Frequency of the R3500Q mutation of the apolipoprotein B-100 gene in a sample screened clinically for familial hypercholesterolemia in Hungary

doi:10.1016/S0021-9150(00)00648-1

Atherosclerosis

Volume 154, Issue 1, January 2001, Pages 247-251

https://doi.org/10.1016/S0021-9150(00)00648-1 Get rights and content

Abstract

Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) cause early onset of coronary heart diseases (CHD). According to the recommendations of the international MEDPED program, we tried to find FH cases. We analyzed 73 FH probands and their 304 first-degree relatives. A total of 39 probands were found from the 21 000 subjects screened (1:538) from family doctors’ registers recording all citizens, while the remaining 34 were derived from screened patients from lipid clinics. In our FH probands, four cases of FDB (R3500Q mutation) were diagnosed with allele-specific PCR, and the mutation was also detectable in five cases out of seven living family members. In the remaining 69 FH families, 156 people were diagnosed clinically with FH, and 31.8% of the males (against 13% of the not clinically diagnosed FH males, P<0.01), and 32.4% of the females (against 13.5% of the not clinically diagnosed FH females, P<0.01) suffered from early onset CHD. The plasma total cholesterol level of the FDB patients, especially in the younger patients, was very close to normal values. Therefore, the FDB patients seem to be under-represented in this type of survey. Because FDB is one of the independent causes of early onset CHD, the R3500Q mutation should be considered in families with a high frequency of cardiovascular diseases.

Introduction

Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are monogenic, autosomal, dominantly inherited diseases belonging to the type II/a primary hyperlipidemia group based on Fredrickson's classification [1]. Both can cause early onset of cardio- and cerebrovascular diseases and early death [2]. In the European populations the percentage of heterozygous FH patients is estimated at 0.2%, which means ∼20 000 FH patients in our country [3]. Similar values are known for the frequency of heterozygous FDB [4]. In both diseases, occurrence of homozygous cases is very rare (1:1 000 000).

FH, due to the defective function of receptors, is caused by over 400 mutations. In the case of FDB, the receptor binding domain of apolipoprotein B-100, the main apoprotein of the LDL-molecule, is damaged, which may have genetic causes. The decrease of binding to the LDL-receptor also leads to accumulation of LDL-cholesterol in the plasma. The plasma cholesterol level in the heterozygous form of FH patients is twice as high as normal, while in FDB patients a smaller degree of elevation can be detected [5], [6], [7].

The objective of our study was to define, by an internationally accepted clinical method, the occurrence of FH in the Hungarian population, and to investigate by a genetic method, the frequency of FDB diagnosed as clinically FH.

Section snippets

Methods

We have been involved in the international MEDPED program (Make Early Diagnoses-Prevent Early Deaths) to detect and treat FH families as coordinated by the center in Salt Lake City, USA [8]. The FH patients have been screened from the family doctors’ register of two districts in Budapest and our lipid clinics between 1996 and 1998. Every Hungarian citizen (both healthy and ill) has to be recorded in the family doctors’ registers.

We followed the recommendations of the MEDPED program (Table 1) as

Results

The data of the probands and their relatives clinically diagnosed as having FH are summarized in Table 2, Table 3. We found 39 FH cases in the family doctors’ registers (1:538) and 34 FH cases in the lipid clinics’ registers. The 377 (alive: 292, deceased: 85) members of the 73 FH families were analyzed. Of the 73 FH probands, four (5.5%) were diagnosed as having FDB by PCR examination. In the remaining 69 FH families, the number of the first degree relatives was 360 (alive: 281, deceased: 79).

