Abstract-Serum paraoxonase (PON) is an HDL-bound enzyme protecting LDL from oxidation. A common polymorphism of the paraoxonase gene (PON1) involving a Gln-to-Arg interchange at position 192 has been demonstrated to modulate PON activity toward paraoxon, a nonphysiological substrate; Arg192 (allele B) is associated with higher activity than Gln192 (allele A). This polymorphism has been proposed as a genetic marker of risk for coronary artery disease (CAD). However, the relationships between codon 192 PON1 genotypes, coronary atherosclerosis, and the occurrence of myocardial infarction (MI) are still controversial. PON1 genotypes were determined in 472 consecutive subjects (Ͼ40 years old) who underwent coronary angiography. CAD (Ͼ50% stenosis) was detected in 310 subjects (CADϩ); 162 subjects with Ͻ10% stenosis served as controls (CADϪ). We also evaluated 204 randomly selected individuals as population controls. PON1 genotypes were determined by PCR and AlwI restriction enzyme digestion. Frequencies of alleles A and B were 0.70 and 0.30 in angiographically assessed subjects and 0.73 and 0.27 in population controls, respectively ( 2 ϭ2.0; PϽ0.3). Distribution of PON1 genotypes in CADϩ were not significantly different from those in CADϪ ( 2 ϭ2.10; PϽ0.3). Similarly, no differences were observed in the subgroup of CADϩ with MI nor in that at higher oxidative risk (smokers and/or diabetics). After controlling for other coronary risk factors, no association was found between PON1 alleles and the presence of CAD. PON1 AA genotype was associated with reduced concentration of apolipoprotein B-containing triglyceride-rich lipoproteins. This study did not provide evidence of a significant association between codon 192 PON1 genotypes and coronary atherosclerosis in Italian patients. However, it did confirm that the PON1 low-activity allele is associated with a less atherogenic lipid profile. (Arterioscler Thromb

Abstract-We previously described a Sardinian family in which the probands had a severe form of hypercholesterolemia, suggestive of familial hypercholesterolemia (FH). However, low density lipoprotein (LDL) receptor activity in fibroblasts from these subjects and LDL binding ability were normal. The characteristics of the pedigree were consistent with an autosomal recessive trait. Sitosterolemia and pseudohomozygous hyperlipidemia were ruled out. A second Sardinian kindred with similar characteristics was identified. Probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoprotein (apo) B, sitosterolemia, and cholesteryl ester storage disease were excluded by in vitro studies. We addressed the metabolic basis of this inherited disorder by studying the in vivo metabolism of LDL in 3 probands from these 2 families. 125 I-LDL turnover studies disclosed a marked reduction in the fractional catabolic rate (0.19Ϯ0.01 versus 0.36Ϯ0.03 pools per day, respectively; PϽ0.001) and a significant increase in the production rate [20.7Ϯ4.4 versus 14.0Ϯ2.4 mg ⅐ kg, respectively; PϽ0.01] of LDL apoB in the probands compared with normolipidemic controls. We then studied the in vivo biodistribution and tissue uptake of 99m technetium-labeled LDL in the probands and compared them with those in normal controls and 1 FH homozygote. The probands showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. Our findings suggest that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appears to be caused by a selective reduction in hepatic LDL uptake. We propose that in this new lipid disorder, a recessive defect causes a selective impairment of LDL receptor function in the liver. Key Words: hypercholesterolemia Ⅲ genetics Ⅲ LDL turnover Ⅲ LDL receptor Ⅲ apoB S everal conditions have been identified causing severe primary hypercholesterolemia. 1 The best characterized are familial hypercholesterolemia (FH) and familial defective apoB (FDB). FH is an autosomal dominant disease caused by mutations in the LDL receptor (LDLR) gene. 2 The LDLR is a cell surface transmembrane protein that mediates the specific uptake of plasma LDL. Receptor defects markedly impair LDL catabolism, and FH patients typically show severe elevations of plasma LDL cholesterol (LDL-C), tendon xanthomas, and premature coronary atherosclerosis. 3 FDB is a genetic disorder caused by point mutations in the gene encoding for apoB100 that reduces the binding ability of LDL particles to the LDLR; as a consequence, LDL removal is reduced, and affected individuals develop high plasma cholesterol concentrations. 4 Two other rare, autosomal recessive diseases, sitosterolemia and cholesteryl ester storage disease (CESD), can result in severe hypercholesterolemia. Sitosterolemia is characterized by an accumulation of plant sterols, ma...