Familial Combined Hyperlipidemia: Genetic Background

家族性混合性高脂血症：遗传背景

• 批准号: 7312439
• 负责人: Paivi Pajukanta
• 金额: $ 46.43万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7312439
• 关键词: British Isles; Europe; Scandinavian country; biopsy; cardiovascular disorder risk; family genetics; genetic mapping; genetic susceptibility; human genetic material tag; human population genetics; hyperlipidemia; inborn lipid /lipoprotein disorder; metabolic syndrome; single nucleotide polymorphism

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.

冠心病（CHD）是西方社会死亡的主要原因。项目II的总体目的是鉴定易感冠心病的家族性血脂异常的基因，家族性高脂血症（FCHL）。 FCHL的特征是总胆固醇，甘油三酸酯或两者兼而有之。 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，即上游转录因子1（USF1），用于FCHL的FCHL家族中，该基因来自基因分离的芬兰人群。具体目标1与研究共享单倍型的USF1变体有关 协会使用较长的荷兰人群的扩展FCHL家庭来阐明USF1作为FCHL候选人在几个人群中的重要性。在特定的目标2中，我们计划通过基因分型基因分型来确定荷兰和英国家族的链接信号的FCHL基因，从这些FCHL家族中的单倍型TAG TAG单核苷酸多态性（HTSNP）来定义连锁区域的连锁不平衡结构和链接区域的共同单型。我们假设这些常见的单倍型捕获了大多数遗传变异，并且可以在FCHL家族中测试形成它们的HTSNP。同时提出了限制数量的相关区域候选基因的测序 替代方法。特定的目标3与检测基因表达变化FCHL的特征有关传统基因映射的互补方式。 FCHL受试者和对照组之间的表达差异将在基因组水平上以及使用Finnish和荷兰脂肪活检的USF1风险单倍型的载体状态进行比较。我们还将生产11便士的区域表达阵列，以解决候选基因及其剪接变体。完成这些特定目标将更好地理解FCHL和CHD的未知遗传和分子机制。