Familial Combined Hyperlipidemia: Genetic Background

在西方社会，冠心病(CHD)是主要的死亡原因。项目II的总体目标是确定最常见的家族性血脂异常易患冠心病的基因，即家族性混合性高脂血症(FCHL)。FCHL的特点是总胆固醇和/或甘油三酯水平升高。FCHL的许多代谢特征，如高甘油三酯血症和胰岛素抵抗，也代表了代谢综合征的特征成分。我们最近在FCHL家族中发现了FCHL的第一个主要基因，上游转录因子1(USF1)，起源于遗传隔离的芬兰人。具体目标1涉及研究共享单倍型的USF1变体和 该协会使用来自更外交化的荷兰人口的扩大的FCHL家庭，以澄清USF1作为FCHL候选在几个群体中的重要性。在具体目标2中，我们计划通过对荷兰和英国FCHL家系的单倍型标签单核苷酸多态(HtSNPs)进行基因分型，以确定连锁不平衡结构和连锁区域的常见单倍型，从而鉴定11p上的FCHL基因，以揭示这些FCHL家族的连锁信号。我们推测，这些常见的单倍型捕获了大部分的遗传变异，形成它们的htSNP可以在FCHL家族中进行关联测试。建议同时对有限数量的相关区域候选基因进行测序 另一种方法。具体目标3是检测FCHL特有的基因表达变化，作为对传统基因定位的补充。FCHL受试者和对照组之间的表达差异将在基因组水平上进行比较，并基于他们USF1风险单倍型的携带者状态，使用芬兰和荷兰的脂肪活检。我们还将为11P制作区域表达阵列，以应对候选基因及其剪接变体。实现这些特定的目标将有助于更好地了解FCHL和CHD的未知遗传和分子机制。

Coronary heart disease (CHD) is the leading cause of death in the Western societies. The overall aim in Project II is to identify genes for the most common familial dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL). FCHL is characterized by elevated levels of total cholesterol, triglycerides, or both. Many of the metabolic features of FCHL, e.g. hypertriglyceridemia and insulin resistance, also represent trait components of metabolic syndrome. We recently identified the first major gene, the upstream transcription factor 1 (USF1), for FCHL in FCHL families originating from the genetically isolated Finnish population. Specific Aim 1 is concerned with investigating the USF1 variants for shared haplotypes and association using extended FCHL families from the more outbred Dutch population to clarify the significance of USF1 as an FCHL candidate in several populations. In Specific Aim 2, we plan to identify the FCHL gene on 11 p underlying the linkage signals of Dutch and British families by genotyping the haplotype tag single nucleotide polymorphisms (htSNPs) in these FCHL families to define the linkage disequilibrium structure and common haplotypes of the linked region. We hypothesize that these common haplotypes capture most of the genetic variation, and the htSNPs forming them could be tested for association in the FCHL families. Simultaneous sequencing of a restricted number of relevant regional candidate genes is proposed as an alternative approach. Specific Aim 3 is concerned with detecting gene expression changes characteristic of FCHL as a complementary way to traditional gene mapping. Expression differences between FCHL subjects and controls will be compared at the genomic level as well as based on their carrier status for the USF1 risk haplotype using Finnish and Dutch fat biopsies. We will also produce regional expression arrays for 11p to tackle candidate genes and their splice variants. Accomplishing these specific aims will provide a better understanding of the unknown genetic and molecular mechanisms of FCHL and CHD.