Platelet-Derived-Growth-Factor-Receptor-beta (PDGFB) and atherosclerotic cardiovascular disease presentation in genetically diagnosed familial hypercholesterolemia

Abstract Background Individuals with genetically defined familial hypercholesterolemia (FH) have significant premature atherosclerosis (ASCVD) with clinical event presentation than those with similar LDL-C levels but without FH, primarily due to a lifelong high LDL-C burden. However, ASCVD varies among patients with the same mutation. Identifying molecular factors beyond FH mutations in patients with ASCVD (FH-CVD) versus those without ASCVD(FH-nCVD) may help to develop personalised treatment strategies and improve risk assessment in FH patients. Purpose In FH genotyped patients, this study aimed to identify the differential transcriptomic profile of FH-CVD (myocardial infarction, angina) and FH-nCVD patients (who remained free of clinical disease presentation during an 8-year follow-up). Methods Patients with a genetic diagnosis of FH (N=92) from the SAFEHEART Cohort were included in the study. Blood cells transcriptomics were performed by NGS (N=12/group with and without CVD). Candidate transcripts were validated in independent FH patient groups using Real-Time qPCR (FH-nCVE: N=39; FH-CVE: N=29). Results NGS analysis identified 25 downregulated and 20 upregulated genes (2fold change) in FH-nCVE compared to FH-CVE patients. Additionally, 26 genes were uniquely expressed in FH-nCVE subjects. The 46 genes uniquely expressed or overrepresented in FH-nCVD patients were selected for further analysis, 35% of which were involved in the modulation of inflammation. Five genes (ADAM22, AIFM1, CD84, PDGFRB and SCRIB) were significantly different between FH-nCVE and FH-CVE when validated by Real time qPCR (p≤ 0.02), with all five genes being overexpressed in FH-nCVD patients. Receiver operating characteristic (ROC) analysis identified PDGFRB as the strongest discriminator of CVE in FH patients (AUC: 0.835; P 0.001). The combination of the 5 genes did not improved discrimination between FH-nCVE and FH-CVE groups. However, PDGFRB combined with the SAFEHEART risk score showed greater discrimination power (AUC: 0.912; P0.001) than the SAFEHEART-risk score alone (AUC: 0.785, p0.001). High PDGFRB levels were associated with 8-year ASCVD-free survival in FH patients (Kaplan–Meier HR=10.13; P0.001), with further improvement when combined with the SAFEHEART risk score (Kaplan–Meier HR: 14.17; P0.001). Conclusion High expression of PDGFRB is found in FH-nCVD patients. PDGFRB encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family and it is essential for normal development of the cardiovascular system aiding in rearrangement of the actin cytoskeleton. Including PDGFRB in the SAFEHEART risk score enhances its risk discrimination power.