APO B-100:

DEFECT: The most common mutation in Caucasians is ARG3500GLN, a mutation in the codon for amino acid 3500 that results in the substitution of glutamine for arginine.

FREQUENCY: 1/500 to 1/700 in several Caucasian populations in North America and Europe. The mutation has not been found in Japan, Finland or Israel.

MODE OF ACTION: Apolipoprotein B is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL) and is important in the clearance of LDL cholesterol from blood plasma.

ASSOCIATED RISK: The ARG3500GLN mutation results in familial defective apolipoprotein B-100 (FDB), which is characterized by high levels of LDL cholesterol. The mutation profoundly alters the conformation of the apoB receptor binding domain, resulting in decreased affinity for the LDL receptors and in reduced clearance of LDL cholesterol. 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 familial hypercholesterolemia; at age 50, about 40% of males and 20% of females heterozygous for the mutation have developed coronary artery disease.

POSSIBLE CLINICAL UTILITY: The ARG3500GLN mutation should be screened in Caucasian patients with hyperlipedemia or ischemic heart disease, as well as their family members.

References:

1. Tybjærg-Hansen A, Steffensen R, Meinertz H , Schnohr P, and Nordestgaard BG; Association Of Mutations In The Apolipoprotein B Gene With Hypercholesterolemia And The Risk Of Ischemic Heart Disease. N Engl J Med 1998;338: 1577-84.

The researchers studied the genotypes of 9255 women and men from the general population from Denmark. The Arg3500Gln mutation in the apolipoprotein B gene, which is responsible for familial defective apolipoprotein B-100 and is present in approximately 1 in 1000 persons in Denmark, causes severe hypercholesterolemia and increases the risk of ischemic heart disease. Among carriers of the Arg3500Gln mutation, cholesterol levels were significantly higher than among noncarriers in the general population. Heterozygous carriers of the Arg3500Gln mutation were significantly more common among patients with ischemic heart disease (odds ratio, 7.0; 95 percent confidence interval, 2.2 to 22; P=0.003) and patients with familial hypercholesterolemia (odds ratio, 78; 95 percent confidence interval, 16 to 388; P=0.001) than in the general population.

2. Ludwig EH, Hopkins PN, Allen A, Wu LL, Williams RR, Anderson JL, Ward RH, Lalouel JM, Innerarity TL; Association of genetic variations in apolipoprotein B with hypercholesterolemia, coronary artery disease, and receptor binding of low density lipoproteins. J Lipid Res 1997 Jul;38(7):1361-73

Seven variants of the ApoB gene were found. Only two mutations of apoB in the receptor-binding domain (Arg 3500 Gln and Arg 3531 Cys) were associated with defective LDL binding, hypercholesterolemia, or CAD. Heterozygotes with Arg 3500 Gln bound defectively with the LDL receptor in competitive binding assays. The Arg 3500 Gln substitution was statistically more prevalent in patients with hypercholesterolemia (P = 0.0003). Total cholesterol and LDL-cholesterol were significantly higher (P< 0.0004) in apoB Arg 3500 Gln carriers than in the controls.

3. Soria LF, Ludwig EH, Clarke HR, Vega GL, Grundy SM, McCarthy BJ; Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci U S A 1989 Jan;86(2):587-91

The researchers report a new mutation, Arg3500Gln, that results in the substitution of glutamine for arginine. The mutant allele occurs in six unrelated subjects and in eight affected relatives in two families. The mutation in the codon for amino acid 3500 (CGG----CAG), a CG mutational "hot spot," defines a minor apoB-100 allele associated with defective low density lipoproteins and hypercholesterolemia.

4. Tybjaerg-Hansen A, Humphries SE; Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease. Atherosclerosis 1992 Oct;96(2-3):91-107

The frequency of the Arg3500Gln 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.

5. Defesche JC, Pricker KL, Hayden MR, van der Ende BE, Kastelein JJ; Familial defective apolipoprotein B-100 is clinically indistinguishable from familial hypercholesterolemia. Arch Intern Med 1993 Oct 25;153(20):2349-56

The Arg3500Gln mutation diminishes the binding capacity of the low-density lipoprotein particle for the low-density lipoprotein receptor, which in turn leads to an increase in levels of plasma total and low-density lipoprotein cholesterol. The disorder was clinically indistinguishable from familial hypercholesterolemia in terms of physical characteristics and lipoprotein measures. Response to lipid-lowering therapy with beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors was similar to that reported in patients with familial hypercholesterolemia. The mutation was associated with a similar haplotype, which was also reported in other patients of Western European descent with familial defective apolipoprotein B100. This strongly suggests that the mutation has a common chromosomal background that originated in Western Europe.

6. van der Hoek YY, Lingenhel A, Kraft HG, Defesche JC, Kastelein JJ, Utermann G; Sib-pair analysis detects elevated Lp(a) levels and large variation of Lp(a) concentration in subjects with familial defective ApoB. J Clin Invest 1997 May 1;99(9):2269-73

Mean LDL levels were significantly elevated in Familial defective apolipoprotein B-100 (FDB) subjects compared to non-FDB relatives (P < 0.001). Median Lp(a) levels were not different between FDB subjects and their non-FDB relatives. In contrast, sib-pair analysis demonstrated a significant effect of the FDB status on Lp(a) levels. In sib pairs identical by descent for apo(a) alleles but discordant for the FDB mutation (n = 11) each sib with FDB had a higher Lp(a) level than the corresponding non-FDB sib. Further, all possible sib pairs (n = 105) were grouped into three categories according to the absence/presence of the apoB R3500Q mutation in one or both subjects of a sib pair. The variability of differences in Lp(a) levels within the sib pairs increased with the number (0, 1, and 2) of FDB subjects present in the sib pair. This suggests that the FDB status increases Lp(a) level and variability, and that apoB may be a variability gene for Lp(a) levels in plasma.

7. Gaffney D, Reid JM, Cameron IM, Vass K, Caslake MJ, Shepherd J, Packard CJ; Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler Thromb Vasc Biol 1995 Aug;15(8):1025-9

The researchers describe two families in which a different mutation in the codon 3500 causes an arginine-to-tryptophan substitution. Most adults in these families who have this mutation have hypercholesterolemia. LDL derived from all who have inherited the mutation is dysfunctional in that it allows only poor growth of an LDL cholesterol-dependent cell line. Therefore, the arginine 3500 is essential to the function of apoB and that its loss and replacement by glutamine or tryptophan is responsible for the hypercholesterolemia of familial defective apoB 100.

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