£199.99 £139.99 for one year of Unlimited learning. Offer ends on 14 November 2022 at 23:59 (UTC). T&Cs apply

Find out more
Managing Hypercholesterolemia With Statins and the Role of Pharmacogenomics
Skip main navigation

Managing Hypercholesterolemia With Statins and the Role of Pharmacogenomics

Overview of pharmacological management of hypercholesterolaemia with statins, and the role of pharmacogenomics in predicting adverse effects.
© Wellcome Genome Campus Advanced Courses and Scientific Conferences

Familiar Hypercholesterolemia is associated with impaired Low-density lipoprotein cholesterol (LDL-C) clearance and increased ApolipoproteinB production in the liver and secretion into the circulation both leading to atherosclerosis.

Three main mutations account for 93% of UK FH patients:

The LDL receptor protein is encoded by the LDLR gene on chromosome 1. Normal functioning LDL is the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis using the LDL receptor. LDL receptor is involved in the regulation of cholesterol homeostasis by receptor-mediated endocytosis of lipoprotein particles and thus when abnormal leads to increased circulating LDL.

There are more than 1200 different LDLR gene mutations, accounting for the majority of FH presentations.

Apolipoprotein B (Apo B) is a major protein component of low-density lipoprotein (LDL) comprising >90% of the LDL proteins. Increased plasma concentration of Apo B-containing lipoproteins is associated with an increased risk of developing atherosclerotic disease. Apolipoprotein B is encoded by the APOB gene.

Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) functions by binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations.

APOB and PCSK9 gene mutations account for 5% and 1% of FH cases

Recently it has been reported that a single mutation in the APOE gene, the deletion of amino acid Leucine at position 167, designated p.(Leu167del), will also result in the FH phenotype. Preliminary data suggest this variant may explain around 2% of UK FH patients where a mutation can be found, so as common as the PCSK9 mutation. This research is reported in the article by Cenarro et al in the ‘See Also’ section.

Polygenic origins, i.e not due to single known genes, account for the majority of hypercholesterolaemia.

Ribbon diagram of the extracellular domain of the LDL-Receptor

Hepatic Synthesis of Cholesterol and Action of Statins and Atherosclerosis.

Statins inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) in hepatocytes. HMGCR is the rate-limiting enzyme of the hepatic cholesterol synthetic pathway and converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to melvalonic acid–-a precursor in the de novo cholesterol biosynthetic pathway. Statins through their reductive effect in the hepatic synthesis of cholesterol lower the risk of IHD.

The review by Wang et al in the ‘See also’ section gives more detail about the the underlying biology and pharmacology.

  • The pathological effect of FH is premature atherosclerotic cardiovascular disease
  • Statins through their reductive effect in the hepatic synthesis of cholesterol lower the risk of IHD (difference in survival rates with and without stain treatment).

Pharmacogenomics is the study of how a patient’s genome can influence how they respond to medications. Pharmacogenomic variants may affect the effectiveness of a prescribed medication, or the likelihood of a patient developing an adverse drug reaction (ADR). In the UK national working groups are working towards implementation of Pharmacogenomic testing through the Genomic Test Directory. Over time pharmacogenomics information will help predict for statin adverse effects.

The HEE Genomics Education Programme blog What is Pharmacogenomics? explains more.

Statin treatment may cause problems such as statin myopathy. For example a loss-of-function variant in the SLCO1B1 gene. The SLCO1B1 gene encodes for the hepatic statin transport enzyme and hence variations or polymorphisms in this gene can affect how statins are taken up in the liver to carry out their function which could result in a reduction of statins transported into hepatocytes.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) is an international consortium of volunteers facilitating use of pharmacogenetic tests for patient care. The CPIC guidelines for simvastatin highlight a single coding single-nucleotide polymorphism, rs4149056T>C, in SLCO1B1 which increases systemic exposure to simvastatin and the risk of muscle toxicity.

For more detail, see the Ramsey et al review linked in the ‘See also’ section.

© Wellcome Genome Campus Advanced Courses and Scientific Conferences
This article is from the free online

Genomic Scenarios in Primary Care

Created by
FutureLearn - Learning For Life

Our purpose is to transform access to education.

We offer a diverse selection of courses from leading universities and cultural institutions from around the world. These are delivered one step at a time, and are accessible on mobile, tablet and desktop, so you can fit learning around your life.

We believe learning should be an enjoyable, social experience, so our courses offer the opportunity to discuss what you’re learning with others as you go, helping you make fresh discoveries and form new ideas.
You can unlock new opportunities with unlimited access to hundreds of online short courses for a year by subscribing to our Unlimited package. Build your knowledge with top universities and organisations.

Learn more about how FutureLearn is transforming access to education