Identification of genes predisposing to atherosclerosis

描述（由申请人提供）：冠心病（CHD）是一种复杂的疾病，构成了西方社会的主要健康问题。我们的目的是评估未知的遗传背景的冠心病调查最常见的家族性血脂异常易感冠心病，家族性混合型高脂血症（FCHL）。FCHL的人口患病率估计为1- 2%，该疾病影响10- 20%的早发CHD家庭。在FCHL中，血清胆固醇、甘油三酯或两者均升高。环境和遗传因素都影响复杂的FCHL表型。由于FCHL的分子基础是未知的，大量的遗传易感个体仍然未被识别并暴露于早发CHD。我们将使用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，然后描述染色体1 q21上FCHL疾病的致病基因。具体来说，我们的目标是通过解剖不同的组分性状来进一步限制该区域。我们将对一个扩展的研究样本进行基因分型，该样本包括61个FCHL家族的所有可用家族成员，这些家族成员具有密集的微卫星标记和单核苷酸多态性，以充分利用精细定位中的精细定量表型信息。其次，我们的目标是建立一个转录图谱上的关键区域1 q21-q23和确定区域候选基因中的致病FCHL基因。1 q21-q23上的该区域与小鼠3号染色体上的一个区域正交，在该区域中已鉴定出混合型高脂血症的基因座（Hyplip 1）。我们分析了Hyplip 1基因的人类同源物，但令人惊讶的是，人类Hyplip 1基因被发现距离峰值连锁标记10 Mb，没有证据表明Hyplip 1是FCHL的致病基因。我们鉴定FCHL基因的目标是目前在连锁峰附近显示最强关联的基因。FCHL基因的功能将被表征，以证明生物学功能障碍。确定FCHL基因的特征将提高我们对心血管疾病分子机制的理解，并可能导致更准确的诊断，治疗和预防。

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.