FAMILIAL COMBINED HYPERLIPIDEMIA: GENE IDENTIFICATION IN FINNISH ISOLATE

芬兰人口是研究复杂疾病背后易感基因位点的独特资源。这种有利的情况是由有限的创始人祖先、遗传、环境和文化的同质性、高质量的医疗保健和优秀的人口创造的。我们对31个研究家庭的选择策略强调了合并高脂血症在家族性合并高脂血症（FCHL）诊断中的重要性。在连锁分析中，仅利用受影响个体的表型信息，以尽量减少不完全外显率的影响。对1q21-23染色体8 cM区域的一组标记进行分析，其中2个标记显示连锁证据，最大成对lod评分为3.50 (θ =0.02)，合并2个标记的信息时，lod评分为5.93（0=0.02）。在不久的将来，我们将对这个fchl位点进行精细的定位，以便能够监测连锁不平衡，这将指导我们在芬兰样本中找到一个主要的易感基因。该连锁区域与项目1研究人员最近通过一种表型特征与FCHL非常相似的小鼠品系的连锁研究发现的染色体区域是一致的。在两个物种中发现相同的位点强调了该位点的真正生物学意义。这一新的信息将促进利用小鼠和人的数据对疾病位点进行精细定位的快速进展。在我们确定了一些标记的关联或连锁不平衡后，我们将在最关键的DNA区域建立序列准备图，在数据库中识别EST-contigs，并使用杂交选择或其他策略来构建完整的转录本图。已确定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收集应该有助于突变的识别和快速筛选，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.