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Familial combined hyperlipidemia (FCH) is characterized by a variable expression of hypercholesterolemia and/or hypertriglyceridemia. We evaluated the variability in lipid phenotype expression over a 5-year period and studied factors affecting the lipid phenotype expression. A total of 32 families (299 subjects) were studied in 1994 and in 1999. Subjects were classified as having FCH when total cholesterol and/or triglyceride levels exceeded the 90th percentile adjusted for age and sex. In 1994, 93 (31%) of the 299 subjects were affected, whereas 206 (69%) of the subjects were unaffected relatives. In 1999, a diagnosis of FCH was consistent in 69 (74%) of the 93 subjects. So, 26% of the FCH subjects in 1994 showed a sporadic normolipidemic pattern (ie, total cholesterol and/or triglycerides <90th percentile) in 1999. Among the 206 unaffected relatives in 1994, 178 (86%) remained unaffected in 1999, and 28 (14%) developed an FCH lipid phenotype. Multiple regression analysis showed that sex (odds ratio 2.03, 95% CI 1.09 to 3.87; P=0.03) and body mass index (odds ratio 1.14, 95% CI 1.05 to 1.24; P<0.01) significantly contributed to the variability in lipid phenotype expression. Thus, a diagnosis of FCH, based on plasma total cholesterol and/or triglyceride levels, is consistent in only 74% of the subjects over a 5-year period. Two other major characteristics of our FCH group, compared with the unaffected relatives, included elevated apolipoprotein B (apoB) levels and the presence of small dense low density lipoprotein (LDL), as reflected by a low value of the parameter K (apoB 1461 +/- 305 versus 997 +/- 249 mg/L, respectively [P < 0.001]; K value -0.22 +/- 0.19 versus -0.02 +/- 0.19, respectively [P < 0.001]). We now report that the apoB concentration and the K value show less variability in time and are more consistently associated with FCH, inasmuch as affected FCH subjects, compared with the unaffected relatives, persistently show a higher apoB level and a lower value of parameter K, reflecting small dense LDL, even when they present a sporadic normolipidemic pattern. In conclusion, our results emphasize the need for reevaluation of the diagnostic criteria for FCH. We demonstrate that apoB and small dense LDL are attractive new candidates for defining FCH. Further studies are indicated to evaluate the role of apoB and small dense LDL as diagnostic criteria for FCH.

We compared in 506 members of families with familial combined hyperlipidaemia (FCH), two approaches to selecting subjects with an apparent increased risk for coronary heart disease: assay of apolipoprotein (apo) B only versus measurement of plasma lipids and lipoproteins. When comparing both criteria, there was an overlap of 81.2% at apo B levels < or = 1250 mg/l and of 86.9% at apo B levels > 1250 mg/l. At apo B < or = 1250 mg/l all subjects were normolipidemic. However, 18.8% of these subjects had sub-normal HDL-cholesterol concentrations (< 0.9 mmol/l) but were not considered to have an increased risk because of very low LDL-cholesterol levels (< 2.5 mmol/l). At apo B concentrations > 1250 mg/l we observed a group with normal plasma lipid levels (13.1%). In this group, defined as normolipidemic hyperapobetalipoproteinemia, and considered to have an increased risk for coronary heart disease, apo B determination was thus most informative. The selection of the subgroup with 'normolipidemic hyperapobetalipoproteinemia' on the basis of the conventional approach could be refined using a cut off limit for plasma triglycerides < 1.5 mmol/l. This limit distinguished optimally between an atherogenic very dense LDL pattern versus a dense and buoyant pattern. Thus, based on the results of our study, the determination of apo B appeared to be, if not superior, at least as effective as the conventional lipid and lipoprotein parameters in classifying subjects at increased risk for coronary heart disease.

Familial combined hyperlipidemia (FCHL) is a frequent cause of premature coronary artery disease. Affected family members are characterized by different combinations of elevated cholesterol and/or triglyceride levels. A reduction in lipoprotein lipase (LPL) activity has been observed in a subgroup of FCHL patients. Recently, we have demonstrated an increased frequency of mutations in the LPL gene in Dutch FCHL patients compared to normolipidemic controls. In the present study, we have applied a pedigree-based maximum likelihood method to study the effect of LPL mutations on the phenotypic expression of FCHL in families. In 40 FCHL probandi, three different previously reported mutations in the LPL gene were identified resulting in amino acid changes, D9N, N291S, and S447X. The D9N mutation in exon 2 appeared to be in strong linkage disequilibrium with a T-->G substitution at position -93 in the promoter region of the LPL gene. We present data that the -93T-->G/D9N haplotype is associated with significantly higher levels of LDL and VLDL cholesterol, and VLDL triglycerides. Interestingly, the effect was only observed in male carriers. In line with our previous observations, these results further sustain that the LPL gene is a susceptibility gene for dyslipidemia which explains part of the variability in the phenotype observed among FCHL family members.

