Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease.

Familial defective apolipoprotein B-100 is a recently identified, dominantly inherited genetic disorder caused by a G to A mutation in exon 26 of the apolipoprotein B gene. This creates a substitution of glutamine for arginine in the codon for amino acid 3500 and results in reduced affinity of low density lipoprotein (LDL) to the LDL receptor. We have integrated already published data with hitherto unpublished data from 8 countries and a total of 135 affected individuals from 56 families, in an attempt to focus on the range of expression of this mutation on lipid and lipoprotein levels and on coronary artery disease. The frequency of this mutation may be as high as 1 in 500 to 1 in 700 in Europe and in North America. The vast majority of affected heterozygotes have total and LDL cholesterol levels well above the 95th centile for age and gender; in contrast, high density lipoprotein cholesterol, very low density lipoprotein cholesterol and plasma triglycerides are not affected by the mutation. The risk of premature coronary artery disease in the carriers of the mutation is increased to levels as high as those seen in patients with clinical familial hypercholesterolemia; at age 50, about 40% of males and 20% of females heterozygous for the mutation have developed coronary artery disease. Familial defective apolipoprotein B-100 is thus a significant cause of hypercholesterolemia and premature coronary artery disease in Western societies.