Phenotypic expression and frequency of familial defective apolipoprotein B-100 in Belgian hypercholesterolemics

doi:10.1016/0021-9150(94)90096-5

Atherosclerosis

Volume 111, Issue 2, December 1994, Pages 217-225

https://doi.org/10.1016/0021-9150(94)90096-5 Get rights and content

Abstract

DNA screening for apolipoprotein (apo) B mutations causing familial defective apolipoprotein B-100 (FDB) was performed in 87 hyperlipidemic Belgian individuals using heteroduplex analysis. Eighteen FDB heterozygotes from 5 unrelated families were identified. Three of the index cases reported an early family history of premature coronary heart disease (CHD). The frequency of the apo B₃₅₀₀ mutation was 8% in Belgians with type IIa hyperlipidemia, indicating that the prevalence of FDB may be as high as 1 in 250 in the general Belgian population. Plasma lipid levels of the patients identified in the present study are similar to those previously reported for FDB heterozygotes. We compared these data with results obtained in a genotype/phenotype correlation study of heterozygous familial hypercholesterolemia (FH) in the Afrikaner population of South Africa. Plasma cholesterol levels in FDB heterozygotes were similar to those reported for FH heterozygotes with defective receptors (Asp₂₀₆ → Glu, ≈20% normal receptor activity), but significantly lower than in FH heterozygotes with a mutant protein which virtually lacks receptor activity (Val₄₀₈ → Met, < 2% normal receptor activity). FDB appears to be a significant genetic cause of hypercholesterolemia in Belgium.

References (41)

H. Schuster et al.
Allele-specific and asymmetric PCR amplification in combination: A one step PCR protocol for rapid diagnosis of familial defective apolipoprotein B-100
Anal. Biochem.
(1992)
T.L. Innerarity et al.
Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia
J. Lipid Res.
(1990)
A. Tybjaerg-Hansen et al.
Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases
Atherosclerosis
(1990)
A. Tybjaerg-Hansen et al.
Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary heart disease
Atherosclerosis
(1992)
B. Lewis et al.
Frequency of risk factors for ischaemic heart disease in a healthy British population: with particular reference to serum lipoprotein levels
Lancet
(1974)
T. Hämäläinen et al.
Absence of familial defective apolipoprotein B-100 in Finnish patients with elevated serum cholesterol
Atherosclerosis
(1990)
T.L. Innerarity et al.
Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding
L.F. Soria et al.
Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100
T.L. Innerarity et al.
Demonstration that the Arg₂₅₀₀ — Gln mutation is the cause of familial defective apolipoprotein B 100, using a cell culture expression system for the synthesis of recombinant human LDL
Circulation
(1993)
C.R. Pullinger et al.
Familial ligand-defective apolipoprotein B: Identification of a new mutation that decreases LDL receptor binding affinity
Circulation
(1993)

H. Schuster et al.

Familial defective apolipoprotein B-100. Comparison with familial hypercholesterolemia in 18 cases detected in Munich

Arteriosclerosis

(1990)

J.L. Goldstein et al.

Familial hypercholesterolemia

E.H. Ludwig et al.

Haplotype analysis of the human apolipoprotein B mutation associated with familial defective apolipoprotein B-100

Am. J. Hum. Genet.

(1990)

G. Rauh et al.

Familial defective apolipoprotein B-100: a common cause of primary hypercholesterolemia

Clin. Invest.

(1992)

Kotze, M.J., Langenhoven, E., Peeters, A.V., Theart, L. and Oosthuizen, C.J.J., Detection of two point mutations...

J. Geisel et al.

Familial defective apolipoprotein B-100 in 12 subjects and their kindred

Eur. J. Clin. Chem. Clin. Biochem.

(1992)

A. Peeters et al.

Genetische aspecten van lipidenstoornissen. Het voorbeeld van familiale hypercholesterolemie en familiaal defectief apo B-100

Tijdschr. voor Geneeskunde

(1992)

S.A. Miller et al.

A simple salting out procedure for extracting DNA from human nucleated cells

Nucleic Acids Res.

(1988)

C. Cladaras et al.

The complete sequence and structural analysis of human apolipoprotein B-100: relationship between apo B-100 and apo B-48 forms

EMBO J.

(1986)

J. Keen et al.

Rapid detection of single base mismatches as heteroduplexes on Hydrolink gels

Trends Genet.