The impact of apo E polymorphism on interindividual variation in plasma lipid, lipoprotein concentrations, and LDL subfraction profiles was studied in 201 well-defined patients (88 men and 103 women) with familial combined hyperlipidemia (FCH). When corrected for the concomitant influences of age, gender and obesity, the allelic variation in the apo E gene was shown to explain a statistically significant portion of the variability in lipid and (apo)lipoprotein concentrations. Carriers of the apo epsilon 2 allele exhibited a substantially higher plasma triglyceride concentration and a lower low density lipoprotein (LDL) cholesterol level, while subjects with the apo epsilon 4 allele had significant higher total plasma cholesterol and LDL cholesterol levels. In line with this observation, our FCH population was characterized by an over-representation of the apo E4 allele as compared with a Dutch standard population (chi 2 = 55.2, P < 0.0001). The contribution of apo E polymorphism to trait variability was different between sexes for plasma triglyceride, VLDL cholesterol, VLDL triglycerides, and high density lipoprotein (HDL) cholesterol levels. Apo E polymorphism had no impact on chemical composition of VLDL; for LDL particles the apo epsilon 2 allele was associated with a lower cholesterol to protein (C/P) ratio, whereas the opposite was true for the apo epsilon 4 allele. Despite the demonstrated impact of apo E polymorphism on plasma lipids and LDL chemical composition, in all phenotypic groups a dense LDL subfraction profile predominated. Thus, apo E polymorphism contributes to the lipid phenotypic expression in FCH, whereas further evidence was obtained that a dense LDL subfraction profile is an integral feature of FCH.

Familial combined hyperlipidaemia (FCHL) is one of the major genetic causes of coronary heart disease (CHD) and is characterised by elevated levels of plasma cholesterol and/or triglycerides in individuals within a single family. Decreased lipoprotein lipase (LPL) activity has been found in some cases of FCHL. A recent study revealed a common mutation in the LPL gene, LPL(Asn291-->Ser), with a frequency of 9.3% in Dutch FCHL patients (Reymer et al,. Circulation, 90 (1994) I-998). This mutation was found in 3 out of 17 FCHL families. Extensive family studies were subsequently performed to determine the effect of this mutation on the phenotypic expression of FCHL. Using a pedigree-based maximum likelihood estimate, we demonstrated that the LPL(Asn291-->Ser) mutation significantly affects the levels of plasma and very low density lipoprotein (VLDL) triglycerides (2.03 +/- 0.21 vs. 1.14 +/- 0.13 and 1.21 +/- 0.16 vs. 0.62 +/- 0.09 mmol/l, carriers and non-carriers, respectively) and VLDL- and high density lipoprotein (HDL) cholesterol (0.83 +/- 0.10 vs. 0.38 +/- 0.06 and 1.02 +/- 0.08 vs. 1.29 +/- 0.05 mmol l, carriers and non-carriers, respectively), but not those of plasma and low density lipoprotein (LDL) cholesterol. These findings indicate that the LPL(Asn291-->Ser) mutation is associated with elevated lipid levels, indicating it may be one of the genetic factors predisposing to FCHL in the families studied.

We evaluated in a double-blind, placebo-controlled, randomized trial of 45 well-defined patients with familial combined hyperlipidemia, the effect of gemfibrozil (1,200 mg/day) or simvastatin (20 mg/day) on apolipoprotein-B (apo-B)-containing lipoproteins, low-density lipoprotein (LDL) subfraction profile, and LDL oxidizability. Although both drugs reduced plasma cholesterol and triglyceride concentrations, gemfibrozil reduced plasma triglycerides more effectively and simvastatin reduced plasma cholesterol more effectively. LDL cholesterol was reduced with simvastatin. With both drugs, total serum apo-B concentration decreased. With gemfibrozil, this was due to an exclusive reduction (-46%) of very low/intermediate-density lipoprotein (VLDL + IDL) apo-B, whereas simvastatin decreased apo-B in both VLDL + IDL and LDL (34% and 15%, respectively). Initially, a dense LDL subfraction profile was present in all patients. The decrease in LDL cholesterol with simvastatin was due to a decrease in all isolated LDL subfractions except LDL2; gemfibrozil increased LDL1 and LDL2 cholesterol (p = 0.001) and reduced LDL4 cholesterol, resulting in a more buoyant LDL subfraction profile compared with simvastatin. In both groups, a predominance of small dense LDL remained despite therapy. LDL fatty acid composition showed a shift from oleic acid to linoleic acid after gemfibrozil; arachidonic acid increased after simvastatin. Vitamin E was lower after gemfibrozil. In the measurements of LDL oxidation, only the oxidation rate was significantly reduced with simvastatin. Thus, quantitative and qualitative changes of LDL cholesterol had only a small effect on total in vitro LDL oxidizability in this population with familial combined hyperlipidemia.