Identification of genes predisposing to atherosclerosis

鉴定诱发动脉粥样硬化的基因

• 批准号: 6719598
• 负责人: LEENA PELTONEN
• 金额: $ 37.92万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719598
• 关键词: atherosclerosis; biotechnology; blood lipid; cholesterol; clinical research; coronary disorder; familial hyperlipoproteinemia; family genetics; functional /structural genomics; gene expression; genetic susceptibility; genetically modified animals; genotype; human genetic material tag; human subject; laboratory mouse; linkage mapping; microarray technology; polymerase chain reaction; single nucleotide polymorphism; triglycerides

DESCRIPTION (provided by applicant): Coronary heart disease (CHD) is a complex disorder constituting a major health problem in Western societies. We aim to assess the unknown genetic background of CHD by investigating the most common familial dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL). The population prevalence of FCHL is estimated to be 1-2 percent and the disorder affects 10-20 percent of families with premature CHD. In FCHL, serum cholesterol, triglycerides, or both are elevated. Both environmental and genetic factors are suggested to affect the complex FCHL phenotype. Since the molecular basis of FCHL is unknown, a significant number of genetically predisposed individuals remain unidentified and exposed to premature CHD. We will use our unique study samples from the genetically isolated population of Finland and apply molecular genetic tools to first restrict the genetic locus we have identified and then to characterize the causative gene underlying the FCHL disorder on chromosome 1q21. Specifically, we first aim to further restrict the region by dissecting the different component traits. We will genotype an extended study sample consisting of all available family members of 61 FCHL families with dense sets of microsatellite markers and single nucleotide polymorphisms to fully utilize the refined quantitative phenotype information in fine mapping. Second, we aim to build a transcript map over the critical region on 1q21-q23 and to identify the causative FCHL gene among the regional candidate genes. This region on 1q21-q23 is orthologous to a region on mouse chromosome 3, where a locus (Hyplip 1) for combined hyperlipidemia has been identified. We have analyzed the human homolog of the Hyplip 1 gene but disappointingly, the human Hyplip 1 gene was found 10 Mb from the peak linkage markers and no evidence emerged for Hyplip 1 as a causative gene for FCHL. Our targets to identify the FCHL gene are currently the genes showing strongest association near the linkage peak. The FCHL gene will then be functionally characterized to prove the biological dysfunction. Characterizing one gene for FCHL would improve our understanding of molecular mechanisms of cardiovascular disease, and potentially lead to more accurate diagnosis, treatment and prevention.

描述(申请人提供)：冠心病(CHD)是一种复杂的疾病，在西方社会构成一个主要的健康问题。我们的目的是通过调查最常见的易患冠心病的家族性血脂异常--家族性混合性高脂血症(FCHL)来评估CHD的未知遗传背景。据估计，FCHL的人口患病率为1%-2%，这种疾病影响到10%-20%的早产儿CHD家庭。在FCHL中，血清胆固醇、甘油三酯或两者都升高。环境因素和遗传因素都可能影响复杂的FCHL表型。由于FCHL的分子基础尚不清楚，相当数量的遗传易感个体仍未被识别并暴露于过早的CHD。我们将使用我们来自芬兰遗传隔离人群的独特研究样本，并应用分子遗传学工具首先限制我们已经确定的遗传位点，然后表征染色体1q21上导致FCHL疾病的致病基因。具体地说，我们首先的目标是通过解剖不同的成分特征来进一步限制该地区。我们将对由61个FCHL家系的所有可用家庭成员组成的扩展研究样本进行基因分型，利用密集的微卫星标记和单核苷酸多态，以充分利用精细定位中精致的数量表型信息。第二，我们的目标是在1q21-q23的关键区域建立转录图谱，并在区域候选基因中鉴定致病基因FCHL。1q21-q23上的这个区域与小鼠3号染色体上的一个区域同源，在那里已经确定了混合性高脂血症的一个基因座(Hyplip1)。我们已经分析了人类Hyplip 1基因的同源性，但令人失望的是，从峰值连锁标记中发现了人类Hyplip 1基因10Mb，没有证据表明Hyplip 1基因是FCHL的致病基因。我们鉴定FCHL基因的目标是目前在连锁高峰附近表现出最强关联性的基因。然后将对FCHL基因进行功能鉴定，以证明生物功能障碍。鉴定FCHL的一个基因将提高我们对心血管疾病分子机制的理解，并有可能导致更准确的诊断、治疗和预防。