Knoblauch Hans, Bauerfeind Anja, Toliat Mohammad Reza, Becker Christian, Luganskaja Tatjana, Günther Ulf Peter, Rohde Klaus, Schuster Herbert, Junghans Christine, Luft Friedrich C, Nürnberg Peter, Reich Jens Georg
Medical Faculty of the Charité, Franz Volhard Clinic, Helios Klinikum, Berlin, Germany.
Hum Mol Genet. 2004 May 15;13(10):993-1004. doi: 10.1093/hmg/ddh119. Epub 2004 Mar 25.
Single nucleotide polymorphisms (SNPs) and derived haplotypes within multiple genes may explain genetic variance in complex traits; however, this hypothesis has not been rigorously tested. In an earlier study we analyzed six genes and have now expanded this investigation to include 13. We studied 250 families including 1054 individuals and measured lipid phenotypes. We focused on low-density cholesterol (LDL), high-density cholesterol (HDL) and their ratio (LDL/HDL). A component analysis of the phenotypic variance relying on a standard genetic model' showed that the genetic variance on LDL explained 26%, on HDL explained 38% and on LDL/HDL explained 28% of the total variance, respectively. Genotyping of 93 SNPs in 13 lipid-relevant genes generated 230 haplotypes. The association of haplotypes in all the genes tested explained a major fraction of the genetic phenotypic variance component. For LDL, the association with haplotypes explained 67% and for HDL 58% of the genetic variance relative to the polygenic background. We conclude that these haplotypes explain most of the genetic variance in LDL, HDL and LDL/HDL in these representative German families. An analysis of the contribution to the genetic variance at each locus showed that APOE (50%), CETP (28%), LIPC (9%), APOB (8%) and LDLR (5%) influenced variation in LDL. LIPC (53%), CETP (25%), ABCA1 (10%), LPL (6%) and LDLR (6%) influenced the HDL variance. The LDL/HDL ratio was primarily influenced by APOE (36%), CETP (27%) and LIPC (31%). This expanded analysis substantially increases the explanation of genetic variance on these complex traits.
多个基因内的单核苷酸多态性（SNP）及其衍生单倍型可能解释复杂性状中的遗传变异；然而，这一假说尚未得到严格验证。在早期的一项研究中，我们分析了6个基因，现在已将这项研究扩展至13个基因。我们研究了250个家庭，共1054名个体，并测量了血脂表型。我们重点关注低密度胆固醇（LDL）、高密度胆固醇（HDL）及其比值（LDL/HDL）。基于标准遗传模型的表型方差成分分析表明，LDL的遗传方差分别解释了总方差的26%，HDL的遗传方差解释了38%，LDL/HDL的遗传方差解释了28%。对13个血脂相关基因中的93个SNP进行基因分型产生了230种单倍型。在所有测试基因中，单倍型的关联解释了大部分遗传表型方差成分。对于LDL，与单倍型的关联相对于多基因背景解释了67%的遗传方差，对于HDL则为58%。我们得出结论，在这些具有代表性的德国家庭中，这些单倍型解释了LDL、HDL和LDL/HDL中大部分的遗传方差。对每个基因座对遗传方差贡献的分析表明，载脂蛋白E（APOE，50%）、胆固醇酯转运蛋白（CETP，28%）、肝脂酶（LIPC，9%）、载脂蛋白B（APOB，8%）和低密度脂蛋白受体（LDLR，5%）影响LDL的变异。LIPC（53%）、CETP（25%）、ATP结合盒转运体A1（ABCA1，10%）、脂蛋白脂肪酶（LPL，6%）和LDLR（6%）影响HDL的方差。LDL/HDL比值主要受APOE（36%）、CETP（27%）和LIPC（31%）的影响。这项扩展分析显著增加了对这些复杂性状遗传方差的解释。
