Segregation analysis of plasma apolipoprotein B levels in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is a heritable lipid disorder that is associated with an increased risk of premature cardiovascular disease. An elevated plasma apolipoprotein (apo) B concentration is reported to be a diagnostic feature of the disorder. Recently we demonstrated a strong relation between plasma apoB concentrations and the cholesterol concentration in VLDL plus LDL, both elevated in FCH families. Therefore, examination of the inheritance of elevated plasma apoB levels in FCH families may reveal important information about the mechanism responsible for the aggregation of elevated plasma lipids in FCH. This study included 663 Dutch family members in 40 families ascertained through FCH probands. Plasma apoB concentration correlated significantly with apoB-related cholesterol both in the probands and the relatives (r=.83 and r=.90, respectively). Adjustment for age, sex, body mass index, and smoking habits accounted for 35.7% of the variation in apoB levels, and there was strong familial aggregation in adjusted apoB levels in these families. Complex segregation analysis was performed to determine the mechanism of inheritance behind this familial aggregation. The aggregation of elevated apoB levels was best explained by a major gene effect inherited by a codominant mechanism. Estimated mean apoB levels for the three supposed genotypes AA, AB, and BB were 111.5, 126.7, and 165.7 mg/dL, respectively, with relative frequencies of 43.5%, 44.9%, and 11.6%, respectively. In conclusion, despite assumed metabolic and genetic heterogeneity of FCH, there is clear evidence for a single gene effect on apoB concentrations in families ascertained through FCH. Linkage studies based on this analysis may further clarify the molecular basis of the apoB regulation in these families.