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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Implementation of a biochemical, clinical, and genetic screening programme for familial hypercholesterolemia in 26
Teresa Arrobas Velilla1, Ángel Brea2, Pedro Valdivielso3
1Laboratorio de Nutrición y Riesgo Cardiovascular de Bioquímica Clínica, Unidad de Lípidos, Hospital Universitario Virgen de la Macarena, Sevilla, Spain.
Insights
A national screening program identified numerous individuals with familial hypercholesterolemia (FH) by linking clinical labs and lipid units. This collaboration enhances FH diagnosis and reduces vascular risk.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Clinical Diagnostics
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder characterized by high LDL cholesterol levels, leading to premature cardiovascular disease.
- FH remains significantly underdiagnosed and undertreated globally, necessitating improved screening strategies.
- Early identification and management of FH are crucial for mitigating long-term vascular complications.
Purpose of the Study:
- To evaluate the effectiveness of a joint national screening program involving clinical laboratories and lipid units for identifying FH patients.
- To assess the benefits of systematic collaboration in diagnosing and managing individuals with suspected familial hypercholesterolemia.
- To determine the yield of genetic testing in a large cohort identified through laboratory screening.
Main Methods:
- Retrospective analysis of clinical laboratory data from 2017-2018, identifying patients with LDL cholesterol >250 mg/dl.
- Exclusion of secondary causes of hypercholesterolemia, followed by referral to lipid units for Dutch Lipid Clinic Network scoring and genetic testing.
- Next Generation Sequencing of FH-associated genes (LDLR, APOB, PCSK9, APOE) and related genes (LDLRAP1, LIPA), alongside polygenic risk score calculation.
Main Results:
- Out of 3,827,513 analyzed patients, 6,765 had elevated LDL-C. After exclusions, 3,015 subjects were included in the study.
- Genetic testing was performed on 153 patients, revealing 67 pathogenic variants for FH (66 in LDLR, 1 in APOB).
- A higher polygenic risk score was observed in individuals without pathogenic variants compared to those with identified variants.
Conclusions:
- Systematic collaboration between clinical laboratories and lipid units is effective in identifying a substantial number of patients with phenotypic or genetic FH.
- This integrated approach facilitates FH diagnosis, enabling timely interventions to reduce patient vascular risk.
- The findings support the routine integration of such collaborative screening programs into clinical practice.
Abstract:
Background: Familial hypercholesterolemia (FH) is clearly underdiagnosed and undertreated. The aim of this present study is to assess the benefits of FH screening through a joint national program implemented between clinical laboratories and lipid units. Methods: All clinical laboratory tests from 1 January 2017 to 31 December 2018 were reviewed, and those with LDL cholesterol (LDL-C) levels >250 mg/dl were identified in subjects >18 years of age of both sexes. Once secondary causes had been ruled out, the treating physician was contacted and advised to refer the patient to an LU to perform the Dutch Lipid Clinic Network score and to request genetic testing if the score was ≥6 points. Next Generation Sequencing was used to analyse the promoter and coding DNA sequences of four genes associated with FH (LDLR, APOB, PCSK9, APOE) and two genes that have a clinical overlap with FH characteristics (LDLRAP1 and LIPA). A polygenic risk score based on 12 variants was also obtained. Results: Of the 3,827,513 patients analyzed in 26 centers, 6,765 had LDL-C levels >250 mg/dl. Having ruled out secondary causes and known cases of FH, 3,015 subjects were included, although only 1,205 treating physicians could be contacted. 635 patients were referred to an LU and genetic testing was requested for 153 of them. This resulted in a finding of sixty-seven pathogenic variants for FH, 66 in the LDLR gene and one in APOB. The polygenic risk score was found higher in those who had no pathogenic variant compared to those with a pathogenic variant. Conclusion: Despite its limitations, systematic collaboration between clinical laboratories and lipid units allows for the identification of large numbers of patients with a phenotypic or genetic diagnosis of FH, which will reduce their vascular risk. This activity should be part of the clinical routine.
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