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）是西方社会的首要死因。项目 II 的总体目标是确定最常见的易患冠心病的家族性血脂异常，即家族性混合性高脂血症 (FCHL) 的基因。 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，例如高甘油三酯血症和胰岛素抵抗也代表代谢综合征的特征成分。我们最近在源自基因隔离的芬兰人群的 FCHL 家族中鉴定出了 FCHL 的第一个主要基因，上游转录因子 1 (USF1)。具体目标 1 涉及研究共享单倍型的 USF1 变体和 协会使用来自近亲繁殖的荷兰人口的扩展 FCHL 家族来阐明 USF1 作为 FCHL 候选者在多个人群中的重要性。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 (htSNP) 进行基因分型，确定荷兰和英国家族连锁信号下的 11 p 上的 FCHL 基因，以定义连锁不平衡结构和常见单倍型。链接区域。我们假设这些常见的单倍型捕获了大部分遗传变异，并且可以测试形成它们的 htSNP 在 FCHL 家族中的关联性。提出对有限数量的相关区域候选基因进行同时测序作为 替代方法。具体目标 3 涉及检测 FCHL 特征的基因表达变化，作为传统基因作图的补充方式。 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，并根据他们使用芬兰和荷兰脂肪活检的 USF1 风险单倍型携带者状态进行比较。我们还将生产 11p 的区域表达阵列来处理候选基因及其剪接变体。实现这些具体目标将有助于更好地了解 FCHL 和 CHD 的未知遗传和分子机制。