Genetics of elevated apolipoprotein-B and dense LDL in familial combined hyperlipidemia

Background Familial combined hyperlipidemia (FCH) is characterized by elevations of plasma cholesterol and/or triglycerides in first-degree relatives and an elevation of apolipoprotein-B (apoB). A predominance of small dense atherogenic low-density lipoprotein (LDL) particles is frequently observed. Previously, we have demonstrated a major recessive locus control of dense LDL inheritance and a codominant mechanism involved in the aggregation of elevated apoB levels in 40 FCH Families. To establish whether distinct genetic mechanisms express both traits, we now evaluated the inheritance of small dense LDL after correction for the predicted genetic influence of a putative apoB locus. Methods and Results. By means of a segregation analysis of apoB, individual apoB genotypes could be assigned to 85% of all individuals. LDL subfraction profiles expressed by a continuous variable K differed significantly between apoB genotypes, supporting the metabolic relation between apoB and LDL subfraction profile. Subsequently, LDL subfraction profiles were adjusted for predicted apoB influence by subtracting the apoB genotype specific mean K value from the individual K values. These apoB genotype specific mean K values were obtained from those individuals with their apoB genotype probability greater than or equal to 70%. Segregation analysis of residual LDL subfraction profiles provided substantial evidence for a major locus inheritance pattern. Conclusion. Two distinct genetic mechanisms influence the appearance of elevated plasma apoB and the predominance of dense LDL in these FCH families.