(1991)

Cited by (31)

Current familial hypercholesterolemia diagnostic criteria underdiagnose APOB mutations: Lessons from the Amish community
2016, Journal of Clinical Lipidology
Familial defective apolipoprotein B-100 in Slovakia. Are differences in prevalence of familial defective apolipoprotein B-100 explained by ethnicity?
2007, Atherosclerosis
The objective of this study was to examine frequency of familial defective apo-B-100 (FDB, R3500Q mutation) in probands with the phenotype of familial hypercholesterolemia (FH) and in the general population of 40-year-old subjects in Slovakia and to characterize their lipid and clinical criteria and to compare the frequency of FDB with other populations. We identified 35 patients with FDB among 362 probands with clinical diagnosis of FH and two cases of FDB in the 40-year-old cohort of 2323 subjects from general Slovak population. Probands with FDB differed from those with FH only in plasma triglyceride concentrations (1.84 ± 1.4 mmol/l versus 1.45 ± 0.98 mmol/l, respectively, p < 0.01). Evaluation of personal history of premature atherosclerosis did not show any differences (11.4% in FDB versus 20% in FH, p < 0.16). The FDB patients had similar manifestation of xanthomatosis as the FH patients (17.1% versus 8.25%, p < 0.25). The frequency of FDB of 9.7% found in the FH patients is among the highest of those reported to date. The frequency of R3500Q mutation of 0.09% found in Slovak 40-year-old subjects did not differ significantly from published population molecular data. Our comparison of estimated FDB frequencies with those which were found by DNA analysis demonstrated that estimated frequencies were not only wider in range, but also significantly higher than those which were assessed by the analysis.
The definitive answer to the prevalence of FDB and its biochemical and clinical characteristics requires screening of unbiased samples of the general population from different ethnic groups based on molecular genetic methods.
Differences in clinical presentation between subjects with a phenotype of familial hypercholesterolemia determined by defects in the LDL-receptor and defects in Apo B-100
2003, Revista Espanola de Cardiologia
La hipercolesterolemia familiar y la apo B-100 defectuosa familiar resultan fenotípicamente indistinguibles. Hoy día es posible diferenciarlas mediante la realización de un análisis genético.
Comparamos las características clínicas de 13 sujetos con apo B-100 defectuosa familiar y 39 sujetos con hipercolesterolemia familiar. Para comparar la morbimortalidad de ambos grupos utilizamos datos de sus familiares de primer grado.
Observamos diferencias significativas en los valores de colesterol total (CT) y colesterol unido a lipoproteínas de baja densidad (cLDL) de los sujetos afectados, que fueron menores en el grupo de apo B 100 defectuosa familiar (CT 357 ± 37,3 frente a 415 ± 79,7 mg/dl; y cLDL 270 ± 34,2 frente a 355 ± 72,4 mg/dl). No observamos diferencias en cuanto a la presencia de xantomas, arco corneal, hábito tabáquico, episodio vascular, presión arterial, índice de masa corporal (IMC) e índice cintura/cadera.
No hubo diferencias significativas en cuanto a las proporciones de fallecidos y afectados de enfermedad cardiovascular de uno y otro grupo.
La diferencia de medias de edad alcanzada sin enfermedad cardiovascular (45,3 ± 19,9 años en la hipercolesterolemia familiar y familiares, y 51,5 ± 20,8 años en la apo B100 defectuosa familiar y familiares) resultó significativa (p = 0,023).
La apo B-100 defectuosa familiar produce una hipercolesterolemia clínicamente más benigna que la hipercolesterolemia familiar, por lo que su diferenciación puede ayudar a estratificar el riesgo en los sujetos con estas hipercolesterolemias hereditarias.
Familial hypercholesterolemia and familial defective Apo B-100 are phenotypically indistinguishable. At present they can be distinguished by genetic analysis.
We compared the clinical features of 13 subjects with familial defective Apo B-100 and 39 subjects with familial hypercholesterolemia. We used data from first degree relatives to compare morbidity and mortality between the two groups.
We found statistically significant differences in total cholesterol and LDL cholesterol, which were lower in the familial defective Apo B-100 group (TC = 357 ± 37.3 mg/dl vs 415 ± 79.7 mg/dl and LDLc = 270 ± 34.2 mg/dl vs 355 ± 72.4 mg/dl). We found no differences in xanthomas, corneal arcus, smoking status, vascular events, blood pressure, BMI or waist/hip ratio. There were no differences between the two groups in the proportions of patients with cardiovascular disease or patients who died. We found statistically significant differences between the groups (p = 0.023) in the mean age at first vascular event (familial hypercholesterolemia and first degree relatives: 45.3 ± 19.9 years; familial defective Apo B-100 and first degree relatives: 51.5 ± 20.8 years)
We conclude that familial defective Apo B-100 results in clinically milder hypercholesterolemia than familial hypercholesterolemia, and that discerning between them could be helpful to stratify the risk in persons with hereditary hypercholesterolemia.
The apolipoprotein B R3500Q gene mutation in Spanish subjects with a clinical diagnosis of familial hypercholesterolemia
2002, Atherosclerosis
Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are autosomal codominant diseases characterized by elevated LDL cholesterol levels and premature coronary artery disease. Mutations of the LDL-receptor and apolipoprotein B genes, which affect the binding domains of their protein products, are the causal defects. Securing the diagnosis of these conditions by molecular assays is important because it mandates early intervention for coronary risk reduction. DNA screening for apolipoprotein B R3500Q gene mutation was performed in 913 unrelated Spanish individuals with a clinical diagnosis of FH using a modified polymerase chain reaction protocol and restriction enzyme genotyping. Thirteen FDB heterozygotes were identified (frequency of 1.4% in subjects with a clinical diagnosis of FH). The prevalence of hypercholesterolemic subjects with FDB in the general Spanish population was estimated to be as low as 2.8×10⁻⁵ (95% CI, −3.1×10⁻⁴ to 3.7×10⁻⁴). The ancestors of 11 out of 13 FDB carriers were from Galicia, a region of Celtic ancestry in Northwestern Spain. As the series included 100 unrelated subjects of Galician ancestry, FDB appears to be an important genetic cause of hypercholesterolemia in this region. All the R3500Q mutations were found on the same allele, assigned to haplotype XbaI−/MspI+/EcoRI−/3HVR48, suggesting that the mutant alleles are identical by descent in people from Spain, as observed in other Caucasian populations. In conclusion, the R3500Q mutation of the apolipoprotein B gene, a common cause of FH in central Europe, is infrequent in the general Spanish population, but it is common in Galicia.
Low-density lipoprotein receptor gene mutation analysis and clinical correlation in Belgian hypercholesterolaemics
2001, Molecular and Cellular Probes
It is generally believed that patients with familial hypercholesterolaemia (FH) have a higher cardiovascular risk than hypercholesterolaemics without a defect in the low-density lipoprotein receptor (LDLR) gene. However, no conclusive evidence to support this view has yet been presented. We investigated this aspect in Belgian hyperlipidaemics as part of a comprehensive effort to determine the impact of FH in this population. DNA samples of 98 unrelated Belgian patients with a family history of autosomal dominant hypercholesterolaemia were screened for mutations in the LDLR gene, after exclusion of known mutations causing familial defective apolipoprotein B-100 (FDB). Eight of the 22 distinct LDLR gene mutations identified in 27 subjects have not previously been described in other populations. As expected, the mutation-positive patients had a significantly worse lipid profile than the mutation-negative subjects (p<0·05), but this did not correlate with clinical cardiovascular status. In conclusion, the presence of a mutation in the LDLR gene was not a reliable predictor of cardiovascular risk in the hyperlipidaemic subjects included in this study. However, it is possible that prolonged exposure to the high levels of LDL cholesterol in genetically proven FH patients will in future cause a higher incidence of coronary heart disease. Our data may reflect the genetic heterogeneity of inherited hypercholesterolaemia, recently shown to be caused by several major genes.
Familial defective apolipoprotein B-100: A mutation emerged in the Mesolithic period [1]
2001, Atherosclerosis

