Molecular Basis of Autosomal Dominant Hypercholesterolemia in a Multiethnic Cohor

多民族群体中常染色体显性高胆固醇血症的分子基础

• 批准号: 8724548
• 负责人: Zahid Ahmad
• 金额: $ 15.53万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724548
• 关键词: Address; African; African American; Arcus Senilis; Birth; Cholesterol; Cholesterol Homeostasis; Chronic Disease; Cities; Clinic; Consensus; Cornea; Coronary artery; Coronary heart disease; Country; DNA; Data; Deposition; Development; Diagnosis; Disease; Ethnic group; Etiology; Europe; European; Exons; Family; Frequencies; Genes; Genetic; Health; Heart Diseases; Hispanics; Hybrids; Inborn Genetic Diseases; Japan; LDL Cholesterol Lipoproteins; Lead; Life; Ligation; Light; Lipids; Low Density Lipoprotein Receptor; Methods; Molecular; Morbidity - disease rate; Mutation; Not Hispanic or Latino; Participant; Patients; Peripheral; Plasma; Population; Prevention; Process; RNA Splicing; Recruitment Activity; Site; Subtilisin Like Proprotein Convertases; Techniques; Tendon structure; Testing; Texas; Tissues; United States; Variant; Xanthomas; apolipoprotein B-100; base; clinical phenotype; cohort; genetic linkage analysis; heart disease prevention; hypercholesterolemia; kexin; lipid metabolism; medical specialties; mortality; next generation sequencing; novel; novel therapeutics; positional cloning; premature; programs; screening

PROJECT DESCRIPTION: Autosomal dominant hypercholesterolemia (ADH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Despite the clear benefit of LDL-C lowering with regards to CHD prevention, less than 10% of cases with ADH have been diagnosed, and only 5% of ADH patients are adequately treated. ADH is genetically heterogeneous and has been associated with variants in at least three genes including LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtilisin-like kexin type 9 (PCSK9). Systematic screenings to identify ADH patients with mutations in these genes has been undertaken in several countries through nationwide screening programs and lipid clinic networks. These studies have found that approximately 5%-53% of patients with a clinical phenotype of ADH do not have mutations in any of the three known loci. Most of these studies were performed in ethnically and racially homogenous populations from Europe or Japan. Thus, there is paucity of data about the molecular basis of ADH in multi-ethnic cohorts, especially African Americans. Our preliminary data in a multi-ethnic cohort of 93 unrelated ADH patients revealed a strikingly high percentage (66%) of patients without any variants in LDLR, APOB and PCSK9 ("unexplained ADH"). Interestingly, the frequency of "unexplained ADH" was much higher among African Americans (77%) than among non-Hispanic whites (57%) or Hispanics (53%). Therefore, we hypothesize that mutations in novel genes may underlie a large proportion of ADH in multi-ethnic cohorts, especially of African descent. The overall aim of this project is identify new genetic defects responsible for hypercholesterolemia in patients who have an undetermined etiology of ADH. To address this aim, we propose to study 400 patients with ADH. Patients will be ascertained from specialty lipid clinics, and their entire families will be recruited. DNA will be screened with standard sequencing techniques for mutations in the exons and consensus splice sites of LDLR, APOB and PCSK9 or by linkage analysis using informative markers at these loci. Deletions and duplications of LDLR exons will be detected with multiplex ligation-dependent probe amplification technique. Based on preliminary data, we expect to establish a cohort of 240 patients with ADH of unknown etiology. To rapidly identify new ADH genes in this cohort of "unexplained ADH" patients, we will utilize a hybrid method that combines next generation sequencing with positional cloning. Elucidation of new genes with major effects on lipid metabolism will shed light on the molecular processes that lead to development of high plasma levels of LDL-C and premature CHD. The studies outlined in this project will provide the basis for the development of new therapeutic options for the prevention of this potentially life-threatening chronic disease.

项目描述：常染色体显性遗传性高胆固醇血症（Autosomal dominant hypercholesterolemia，ADH）是一种先天性显性遗传性疾病，可引起血浆低密度脂蛋白胆固醇（low-density lipoprotein cholesterol，LDL-C）水平显著升高，并可导致早发冠心病（premature coronary heart disease，CHD）。尽管降低LDL-C对预防CHD有明显的益处，但只有不到10%的ADH病例被诊断出来，只有5%的ADH患者得到了充分的治疗。ADH具有遗传异质性，并且与至少三种基因的变体相关，包括LDL受体（LDLR）、载脂蛋白B-100（APOB）和前蛋白转化酶枯草杆菌蛋白酶样kexin 9型（PCSK 9）。通过全国性筛查项目和脂质诊所网络，在几个国家进行了系统筛查，以确定这些基因突变的ADH患者。这些研究发现，大约5%-53%的ADH临床表型患者在三个已知基因座中的任何一个都没有突变。这些研究大多在欧洲或日本的人种和种族同质人群中进行。因此，在多种族人群中，特别是非洲裔美国人中，关于ADH分子基础的数据很少。我们在93例无关ADH患者的多种族队列中的初步数据显示，LDLR、APOB和PCSK 9（“原因不明的ADH”）中无任何变异的患者百分比非常高（66%）。有趣的是，非洲裔美国人（77%）中“无法解释的ADH”的频率远远高于非西班牙裔白人（57%）或西班牙裔（53%）。因此，我们假设新基因的突变可能是多种族人群中，尤其是非洲裔人群中，ADH比例较高的原因。该项目的总体目标是确定导致ADH病因不明患者高胆固醇血症的新遗传缺陷。为了实现这一目标，我们建议研究400名抗利尿激素缺乏症患者。患者将从专业脂质诊所确定，他们的整个家庭将被招募。将使用标准测序技术筛选LDLR、APOB和PCSK 9外显子和共有剪接位点突变的DNA，或使用这些基因座的信息标记进行连锁分析。将采用多重连接依赖性探针扩增技术检测LDLR外显子的缺失和重复。基于初步数据，我们期望建立一个由240名病因不明的ADH患者组成的队列。为了在这群“原因不明的ADH”患者中快速鉴定新的ADH基因，我们将利用一种结合下一代测序和定位克隆的混合方法。阐明对脂质代谢具有主要影响的新基因将阐明导致高血浆LDL-C水平和早发CHD的分子过程。本项目中概述的研究将为开发预防这种可能危及生命的慢性疾病的新治疗方案提供基础。