Discussion

In 1986, Vega and Grundy [11] called attention to the fact that in five of their 15 FH cases the defect in the LDL-receptor was absent. The high plasma level of the LDL was explained by a binding deficiency arising from structural deformity of the LDL. Innerarity et al. [12] determined that this binding inability of the LDL can be based on a genetic defect of apoB-100, and they named this disease familial defective apolipoprotein B-100 (FDB). According to testing carried out by Soria et al. [13]

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Cited by (21)

Familial defective apolipoprotein B-100: A review
2016, Journal of Clinical Lipidology
Citation Excerpt :
This paradigm for the origin of the R3500Q variant was based in part on a higher estimated prevalence of R3500Q in Switzerland and the Rhein-Main area of Germany than in surrounding regions.46 The contribution that the R3500Q and R3500 W variants make to clinical FH in genotyped European cohorts has varied significantly; in general, R3500Q has been consistently reported in cohorts of subjects diagnosed with general hypercholesterolemia or FH in Central, Northern, and Eastern Europe, as well as countries containing populations of European background.44,47–55 The prevalence of R3500Q appears to be reduced in Southern Europe, but a small founder population for the variant has been reported in Spain.56–60
Familial defective apolipoprotein B-100 (FDB) is an autosomal dominant genetic disorder of lipid metabolism associated with hyperlipidemia and elevated risk for atherosclerosis. FDB is caused by mutations in APOB reducing the binding affinity between apolipoprotein B-100 and the low-density lipoprotein receptor. Population studies suggest that approximately 0.1% of Northern Europeans and US Caucasians carries the R3500Q variant in APOB most commonly associated with FDB; in addition, the APOB R3500 W variant is known to make a significant contribution to familial hypercholesterolemia (FH) among East Asians. However, the elevation of plasma low-density lipoprotein cholesterol observed in FDB is frequently milder than that of FH due to mutations in LDLR, and FDB is subsequently underdiagnosed according to standard FH diagnostic criteria.
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.
Familial hypercholesterolemia due to ligand-defective apolipoprotein B100. First case report in a Mexican family
2003, Archives of Medical Research
Familial defective apolipoprotein B100 (FDB) is one of the known causes of familial hypercholesterolemia (FH). Its frequency among subjects with FH varies among ethnic groups; information on FH is insufficient for populations from Latin America. We proposed to describe prevalence of FDB in a cohort of Mexican FH probands (n = 30).
We searched for the known FDB mutations using polymerase chain reaction assays. In this set of patients, mean lipid values were representative of FH (cholesterol 351 mg/dL, LDL cholesterol 274 mg/dL, HDL cholesterol 51 mg/dL, and triglycerides 132 mg/dL).
One subject with Arg3500Gln mutation was found: a 44-year-old male with a history of coronary heart disease (CHD) among paternal relatives. His lipid profile was cholesterol 370 mg/dL, LDL-cholesterol 300 mg/dL, HDL-cholesterol 32 mg/dL, and triglycerides 189 mg/dL. Tendinous xanthomata were detected. Three of four siblings, one of three sons, and one of nine nieces and nephews carried the mutation. The mutation was confirmed by automated sequencing. Tendinous xanthomata were absent in affected subjects younger than age 20 years; additionally, the subjects had borderline cholesterol levels.
Our data suggest that FDB explains the small number of FH cases in Mexico. Inclusion of molecular biology assays to the clinical laboratory makes it possible to diagnose affected individuals with borderline cholesterol levels or without tendinous xanthomata.
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.

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Frequency of the R3500Q mutation of the apolipoprotein B-100 gene in a sample screened clinically for familial hypercholesterolemia in Hungary

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Am. J. Cardiol.

Atherosclerosis

Atherosclerosis

Atherosclerosis

Lancet

Plasma lipoproteins: micellar models and mutants

Trans. Assoc. Am. Phys.

Handbook of hyperlipidemia

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

Am. J. Hum. Genet.

An arginine 3500 glutamine mutation in familial defective apoB-100 subjects with LDL defective in binding to the apoB,E (LDL) receptor

Circulation

Characteristics of 46 heterozygous carriers and 57 unaffected relatives in five Danish families with familial defective apolipoprotein B-100

Arterioscler. Thromb.

World Health Organization Human Genetics Programme Division of Noncommunicable Diseases: familial hypercholesterolaemia

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

Nucleic Acids Res.

Allele-specific and asymmetric polymerase chain reaction amplification in combination: a one step polymerase chain reaction protocol for rapid diagnosis of familial defective apolipoprotein B-100

Anal. Biochem.

In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia

J. Clin. Invest.