Fine mapping of Hyplip1 and the human homolog, a potential locus for FCHL

Familial combined hyperlipidemia (FCHL) is a common genetic dyslipidemia pr edisposing to premature coronary heart disease (CHD). We previously identif ied a locus for FCHL on human Chromosome (Chr) 1q21-q23 in 31 Finnish FCHL families. We also mapped a gene for combined hyperlipidemia (Hyplip1) to a potentially orthologous region of mouse Chr 3 in the HcB-19/Dem mouse model of FCHL. The human FCHL locus was, however, originally mapped about 5 Mb t elomeric to the synteny border, the centromeric part of which is homologous to mouse Chr 3 and the telomeric part to mouse Chr 1. To further localize the human Hyplip1 homolog and estimate its distance from the peak linkage m arkers. we fine-mapped the Hyplip1 locus and defined the borders of the reg ion of conserved synteny be tween human and mouse. This involved establishi ng a physical map of a bacterial artificial chromosome (BAC) contig across the Hyplip1 locus and hybridizing a set of BACs to both human and mouse chr omosomes by fluorescence in situ hybridization (FISH). We narrowed the loca tion of the mouse Hyplip1 gene to a 1.5-cM region that is homologous only w ith human 1q21 and within approximately 5-10 Mb of the peak marker for link age to FCHL. FCHL is a complex disorder and this distance may, thus, reflec t the well-known problems hampering the mapping of complex disorders. Furth er studies identifying and sequencing the Hyplip1 gene will show whether th e same gene predisposes to hyperlipidemia in human and mouse.