Familial Combined Hyperlipidemia: Genetic Background

冠心病（Coronary Heart Disease，CHD）是西方社会的主要死亡原因。项目II的总体目标是确定最常见的家族性血脂异常易感冠心病，家族性混合性高脂血症（FCHL）的基因。FCHL的特征是总胆固醇、甘油三酯或两者水平升高。FCHL的许多代谢特征，例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。我们最近确定了第一个主要基因，上游转录因子1（USF1），FCHL的FCHL家族起源于遗传隔离的芬兰人口。具体目标1涉及研究USF1变体的共享单倍型， 关联使用扩展FCHL家庭从更多的远交荷兰人口澄清的意义USF1作为FCHL候选人在几个人口。在具体目标2中，我们计划通过对这些FCHL家族中的单倍型标签单核苷酸多态性（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，从而确定荷兰和英国家族连锁信号的11 p上的FCHL基因。我们假设这些常见的单倍型捕获了大部分的遗传变异，并且可以测试形成它们的htSNPs在FCHL家族中的关联。同时测序有限数量的相关区域候选基因被提出作为一种方法， 替代方法。具体目标3涉及检测FCHL的基因表达变化特征，作为传统基因定位的补充方式。FCHL受试者和对照之间的表达差异将在基因组水平上进行比较，并基于其USF1风险单倍型的携带者状态，使用芬兰和荷兰脂肪活检。我们还将生产11p的区域表达阵列，以解决候选基因及其剪接变体。实现这些特定的目标将提供一个更好地了解FCHL和CHD的未知的遗传和分子机制。

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.