Occurrence of species of low‐density lipoprotein with defective clearance in patients with primary moderate hypercholesterolaemia

Recent studies have shown that one cause of primary moderate hypercholesterolaemia is familial defective apolipoprotein B‐100 (FDB), a condition in which a mutation in apolipoprotein B‐100 (apo B‐100) causes low‐density lipoproteins (LDL) to bind poorly to LDL receptors. One specific mutation, a glutamine‐for‐arginine transformation at position 3500 of apo B‐100, has been reported to produce FDB. However, other mutations in apo B‐100 might also cause FDB. The present study was designed to determine whether some patients with hypercholesterolaemia, who do not have the 3500 defect, may have a slowly cleared subfraction of LDL compatible with other forms of FDB. It was postulated that slowly removed LDL should accumulate excess cholesterol ester and hence be less dense than normal LDL. If so, in patients who are heterozygous for FDB. two forms of LDL might be separable by ultracentrifugation. To test this hypothesis, less‐dense (d = 1.030 g ml⁻¹) and more‐dense (d = 1.040 g ml⁻¹) subfractions of LDL were isolated from a patient with proven FDB (3500 mutation); the two forms of LDL were labelled with different isotopes of radioiodine and re‐injected into the patient. The less‐dense form was removed much more slowly (0.285 pools day⁻¹) than more‐dense LDL (0.570 pools day⁻¹). This finding appeared to confirm the validity of the approach. The same procedure was then applied to 18 other patients having elevated LDL cholesterol but not the 3500 mutation. In 13 patients, the two forms of LDL were removed at essentially identical rates, suggesting that they did not have an abnormal form of LDL. In the other five, less‐dense LDL were removed at a significantly slower rate than more‐dense LDL: this finding suggests that a significant portion of patients with moderate hypercholesterolaemia have an abnormal LDL species, which is not the 3500 mutation, but delays clearance of LDL from the circulation. 1992 Blackwell Publishing Ltd