FAMILIAL COMBINED HYPERLIPIDEMIA: GENE IDENTIFICATION IN FINNISH ISOLATE

芬兰人口代表着一种独特的资源，可以用来研究复杂疾病背后的易感基因位点。创始人祖先数量有限，遗传、环境、文化同质性，加上高质量的医疗保健和优秀的人口，创造了这一有利局面。我们对31个家系的选择策略强调了混合性高脂血症在家族性混合性高脂血症(FCHL)诊断中的重要性。对于连锁分析，仅利用来自受影响个体的表型信息来最小化不完全外显的影响。当分析染色体1q21-23上8 cM区域的一组标记时，其中两个标记的最大成对Lod得分为3.50(theta=0.02)，合并这两个标记的信息后，Lod得分为5.93(0=0.02)。在不久的将来，我们将对这个FCHL基因座进行精细的定位，以便能够监测连锁不平衡，这将引导我们找到芬兰样本中的一个主要易感基因。该连接区域与项目1研究人员最近通过对具有与FCHL非常相似的表型特征的小鼠品系进行的连锁研究而确定的染色体区域是同步的。在两个物种中识别的相同的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利用来自老鼠和人的数据在精细绘制疾病基因座方面的快速进展。在我们确定了与某些标记的关联或连锁不平衡之后，我们将在最关键的DNA区域建立一个序列就绪的图谱，在数据库中鉴定EST-重叠群，并使用杂交选择或其他策略来构建完整的转录图谱。已识别的基因将成为突变分析的目标，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并对它们进行快速筛查，以确立对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.