Severe polygenic hypercholesterolaemia
Polygenic hypercholesterolaemia describes the effect of small gene changes increasing our cholesterol levels and not just one single dominant gene as in a monogenic condition such as Familial Hypercholesterolaemia. Researchers have found 12 different small gene changes (SNPs) which they think are involved in polygenic hypercholesterolaemia in genetic testing laboratories. Each of these small gene changes can raise LDL cholesterol level a little (+10%) on its own, however if a person has inherited many of these, not just one or two, then altogether this can cause a severe increase in their LD cholesterol level in a cumulative manner.
Healthcare professionals who test people who they think have FH believe that this is the most frequent cause of high cholesterol in people where no dominant or monogenic FH causing gene is found in routine genetic tests.
Now lipid clinics can offer what is known as next generation sequencing (NGS) where they can look for the monogenic dominant FH causing genes well as these 12 different small gene changes (SNPs) at the same time, to see which is the cause for the high cholesterol. Although high cholesterol caused by this “polygenic” condition is not usually present from birth and may not be as “severe” as monogenic FH, people are still at risk of developing cardiovascular disease and should be offered cholesterol lowering medication to reduce their levels, and address any other risk factors they may have.
As all of the small gene changes (SNPs) in polygenic hypercholesterolaemia are not inherited together, cascade testing i.e. the genetic testing of other close family members is not recommended, as it is unlikely to be cost effective. Instead, relatives can be offered cholesterol testing and if they are found to have a raised cholesterol level then they should receive appropriate advice regarding cholesterol and other risk factors. This should include assessing their overall risk of cardiovascular disease using a risk assessment tool.
People who have had a single FH causing gene mutation identified (monogenic FH) can also have an additional background of “polygenic” small gene changes. For example, of two sisters who were tested for FH, the first sister had a total cholesterol level of 15 mmol/L and the second sister had a total cholesterol level of 8.5mmol/L. The first sister was found to have a known FH causing single gene plus a polygenic background, whereas the second sister did not have the genetic alteration but did show the polygenic background. Both sisters met the diagnostic criteria for FH, but only the first sister required further cascade testing of her family.
Further investigation
Specialists recognise there are at least 40% of those thought to have FH where a monogenic cause cannot be found, and around 80% of these probably have a polygenic reason.
For those who are found to have a low polygenic or SNP score, this may indicate the presence of an undiagnosed, single FH causing gene i.e. a gene exists but the technology has not yet been developed to identify it.
In the past these patients were recruited to the 100.000 Genome Project)
This page was updated on 11th September 2024