A012 Clinical Applications of Polygenic Risk Scores in Coronary Artery Disease and Familial Hypercholesterolaemia

Abstract

Stratifying cardiovascular risk in patients with familial hypercholesterolaemia (FH) has value for targeting novel lipid lowering agents. We describe here the development of a 27 SNP polygenic risk score (PRS), used alongside a registry for FH in New Zealand. A 27 SNP panel was created on a MassArray platform with automated interpretive software which was then validated in two cohorts of mixed ethnicity (n=796), with and without acute coronary syndrome (ACS). 68 patients with suspected FH were sequenced for LDLR and ApoB mutations using high resolution melt curve (HRM) analysis multiplex probe ligation amplification (MLPA). 27PRS was clinically applied in 37 patients with and without gene positive FH. Mean GRS27 in those without a history of ACS was significantly lower than GRS27 in an ACS cohort, mean 1.33 vs 1.42, 95% CI 0.04 to 0.14, p = 0.0002. Inter-ethnic differences in SNP frequencies were identified e.g. (Figure 1), and population distributions and quintiles of risk mapped. 13 (20%) of suspected FH patients had a pathogenic variants, 10 LDLR, 3 ApoB and 1 LDLR variant of uncertain significance (VUS). 1 patient had both a pathogenic LDLR mutation and high PRS. From the registry 5 FH patients were recalled for a Phase I siRNA trial targeting ANGPTL3. A CAD 27PRS distinguishes risk in patients with and without ACS. Interethnic variances in PRS deserve further study before widespread adoption. PRS can be delivered clinically to stratify risk in FH and registries facilitate the trial of novel therapies.