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Familial Hypercholesterolaemia Polygenic Assessment


Number of variants called: 234

A proportion of all clinically diagnosed cases of Familial Hypercholesterolemia (FH) are now known to be polygenic (caused by several genes), due to the inheritance of a greater than average number of common Low Density Lipoprotein Cholesterol (LDL-C)-raising genetic variants (each causing a cumulative effect), leading to an increase in LDL-C.

The LDL-C PRS is included by reporting the decile in which the individual scores. Deciles have been calculated using over 400,000 healthy UK White Caucasians from the UK BioBank study (Futema et al 2018).

Although using smaller sample numbers, the data suggests that these decile cut-offs are also appropriate for individuals from the Indian Subcontinent, but not in those of Afro-Caribbean origin. (Trinder et al 2020).

In those where no monogenic cause for their FH phenotype has been identified, the report states that that there is a “high” likelihood of an individual in the 6th-10th decile of the PRS having a genetic cause for their hyperlipidaemia, those in the 4th-6th decile an “intermediate” and those in the 1st-3rd decile as having a “low” likelihood. (Futema et al 2016)

Patients who have a PRS greater than the 8th decile are at high risk of Cardiovascular Disease (CVD) because of their genetic burden and should be considered for more intensive lipid lowering therapy following local guidelines, or shared care agreements.

There is mounting evidence that individuals with clinical FH and both a monogenic cause and a high polygenic score have a higher CVD risk than those with monogenic FH and a low score. In a meta-analysis of over 1000 FH mutation positive individuals from three different cohorts (including UK BioBank), those with an LDL-SNP PRS above the 8th decile had a 48% higher HR for CVD. This risk was in part but not fully explained by their higher LDL-C. (Trinder et al 2020). Based on this data it is appropriate to consider using more intense lipid-lowering therapy and even lower LDL-C on treatment targets for those with a PRS greater than the 8th decile, for example using PCSK9i agents.

Patients with a monogenic cause for their FH.

– Individuals with clinical FH and with a monogenic cause for their FH should be managed using intensive LDL-C lowering under the care of a lipid specialist. The target is to lower LDL-C to 50% of the pre-treatment value using high-dose statins and combination therapy as appropriate.(eg Ezetimibe, PCSK9i).*
– Individuals with a monogenic cause for their FH and with PRS >8th decile should be considered for more intensive lipid lowering therapy to reduce their higher CVD risk.
– In those where a mutation can be found, systematic cascade testing (CT) using the family mutation for unambiguous identification of FH relatives should be carried out, with identified subjects treated with high intensity lipid lowering therapies to reduce their very considerable risk of early CHD.*