loci influencing levels of serum lipids and (apo)lipoproteins may aid in the search for determinants of susceptibility to atherosclerotic diseases. Since apolipoprotein A-I is the primary protein constituent of high-density lipoprotein, it is considered to be critical for the antiatherogenic effect of high-density lipoproteins. We describe here an effort to map loci influencing apolipoprotein A-I levels. Measurements of apolipoprotein A-I levels and genome scans with more than 1000 microsatellite markers were successfully performed in both members of 501 pairs of fraternal twins from Sweden. Variance component linkage analysis was undertaken to map quantitative trait loci. In the total study sample, two loci showed comparable suggestive evidence of linkage, 6p21-12 (LOD=2.4) and 12q23 (LOD=2.4). Sex-limited analyses revealed significant female-specific linkage at marker D15S156 on 15q11-13 (LOD=4.1). The loci on 12q and 15q in the present study confirm previously reported loci for apolipoprotein A-I, while the peak on chromosome 6p lends further support to a locus influencing several phenotypes related to atherosclerosis. Intriguingly, the presence of genes belonging to the phospholipase A2 superfamily under three out of four observed linkage peaks would lend some support to the view that this group of genes might collectively represent candidates as apolipoprotein A-I level regulators.
动脉粥样硬化潜在的基因变异效应被认为是通过诸如血清胆固醇水平等中间表型介导的。影响血清脂质和（载）脂蛋白水平的数量性状位点的定位可能有助于寻找动脉粥样硬化疾病易感性的决定因素。由于载脂蛋白A-I是高密度脂蛋白的主要蛋白质成分，它被认为对高密度脂蛋白的抗动脉粥样硬化作用至关重要。我们在此描述了一项定位影响载脂蛋白A-I水平的基因座的工作。在来自瑞典的501对异卵双胞胎的双方中，成功地进行了载脂蛋白A-I水平的测量以及使用1000多个微卫星标记的基因组扫描。采用方差成分连锁分析来定位数量性状位点。在整个研究样本中，两个基因座显示出相当的连锁暗示证据，分别是6p21 - 12（LOD = 2.4）和12q23（LOD = 2.4）。性别限定分析显示在15q11 - 13上的标记D15S156处存在显著的女性特异性连锁（LOD = 4.1）。本研究中12q和15q上的基因座证实了先前报道的载脂蛋白A-I的基因座，而6号染色体p臂上的峰值进一步支持了一个影响与动脉粥样硬化相关的几种表型的基因座。有趣的是，在四个观察到的连锁峰值中的三个峰值下存在属于磷脂酶A2超家族的基因，这将为这组基因可能共同代表载脂蛋白A-I水平调节因子的候选基因这一观点提供一些支持。
