Related Experiment Video
Updated: May 16, 2025
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Genetic Determinants of the Familial Hypercholesterolaemia Phenotype
Steve Eric Humphries1, Marta Futema1,2
1Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK.
Insights
Familial hypercholesterolaemia (FH) is a common inherited disorder causing high LDL-C from birth, leading to early heart disease. Genetic factors, including single gene variants and polygenic influences, explain FH phenotypes.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Metabolic Disorders
Background:
- Familial hypercholesterolaemia (FH) is characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) from birth.
- This condition significantly increases morbidity and mortality due to premature coronary heart disease (CHD).
- FH is a common inherited disorder with a prevalence of approximately 1/280, impacting LDL-C clearance by the liver.
Purpose of the Study:
- To review research elucidating the genetic architecture of the FH phenotype.
- To discuss recent studies on genetic factors contributing to FH.
- To explore future prospects in identifying additional genes associated with FH.
Main Methods:
- Review of existing research on the genetic basis of FH.
- Analysis of studies identifying genetic variants (monogenic and polygenic) related to FH.
- Examination of the role of Lp(a) in non-monogenic FH cases.
Main Results:
- Monogenic FH is caused by variants in LDLR, APOB, PCSK9, or APOE genes.
- Only 20%-30% of clinically diagnosed FH subjects have identifiable single gene variants.
- Polygenic hypercholesterolaemia and Lp(a) overproduction explain FH in many 'no-variant' individuals.
Conclusions:
- The genetic basis of FH is complex, involving monogenic, polygenic, and Lp(a) related factors.
- Further research is needed to identify additional genes contributing to FH.
- Understanding the full genetic architecture is crucial for improved FH diagnosis and management.
Abstract:
Individuals with familial hypercholesterolaemia (FH) have severely elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) from birth and as a consequence have an elevated morbidity and mortality due to the development of coronary heart disease (CHD). Monogenic FH can be caused by carrying a single copy of a pathogenic variant in any of four genes (LDLR/APOB/PCSK9/APOE), which are all involved in the clearance of LDL-C from the blood by the liver. FH is one of the most common inherited disorders, with an estimated prevalence of carriers of around 1/280 individuals in most populations and ancestry groups. However, such variants can be found usually only in 20%-30% of clinically FH subjects, and in the majority of the no-variant individuals, the phenotype is most likely explained by the inheritance of a greater-than-average number of common variants of small effect, with such individuals better given the diagnosis of 'polygenic hypercholesterolaemia'. Also, in a proportion of no-variant subjects who meet the clinical criteria, the most likely explanation is due to overproduction of Lp(a) which is an LDL-C particle with a bound copy of the 'little-a' protein. Here, we review the research that has elucidated the genetic architecture of the FH phenotype and discuss recent studies and future prospects of finding additional genes where variants can cause FH.
Related Concept Videos
01:11Genetic Lingo
01:35Pedigree Analysis
02:27Background and Environment Affect Phenotype
An example of how genetic background affects phenotype can be seen in horses. The Extension gene in horses is responsible for their coat color. A wild-type gene (EE) produces black pigment in the coat, while a mutant gene (ee) produces red pigment. A...
01:28Human Genetics
The complex relationship between genetics and psychology is observable through common biological components such...
01:29Cholesterol: Significance and Regulation
Considering cholesterol and...
01:43Sex-linked Disorders