Genetic polymorphism of the apolipoprotein B gene locus influences serum LDL cholesterol level in familial hypercholesterolemia

Abstract AIMS To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. METHODS AND RESULTS Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1–6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; −0.2 mmol/L (8 mg/dL) for total cholesterol; −0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; −0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/non-fasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, whereas fasting sampling may be considered when non-fasting triglycerides are >5 mmol/L (440 mg/dL). For non-fasting samples, laboratory reports should flag abnormal concentrations as triglycerides ≥2 mmol/L (175 mg/dL), total cholesterol ≥5 mmol/L (190 mg/dL), LDL cholesterol ≥3 mmol/L (115 mg/dL), calculated remnant cholesterol ≥0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol ≥3.9 mmol/L (150 mg/dL), HDL cholesterol ≤1 mmol/L (40 mg/dL), apolipoprotein A1 ≤1.25 g/L (125 mg/dL), apolipoprotein B ≥1.0 g/L (100 mg/dL), and lipoprotein(a) ≥50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides ≥1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral for the risk of pancreatitis when triglycerides are >10 mmol/L (880 mg/dL), for homozygous familial hypercholesterolemia when LDL cholesterol is >13 mmol/L (500 mg/dL), for heterozygous familial hypercholesterolemia when LDL cholesterol is >5 mmol/L (190 mg/dL), and for very high cardiovascular risk when lipoprotein(a) >150 mg/dL (99th percentile). CONCLUSIONS We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cutpoints. Non-fasting and fasting measurements should be complementary but not mutually exclusive.

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Compound Heterozygous Familial Hypercholesterolemia and Familial Defective Apolipoprotein B-100 Produce Exaggerated Hypercholesterolemia

Clinical Chemistry ◽

10.1093/clinchem/47.3.438 ◽

2001 ◽

Vol 47 (3) ◽

pp. 438-443 ◽

Cited By ~ 10

Author(s):

E Shyong Tai ◽

Evelyn S C Koay ◽

Edmund Chan ◽

Tzer Jing Seng ◽

Lih Ming Loh ◽

...

Keyword(s):

Cell Proliferation ◽

Genetic Analysis ◽

Familial Hypercholesterolemia ◽

Apolipoprotein B ◽

Ldl Cholesterol ◽

Index Case ◽

Ldl Receptor ◽

Cholesterol Concentration ◽

Apo B ◽

First Degree Relatives

Abstract Background: Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) represent ligand-receptor disorders that are complementary. Individuals with both FH and FDB are unusual. We report a family with both disorders and the impact of the mutations on the phenotypes of the family members. Methods: We used single strand conformation polymorphism (SSCP) and denaturing gradient gel electrophoresis (DGGE) for genetic analysis of all 18 exons and the promoter region of the LDL receptor and DGGE for genetic analysis of the apolipoprotein B-100 (apo B-100) gene. The functional significance of the apo B-100 mutation was studied using a U937 cell proliferation assay. Fasting serum lipid profiles were determined for the index case and seven first-degree relatives. Results: One of the patient’s sisters had a missense mutation (Asp407→Lys) in exon 9 of the LDL receptor and a serum LDL-cholesterol concentration of 4.07 mmol/L. Four other first-degree relatives had hyperlipidemia but no LDL-receptor mutation. However, these subjects had a mutation of the apo B-100 gene (Arg3500→Trp). The cell proliferation rate of U937 cells fed with LDL from other subjects with the same mutation was fourfold less than that of controls. The index case had both FH- and FDB-related mutations. Her serum LDL-cholesterol (9.47 mmol/L) was higher than all other relatives tested. Conclusions: Existence of both FH and FDB should be considered in families with LDL-receptor mutations in some but not all individuals with hypercholesterolemia or when some individuals in families with FH exhibit exaggerated hypercholesterolemia.

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Identification of familial hypercholesterolemia in acute coronary syndrome patients: are we missing the mark?

European Heart Journal Acute Cardiovascular Care ◽

10.1093/ehjacc/zuab020.072 ◽

2021 ◽

Vol 10 (Supplement_1) ◽

Author(s):

P Garcia Bras ◽

G Portugal ◽

A Castelo ◽

V Ferreira ◽

J Reis ◽

...

Keyword(s):

