FAMILIAL COMBINED HYPERLIPIDEMIA: GENE IDENTIFICATION IN FINNISH ISOLATE

芬兰的人口代表了一个独特的资源，以接近复杂疾病背后的易感基因位点。这种有利的局面是由有限的创始人祖先，遗传，环境和文化的同质性与高质量的医疗保健和优秀的人口相结合创造的。 我们对31个家系的选择策略强调了混合型高脂血症在家族性混合型高脂血症（FCHL）诊断中的重要性。对于连锁分析，表型信息只利用受影响的个人，以尽量减少不完全连锁的影响。当对染色体1 q21 -23上8 cM区域上的一组标记进行分析时，其中两个标记揭示了与最大成对lod得分3.50（θ = 0.02）连锁的证据，并且当将两个标记的信息合并时，获得了5.93（θ =0.02）的lod得分。在不久的将来，我们将进行精细的定位，这FCHL基因座，能够监测连锁不平衡，这将引导我们在芬兰样本的主要易感基因。该连锁区是同线的染色体区域最近确定的项目1的研究人员通过连锁研究，在小鼠品系的表型特征非常相似的FCHL。在两个物种中发现的同一个基因座强调了该基因座的真正生物学意义。这一新的信息将促进快速的进展，利用小鼠和人的数据在疾病位点的精细映射。在我们已经确定了关联或连锁不平衡的一些标记，我们将建立一个序列准备地图上最关键的DNA区域，确定EST重叠群在数据库中，并使用混合选择或其他策略，以建立完整的转录本地图。鉴定的基因将是突变分析的目标，以测试这些潜在的候选基因。最后，来自芬兰和其他欧洲以及美国人群的优秀DNA收集应该有助于识别突变和快速筛查，以确定FCHL结果的真正意义。

The population of Finland represents a unique resource to approach predisposing gene loci behind complex diseases. The advantageous situation is created by limited number of founder ancestors, genetic, environmental, and cultural homogeneity combined with high quality health care and excellent population. Our selection strategy for the 31 families studied emphasized the importance of combined hyperlipidemia in familial combined hyperlipidemia (FCHL) diagnosis. For linkage analysis, phenotypic information was utilized only from affected individuals to minimized the effects of incomplete penetrance. When a set of markers over an 8 cM region on chromosome 1q21-23 were analyzed, two of there revealed evidence for linkage with the maximum pairwise lod score of 3.50 (theta= 0.02) and when information of two markers was pooled, a lod score of 5.93 (0=0.02) was obtained. In the immediate future we will perform fine mapping of this FCHL-locus to be able to monitor for linkage disequilibrium which will guide us to a major predisposing gene in the Finnish sample. The linked region is syntenic with the chromosomal region recently identified by Project 1 investigators via a linkage study in a mouse strain with phenotypic characteristics very similar to FCHL. The same identified locus in two species emphasizes the true biological significance of this locus. This novel information will facilitate rapid progress in fine mapping of the disease locus utilizing data from both mouse and man. After we have identified association or linkage disequilibrium to some markers, we will build a sequence ready map over the most critical DNA region, identify EST-contigs in databases and use also hybrid selection or other strategies to build the complete transcript map. Identified genes will be targets of mutation analyses to test these as potential candidate genes. Finally, the excellent DNA collections from Finnish and other European as well as US populations should facilitate identification of mutations and rapid screening for them to establish true significance for the outcome of FCHL.