Severe polygenic hypercholesterolaemia

Polygenic hypercholesterolaemia describes the small effect of many genes increasing our cholesterol levels and not just one single dominant gene as in a monogenic condition such as Familial Hypercholesterolaemia. Although at least 140 genes are known to have an effect on LDL-cholesterol levels, 12 common “LDL raising” gene variants (or SNPs) with the largest effects on LDL-cholesterol have been identified in genetic testing laboratories. Each of these common gene variants increases cholesterol level by only a small amount (less than 10%) on its own, however if a person has inherited several of these gene variants, not just one or two, then these can cause a severe increase in their cholesterol level in a cumulative manner.

Doctors who test people who they think have FH believe that this is the most frequent cause of high cholesterol in people where no dominant FH causing gene is found in routine genetic tests. Now lipid clinics can offer what is known as next generation sequencing where they can look for the major dominant gene causes as well as these 12 common LDL raising variants at the same time to see which is the cause for the high cholesterol. Although high cholesterol caused by this “polygenic” condition may not be present from birth and may not therefore be as “severe” as monogenic FH, people are still at risk of developing cardiovascular disease and should still be offered cholesterol lowering medication to reduce their levels and also address any other risk factors they may have. As all of the gene variants in polygenic hypercholesterolaemia are not inherited together, cascade testing i.e. the genetic testing of other family members of people, is not recommended as it is unlikely to be cost effective. Instead, relative can be offered cholesterol testing and if found to have a high cholesterol then they should receive appropriate advice regarding cholesterol and other risk factors.

People who have had a single FH causing gene mutation identified (monogenic FH) can also have an additional background of “polygenic” LDL-cholesterol raising variants. 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

For those who are found to have a low polygenic or “SNP score”, this can indicate the presence of an undiagnosed single FH causing gene. Specialists recognise there are at least 10% of those diagnosed clinically as definite FH (e.g. having tendon xanthoma) in which no monogenic mutation can be found and those with an additional low SNP score may eligible for the whole genome sequencing to find a novel cause (indeed some have been recruited for the 100.000 Genome Project)