NO EVIDENCE OF LINKAGE BETWEEN FAMILIAL COMBINED HYPERLIPIDEMIA AND GENES ENCODING LIPOLYTIC ENZYMES IN FINNISH FAMILIES

Familial combined hyperlipidemia (FCHL) is characterized by different lipid phenotypes (IIa, IIb, IV) and elevated apolipoprotein B (ape B) levels in affected family members. Despite intensive research, the gen es involved in the expression of this complex disorder have not been i dentified, probably because of problems associated with phenotype defi nition, unknown mode of inheritance, and most probably genetic heterog eneity. To explore the genetics of FCHL in the genetically homogeneous Finnish population, we collected 14 well-documented Finnish pedigrees with premature coronary heart disease and FCHL-like dyslipidemia. The lipolytic enzymes lipoprotein lipase (LPL), hepatic lipase (HL), and hormone-sensitive lipase (HSL) were selected as initial candidate gene s because of their central roles in apo B and triglyceride metabolism. On the basis of the pedigree structures, a dominant mode of inheritan ce was adopted for linkage analyses, and serum total cholesterol and/o r triglyceride levels exceeding the 90th percentile level were set as diagnostic criteria (criterion 1). In pairwise linkage analyses with i ntragenic markers, no evidence for linkage was found. Instead, the sig nificantly negative LOD scores suggested exclusion of all three loci f or single major gene effect. LOD scores were -14.63, -5.03, and -5.70 for the three LPL polymorphisms (Theta=0.00); -9.40, -6.30, and -4.74 for the three HL polymorphisms (Theta=0.00); and -15.29 for the HSL po lymorphism (Theta=0.00). The results were very similar when apo B leve ls over the 90th percentile were used as criteria for affected status (criterion 2). Also, when linkage calculations were carried out using an intermediate or recessive mode of inheritance, the results of pairw ise linkage analysis remained negative. Furthermore, when haplotypes w ere constructed from multiple polymorphisms of the LPL and HL genes, n o segregation with the FCHL phenotype could be observed in the 14 Finn ish families. Data obtained by the affected sib-pair method supported these findings, suggesting that the LPL, I-IL, or HSL genes do not rep resent major loci influencing the expression of the FCHL phenotype.