The clinical applicability of polygenic risk scores for LDL-cholesterol: considerations, current evidence and future perspectives

Purpose of review The current review describes the development, clinical relevance and potential caveats of polygenic risk scores (PRS) for LDL cholesterol (LDL-C). Recent findings In recent years, a large number of common variants have been shown to have a small effect on LDL-C levels. The aggregate effect of all of these variants on LDL-C levels can be captured in a PRS and an elevated number of LDL-C increasing common variants is considered to be a cause of high LDL-C levels in patients with familial hypercholesterolemia (FH) without a large effect, rare mutation. PRS do not only serve as a tool in diagnostics, but are also helpful in cardiovascular disease (CVD) risk prediction. Moreover, PRS modulate CVD risk even in patients without a monogenic FH. However, future larger scale PRS directly aimed at CVD risk may serve as more sensitive tools to identify individuals with severely increased CVD risk. LDL-C PRS help explain part of hypercholesterolemia in a proportion of dyslipidemic patients that do not have monogenic FH. Nevertheless, the CVD risk conferred by current PRS does not appear to match that of monogenic FH. LDL-C PRS are currently not widely used in clinical care.

Automated summary

Polygenic risk scores (PRS) for LDL cholesterol (LDL-C) have potential clinical relevance and may serve as sensitive tools for identifying individuals with increased cardiovascular disease (CVD) risk. PRS can help explain part of hypercholesterolemia in patients without monogenic FH and modulate CVD risk even in individuals without monogenic FH. However, current LDL-C PRS do not match the cardiovascular risk conferred by monogenic FH, and they are not widely used in clinical care.