Familial Combined Hyperlipidemia: Genetic Background

冠心病（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的基因，家族性合并高脂血症（FCHL）。FCHL的特点是总胆固醇、甘油三酯或两者水平升高。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。我们最近在芬兰遗传分离人群中发现了FCHL家族中FCHL的第一个主要基因，上游转录因子1 （USF1）。特异性目标1关注于研究共享单倍型的USF1变异和

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.