ASSOCIATION OF GENETIC VARIATIONS IN APOLIPOPROTEIN-B WITH HYPERCHOLESTEROLEMIA, CORONARY-ARTERY DISEASE, AND RECEPTOR-BINDING OF LOW-DENSITY LIPOPROTEINS

To search for unique mutations in the apolipoprotein B (apoB) gene tha t disrupt the binding of LDL to its receptor and cause hypercholestero lemia, we examined more than 800 patients with high LDL cholesterol le vels and/or coronary artery disease (CAD). Analysis of patient DNA by single-strand conformation polymorphism and allele-specific oligonucle otide hybridization of the sequence surrounding the putative receptor- binding domain of apoB (amino acid positions 2965 to 3534) revealed se ven variations. LDL from heterozygotes with either Arg 3500 Gin or Arg 3531 Cys bound defectively with the LDL receptor in competitive bindi ng assays. The Arg 3500 Gln substitution was statistically more preval ent in patients with hypercholesterolemia (P = 0.0003). Total choleste rol and LDL-cholesterol were significantly higher (P < 0.0004) in 34 a poB 3500 Gin carriers than in the controls. The allele encoding the Ar g 3531 Cys substitution was more prevalent (0.8%) in the CAD group (P = 0.05) than in the controls. A Ser 3252 Gly variant was statistically more prevalent in the hypercholesterolemic group (P = 0.03), but LDL with this mutation had normal LDL receptor-binding activity. The other four Variants identified (Leu 3350 Leu, Gin 3405 Glu, Val 3396 Met, a nd Ser 3455 Arg) were not associated with defective LDL-receptor bindi ng, hypercholesterolemia, of CAD, nor were the apoB mutations associat ed with elevated lipid levels in family members. The surprising result that only two mutations of apoB in the receptor-binding domain (Arg 3 500 Gln and Arg 3531 Cys) were associated with defective LDL binding, hypercholesterolemia, or CAD is in stark contrast with familial hyperc holesterolemia, where nearly 150 mutations of the LDL receptor have be en described that disrupt its function. This study strongly suggests t hat a limited number of mutations of apoB markedly influence LDL bindi ng to its receptor.