QUANTITATIVE AND COMPOSITIONAL CHANGES IN HIGH-DENSITY-LIPOPROTEIN SUBCLASSES IN PATIENTS WITH VARIOUS GENOTYPES OF CHOLESTERYL ESTER TRANSFER PROTEIN-DEFICIENCY

High density lipoprotein (HDL) with and without apolipoprotein (apo) E was quantified and characterized in subjects with three genotypes of cholesteryl ester transfer protein (CETP) deficiency: the nonsense mut ation in intron 14 (10 homozygotes and 5 heterozygotes); the missense mutation in the exon 15 (3 homozygotes and 9 heterozygotes); and the I nt14A/D442G in 6 compound heterozygotes. ApoE-poor and apoE-rich HDL-c holesterol levels were elevated significantly in all genotypic groups with the decrease in CETP activity, indicating that both types of HDL- cholesterol can be a substrate for CETP. However, an unchanged or only slightly increased serum apoA-II level in each genotype indicated tha t the HDL particles with apoA-II are relatively resistant to CETP-medi ated lipid transfer. Serum apoE-rich HDL level was considerably higher in the Int14A homozygotes than in the compound heterozygotes, in spit e of similar apoE-poor HDL-cholesterol levels, which may indicate that apoE-rich HDL is a better substrate for CETP than apoE-poor HDL. Alth ough the apoE-rich and apoE-poor HDL subclasses were similar in the ac cumulation of cholesteryl ester and depletion of triglyceride, the acc umulation of free cholesterol was unique to apoE-rich HDL, indicating inhibited cholesterol esterification on this lipoprotein. Clinical lab oratories should be aware of the discrepancy in HDL-cholesterol measur ements that comes from the different recoveries of apoE-rich HDL using commercial reagents. In conclusion, CETP deficiency causes considerab le quantitative and compositional changes in HDL subclasses, reflectin g a significant physiological role for CETP in HDL metabolism.