Family History ◽

Familial Hypercholesterolemia ◽

Cholesterol Level ◽

Ldl Cholesterol ◽

Density Lipoprotein ◽

St Segment Elevation ◽

St Segment ◽

All Cause Mortality ◽

The Mean

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Patients (P) with familial hypercholesterolemia (FH) have considerable elevation in levels of low-density lipoprotein (LDL) cholesterol and a higher risk of premature coronary artery disease (CAD) and acute coronary syndromes (ACS). However, even in a hospital setting with a high volume of ACS P, the diagnosis of FH frequently goes undetected. The aim of this study was to evaluate the application of the Dutch Lipid Clinic Network (DLCN) Criteria in P admitted for ACS and analyse ACS recurrence, hospitalization and mortality in a 30-day follow-up. Methods Retrospective evaluation of P with ACS admitted to a tertiary center from 2005 to 2019. Data from the digital files including family history and laboratory tests was analysed and P were followed up for 30 days for hospitalization, recurrent ACS, all cause mortality and cardiovascular (CV) death. Evaluation of tendinous xanthomata, arcus cornealis and genetic analysis was not undertaken. Results 3811 P were evaluated, mean age 63 ± 13 years, 28% female gender, 1497 P (39%) with active or previous smoking habits, 847 P (22%) with diabetes mellitus, 419 P (11%) with family history of coronary disease, 1340 P (35%) with premature CAD, 53 P (1.4%) with premature cerebral or peripheral vascular disease and 522 (14%) with previous ACS. The mean LDL cholesterol level was 125 ± 43 mg/dL, the mean high-density lipoprotein (HDL) cholesterol level was 40 ± 16 mg/dL and the mean triglyceride level was 132 ± 89 mg/dL. The diagnosis at hospital admission was unstable angina (UA) in 189 P (5%), non-ST-segment elevation myocardial infarction (NSTEMI) in 1024 P (27%) and ST-segment elevation MI (STEMI) in 2598 P (68%). The hospital mortality rate was 4.3% (163P). Applying the DLCN criteria, 3089 P (81%) had a score of <3 ("unlikely FH"), 675 P (17.7%) a score of 3 to 5 ("possible FH"), 41 P (1.1%) a score of 6 to 8 ("probable FH") and 1 P (0.03%) a score of >8 ("definite FH"). Stratifying according to ACS type: among UA, 31 P (16%) had "possible FH" and 4 P (2.1%) had "probable FH". Among NSTEMI, 145 P (14.2%) had "possible FH", 9 P (0.9%) "probable FH" and 1 P (0.03%) had "definite FH". Finally, among STEMI P, 497 P (19.1%) had "possible FH" and 28 P (1.1%) had "probable FH". In a 30-day follow-up, there was an all cause mortality of 2% (78 P) and a CV death of 1.3% (49P), while the all cause hospitalization rate was 3.5% (134P) and the admission rate for recurrent ACS was 1.7% (65P). The DLCN criteria score was significantly correlated with CV death (OR 1.25, CI 95% 1.04-1.50, p = 0.020) and admission for recurrent ACS (OR 1.19, CI 95% 1.04-1.36, p = 0.04). Conclusion Application of the DLCN criteria in P admitted for ACS revealed 675 P (17.7%) with "possible FH" and 41 P (1.1%) with "probable FH" as well as show significant correlation with CV death and recurrent ACS. Routine assessment of these criteria can be an accessible tool to stratify likelihood of FH and proceed accordingly to genetic testing.

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Cumulative LDL Cholesterol level and other risk factors influence on coronary heart disease in patients with familial hypercholesterolemia

Atherosclerosis ◽

10.1016/j.atherosclerosis.2021.06.540 ◽

2021 ◽

Vol 331 ◽

pp. e177

Author(s):

V. Korneva ◽

T. Kuznetsova

Keyword(s):

Risk Factors ◽

Coronary Heart Disease ◽

Heart Disease ◽

Familial Hypercholesterolemia ◽

Cholesterol Level ◽

Ldl Cholesterol

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Identification of a new mutation in the N-terminal region of the apolipoprotein B gene in familial hypercholesterolemia

Atherosclerosis ◽

10.1016/j.atherosclerosis.2016.07.344 ◽

2016 ◽

Vol 252 ◽

pp. e34

Author(s):

M. Abifadel ◽

S. Elbitar ◽

Y. Ghaleb ◽

G. Peloso ◽

N. Stitziel ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Apolipoprotein B ◽

Terminal Region ◽

New Mutation ◽

Apolipoprotein B Gene

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Dietary Fat Clearance in Normal Subjects Is Modulated by Genetic Variation at the Apolipoprotein B Gene Locus

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/01.atv.17.9.1765 ◽

1997 ◽

Vol 17 (9) ◽

pp. 1765-1773 ◽

Cited By ~ 46

Author(s):

J. Lopez-Miranda ◽

J.M. Ordovas ◽

M.A. Ostos ◽

C. Marin ◽

S. Jansen ◽

...

Keyword(s):

Genetic Variation ◽

Dietary Fat ◽

Apolipoprotein B ◽

Gene Locus ◽

Normal Subjects ◽

Apolipoprotein B Gene

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Characterization of Atherosclerosis Formation in a Murine Model of Type IIa Human Familial Hypercholesterolemia

BioMed Research International ◽

10.1155/2018/1878964 ◽

2018 ◽

Vol 2018 ◽

pp. 1-17 ◽

Cited By ~ 1

Author(s):

Chiharu Miyajima ◽

Takayuki Iwaki ◽

Kazuo Umemura ◽

Victoria A. Ploplis ◽

Francis J. Castellino

Keyword(s):

Familial Hypercholesterolemia ◽

Apolipoprotein B ◽

Ldl Cholesterol ◽

Genetic Model ◽

Ldl Receptor ◽

Normal Diet ◽

Atherosclerotic Plaques ◽

Key Features ◽

Very High

A murine genetic model of LDL-cholesterol- (LDL-C-) driven atherosclerosis, based on complete deficiencies of both the LDL-receptor (Ldlr-/-) and key catalytic component of an apolipoprotein B-edisome complex (Apobec1-/-), which converts apoB-100 to apoB-48, has been extensively characterized. These gene deficiencies allow high levels of apoB-100 to be present and inefficiently cleared, thus leading to very high levels of LDL-C in mice on a normal diet. Many key features of atherosclerotic plaques observed in human familial hypercholesterolemia are found in these mice as they are allowed to age through 72 weeks. The general characteristics include the presence of high levels of LDL-C in plasma and macrophage-related fatty streak formation in the aortic tree, which progressively worsens with age. More specifically, plaque found in the aortic sinuses contains a lipid core with relatively high numbers of macrophages and a smooth muscle cell α-actin- and collagen-containing cap, which thins with age. These critical features of plaque progression suggest that the Ldlr-/-/Apobec1-/- mouse line presents a superior model of LDL-C-driven atherosclerosis.

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