The Role of Genetic Variation in Apolipoprotein B and Apolipoprotein E in the Determination of Hyperlipoproteinemia (Coronary Artery Disease, Cholesterol, Triglyceride).

The role of genetic variation in low density lipoprotein B (LDL-B) levels and apolipoprotein E (apo E) in the determination of type II, III, and IV hyperlipoproteinemia (HLP) was assessed. The major conclusions are reviewed here. A single locus with a large effect on the level of LDL-B, responsible for 35% of the total phenotypic variation in LDL-B levels in this sample, was detected using complex segregation analysis. The effects of this locus were independent of the effect of variation in apo E genotype on LDL-B. The genotype frequencies at this single locus with a large effect on LDL-B levels were significantly different between individuals with type II HLP as compared to normals and type IV HLP as compared to normals. An excess of the Bh allele at the LDL-B level locus which is associated with increased LDL-B levels was found in both type II and IV HLP. The Bh allele was found to be associated with significantly increased levels of LDL-B and LDL-C in normal, type II, type III, and type IV HLP subgroups. An increase in cholesterol was also in the normal and type IV group. Although the Bh allele is associated with higher levels of triglycerides and VLDL-B in normals, lower levels of triglycerides and VLDL-B in type IV HLP are associated with the Bh allele. This difference is consistent with heterogeneity in the etiology of type IV HLP compatible with the distinction between Familial Combined Hyperlipidemia and Familial Hypertriglyceridemia. The existence of a single locus with a large influence on LDL-B levels, which also predicts variation in LDL-C levels, cholesterol, and HLP gives a common mechanism for variation in these major risk factors for coronary artery disease. Although this locus is responsible for large amounts of variation in these risk factors, further work to detect other sources of variation is warranted.Ph.D.GeneticsUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/161297/1/8702806.pd