2025/04/02 by Steve Eric Humphries, Steve E. Humphries, Marta Futema · 6 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Apolipoprotein B #Biology #Cancer, Lipids, and Metabolism #Cholesterol #Disease #Endocrinology #Familial hypercholesterolemia #Gene #Genetic architecture #Genetic factors in colorectal cancer #Genetics #Inheritance (genetic algorithm) #Internal medicine #LDL receptor #Lipoprotein #Lipoproteins and Cardiovascular Health #Medicine #PCSK9 #Phenotype
paper · doi:10.1111/ahg.12594
published in Annals of Human Genetics 89(5), 293-304 (Wiley)
openalex publication_date 2025/04/02 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/05
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.