Metabolism and Genetics of Hypobetalipoproteinemia

低β脂蛋白血症的代谢和遗传学

• 批准号: 6844845
• 负责人: GUSTAV SCHONFELD
• 金额: $ 38.94万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844845
• 关键词: abetalipoproteinemias; apolipoprotein B; body weight; chromosomes; clinical research; disease /disorder proneness /risk; family genetics; fatty liver; gas chromatography mass spectrometry; gene frequency; gene mutation; genetic disorder; genetic markers; genetic screening; genetic susceptibility; genotype; human subject; inborn metabolism disorder; insulin sensitivity /resistance; linkage mapping; liver disorder; magnetic resonance imaging; nuclear magnetic resonance spectroscopy; nucleic acid sequence; syndrome; triglycerides; very low density lipoprotein

DESCRIPTION (provided by applicant): This is a competitive renewal application to study the genetics and metabolism of familial hypobetalipoproteinemia (FHBL). Genetic studies: In addition to our families with APOB mutations on chromosome (chr) 2, we reported on seven families with linkage of FHBL to a 2cM region on chromosome 3p21. One of our aims is to find the etiologic gene in the region by positional cloning, using DHPLC (Transgenic Wave) technology and genomic DNA sequencing for mutation detection. A third group of FHBL five families manifests no linkage with either chr 2 or 3. Genomewide genotyping is being performed in these families. Our second aim is to perform linkage analyses to find susceptibility regions and ultimately the gene(s). Metabolic studies: Using magnetic resonance spectroscopy, we found 5-fold increases in liver fat in FHBL subjects bearing apoB truncation mutations compared with matched controls. We have also studied the assembly of VLDL-triglycerides (TG) in these subjects. Infusions of 2H2-palmitate, quantitation of palmitate tracer/tracee ratios in plasma and in VLDL-triglycerides by gas chromatography-mass spectrometry, and kinetic modeling of the data demonstrate that a greater proportion of VLDL-TG is derived from hepatic sources than from plasma palmitate in FHBL subjects than controls. A significant correlation was found between liver fat (by MRI) and the fractional contribution of hepatic sources (r=0.90, p=0.001). Our aim is to extend these studies in our FHBL subjects and to patients with the metabolic Syndrome X, and to evaluate the importance of metabolic "risk factors" such as body weight, insulin resistance on the extent of accumulation of liver fat in these groups.

描述（由申请人提供）：这是一项竞争性更新申请，旨在研究家族性低脂蛋白血症（FHBL）的遗传学和代谢。遗传学研究：除了我们的家族在染色体（chr） 2上有APOB突变外，我们还报道了7个家族在染色体3p21上的2cM区域有FHBL连锁。我们的目标之一是通过定位克隆，利用DHPLC（转基因波）技术和基因组DNA测序进行突变检测，找到该区域的病因基因。第三组FHBL 5家族与chr 2或3均无关联。正在对这些家庭进行全基因组基因分型。我们的第二个目标是进行连锁分析，以找到易感区域并最终找到基因。代谢研究：使用磁共振波谱，我们发现携带载脂蛋白ob截断突变的FHBL受试者的肝脏脂肪比匹配的对照组增加了5倍。我们还研究了vldl -甘油三酯（TG）在这些受试者中的组装。输注2h2 -棕榈酸酯，通过气相色谱-质谱法定量血浆和vldl -甘油三酯中棕榈酸酯示踪/示踪比，以及数据的动力学建模表明，FHBL受试者中来自肝脏的VLDL-TG比来自血浆棕榈酸酯的比例要大。肝脏脂肪（通过MRI）与肝脏来源的部分贡献之间存在显著相关性（r=0.90, p=0.001）。我们的目标是将这些研究扩展到我们的FHBL受试者和代谢综合征X患者，并评估代谢“危险因素”（如体重、胰岛素抵抗）对这些组中肝脏脂肪积累程度的重要性。