Written by Josh Forman, Head of Science, Education & Outreach
High cholesterol is one of the most common health conditions in the UK. For many people, it develops gradually as a result of diet, lifestyle, age and other health factors – the kind of things we all hear about and know as we get older. However, for around 1 in 250 people, high cholesterol has a very different cause. Rather than developing over time, it is inherited.
Whilst Jnetics is best known for recessive carrier screening, there are other genetic conditions impacting the Jewish community that we do not and cannot screen for. One such condition, with a Jewish founder mutation that is inherited via a Dominant inheritance patter is Familial Hypercholesterolaemia (FH).
FH is one of the most common inherited disorders worldwide. Left untreated, it substantially increases the lifetime risk of premature coronary heart disease. The encouraging news is that, once recognised, it is highly treatable.
Despite its name, FH is not really a disorder of cholesterol itself, but of how the body regulates it.
Cholesterol is transported around the bloodstream by High-Density Lipoprotein (HDL), often called “good cholesterol”, and Low-Density Lipoprotein (LDL), or “bad cholesterol”. Persistently raised LDL cholesterol significantly increases the risk of cardiovascular disease.
Under normal circumstances, liver cells regulate LDL cholesterol using specialised proteins called LDL receptors. These receptors act rather like recycling centres, capturing LDL cholesterol from the bloodstream and transporting it into the liver where it can be recycled or broken down. They then return to the cell surface, ready to repeat the process.
In people with FH, a pathogenic variant in the LDLR gene means there are fewer functioning LDL receptors available. With fewer of these recycling centres operating, LDL cholesterol gradually accumulates in the bloodstream, increasing the risk of atherosclerosis, heart attacks and stroke.
Although FH occurs across all populations, one particular LDLR variant became established within Ashkenazi Jewish communities through the founder effect. Known as the Lithuanian founder mutation, it is especially common amongst South African Ashkenazi Jews, whose ancestry largely traces back to Lithuania. Consequently, FH affects approximately 1 in 67 South African Ashkenazi Jews, compared with around 1 in 250 people in the general population.
In one Israeli study, around 35% of Ashkenazi Jewish families with FH carried this founder mutation, whereas it was not identified in any of the non-Ashkenazi families included in the study.
Unlike the recessive conditions included on the Jnetics carrier screening panel, FH is inherited in an autosomal dominant manner, similar to BRCA1 and BRCA2. Inheriting a single altered copy of the gene is enough to develop the condition, meaning individuals with FH are not generally described as “carriers”.
Most people carrying the Ashkenazi founder mutation still retain one healthy copy of the LDLR gene and therefore continue to produce functioning LDL receptors, albeit in reduced numbers. That detail has become particularly important as new treatments are being developed.
For many years, treatment has focused on lowering LDL cholesterol with statins and, more recently, drugs that target a protein called PCSK9. PCSK9 normally breaks down LDL receptors after they have completed their function. In someone with FH, who already has fewer functioning receptors, this is rather like closing down some of the remaining recycling centres, further reducing the liver’s ability to remove LDL cholesterol.
This prompted researchers to ask a fascinating question: rather than repairing the faulty LDLR gene, could they simply preserve the receptors that remain?
The answer came from studying people who naturally carry loss-of-function variants in the PCSK9 gene. These individuals produce less PCSK9, allowing LDL receptors to remain active for longer. The result is lifelong low LDL cholesterol and a substantially reduced risk of coronary heart disease.
Inspired by this natural protection, researchers developed VERVE-102, an investigational gene-editing therapy recently reported in The New England Journal of Medicine. Rather than correcting the faulty LDLR gene, VERVE-102 uses base editing to permanently reduce production of the PCSK9 protein. In effect, instead of building new recycling centres, it aims to keep the existing ones operating for longer, allowing more LDL cholesterol to be removed from the bloodstream.
This approach is particularly relevant to people carrying the Ashkenazi Jewish founder mutation, who generally retain enough functioning LDL receptors for PCSK9-targeted therapies to have a meaningful biological effect.
Early findings from the Heart-2 study demonstrated substantial and sustained reductions in both PCSK9 and LDL cholesterol following a single treatment. Whilst much larger clinical trials are still required, these results represent an important milestone in the development of in vivo gene-editing therapies.
For communities with recognised founder mutations, including the Jewish community, this research demonstrates how our growing understanding of genetics is moving beyond simply explaining inherited disease. Increasingly, it is providing the foundation for entirely new approaches to prevention and treatment. At Jnetics, we often talk about the power of understanding our genetics. Advances such as VERVE-102 show how that same knowledge is beginning to shape the next generation of precision medicine, offering an exciting glimpse of a future in which our genes may not only explain disease, but help us prevent it.