View all citing articles on Scopus

View full text

Research paperPhenotypic expression and frequency of familial defective apolipoprotein B-100 in Belgian hypercholesterolemics

Abstract

Anal. Biochem.

J. Lipid Res.

Atherosclerosis

Atherosclerosis

Lancet

Atherosclerosis

Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100

Demonstration that the Arg2500 — Gln mutation is the cause of familial defective apolipoprotein B 100, using a cell culture expression system for the synthesis of recombinant human LDL

Circulation

Familial ligand-defective apolipoprotein B: Identification of a new mutation that decreases LDL receptor binding affinity

Circulation

Familial defective apolipoprotein B-100. Comparison with familial hypercholesterolemia in 18 cases detected in Munich

Arteriosclerosis

Familial hypercholesterolemia

Haplotype analysis of the human apolipoprotein B mutation associated with familial defective apolipoprotein B-100

Am. J. Hum. Genet.

Familial defective apolipoprotein B-100: a common cause of primary hypercholesterolemia

Clin. Invest.

Familial defective apolipoprotein B-100 in 12 subjects and their kindred

Eur. J. Clin. Chem. Clin. Biochem.

Genetische aspecten van lipidenstoornissen. Het voorbeeld van familiale hypercholesterolemie en familiaal defectief apo B-100

Tijdschr. voor Geneeskunde

A simple salting out procedure for extracting DNA from human nucleated cells

Nucleic Acids Res.

The complete sequence and structural analysis of human apolipoprotein B-100: relationship between apo B-100 and apo B-48 forms

EMBO J.

Rapid detection of single base mismatches as heteroduplexes on Hydrolink gels

Trends Genet.

Research paper
Phenotypic expression and frequency of familial defective apolipoprotein B-100 in Belgian hypercholesterolemics

Demonstration that the Arg₂₅₀₀ — Gln mutation is the cause of familial defective apolipoprotein B 100, using a cell culture expression system for the synthesis of recombinant human LDL