Phenotypic Variation in Patients Heterozygous for Familial Defective Apolipoprotein B (FDB) in Three European Countries

Abstract

A glutamine-for-arginine substitution at amino acid position 3500 of apolipoprotein B (apo B) causes synthesis of LDL with reduced binding affinity to the LDL receptor (LDLR). The associated clinical syndrome has been named familial defective apolipoprotein B- 100 (FDB). In 205 FDB patients from Germany (n = 73). The Netherlands (n = 87), and Denmark (n = 45), we tried to assess determinants of variation in lipid concentrations. Besides age, sex, and geographic origin, variation in the LDLR gene was the most powerful determinant of variation in total cholesterol and LDL cholesterol levels. Polymorphic variation in the LDLR gene (SfaNI, exon 2; Nco I, exon 18) was associated with total cholesterol (TC) and LDL cholesterol (LDL-C) variation in women (SfaNI: P = .04 and .03 for TC and LDL-C, respectively; Nco I; P = .003 and .006, respectively), whereas the Ava II (exon 13) and the Pvu II (intron 15) polymorphisms were not. Combined information from all three LDLR exon polymorphisms showed that subjects with at least one S + A + N + allele had 13% to 20% higher TC than non-S + A + N + subjects (P = .02 [TC, men]; P = .01 [LDL-C, men]; P = .005 [TC, women]; and P = .004 [LDL-C, women]) and, together with age and geographic origin, accounted for 20% (women) and 19% (men) of the variation in LDL-C. The expected association of the apo E genotypes (e3e2, e3e3, and e3e4) with cholesterol concentrations was seen in S + A + N + but not in non-S + A + N + subjects and in P-P- but not in P + P + or P + P- subjects. With regard to clinical expression, FDB patients had lower TC and LDL-C levels and a lower prevalence of cardiovascular disease than 101 Danish patients with familial hypercholesterolemia.

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

“…It has emerged that some people with familial liganddefective apoB100 due to R3500 and R3531 mutations have plasma cholesterol levels within the normal range (302)(303)(304)(305)(306), despite defective LDL binding and accumulation of the mutant allotype in blood. In one study, Pullinger et al ( 304 ) showed by using a monoclonal antibody and dynamic light scattering that the mass ratio of Gln3500 to Arg 3500 in the LDL of heterozygote apoB100 R3500Q patients was ‫ف‬ 73:27 and that in vitro the mutant LDL had <10% of the normal affi nity for the LDLR.…”

Genetic Localization to Chromosome 1p32 of the Third Locus for Familial Hypercholesterolemia in a Utah Kindred

“…2 There is some evidence that LDL cholesterol levels show some variation among affected persons in FH and FDB families. [3][4][5] However, one is usually not able to distinguish clinically between FH and FDB, 6 although there may be a trend toward lower LDL cholesterol levels in FDB patients. 4 There are Ͼ600 mutations described for the LDL receptor.…”

“…[3][4][5] However, one is usually not able to distinguish clinically between FH and FDB, 6 although there may be a trend toward lower LDL cholesterol levels in FDB patients. 4 There are Ͼ600 mutations described for the LDL receptor. 7 Despite this large number, mutations have not been identified in up to 30% of all persons with FH.…”

Clinical Criteria Versus DNA Diagnosis in Heterozygous Familial Hypercholesterolemia

“…In the apoB gene, the arginine 3500 to glutamine mutation is also common and affects about one in 600 people. 2 This mutation seems to be of central European origin and could not be identified in other Europeans, such as Finns and Russian.…”