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.
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