Identification of clinical and genetic factors of familial hypercholesterolaemia among premature coronary artery disease patients / Sukma Azureen Nazli

Coronary artery disease (CAD) is the major cause of death worldwide and highly associated with familial hypercholesterolaemia. Familial hypercholesterolaemia (FH) is an autosomal dominant disorder of lipoprotein metabolism, resulting in an increase in LDL-c levels with subsequent increased risk of premature CAD (PCAD). The prevalence of PCAD and FH among angiogram-proven PCAD (AP-PCAD) patients among Malaysian population is currently under reported. Besides, the genotype of FH-causing gene variants among PCAD patients in Malaysia is not extensively studied yet. Hence, this study aimed to (1) investigate the prevalence of PCAD and their coronary risk factors according to different age cut-offs that define PCAD, (2) determine the prevalence of clinically diagnosed FH in PCAD patients and determine their risk factors and (3) to investigate the spectrum of FH-causing gene variants in clinically diagnosed FH patients among PCAD patients. There were two phases in this study. Phase I was a retrospective study of Malaysians who underwent percutaneous coronary intervention (PCI) from 2007 to 2018 in two Cardiology Specialist Centres. For PCAD prevalence, the patients were grouped into four age groups that commonly defines PCAD based on previous studies. Phase II was a cross-sectional study where AP-PCAD patients (age onset: males: <55 years; females: <60 years) were recruited from Cardiology and Specialist Lipid Clinics. Three-hundred-nineteen AP-PCAD patients were identified and were clinically diagnosed as FH using Dutch Lipid Clinic Network Criteria (DLCC). Targeted next-generation sequencing for identification of FH-candidate genes (FHCG) [LDLR, APOB, PCSK9 and LDLRAP1] and hypercholesterolaemia-associated gene (HCAG) [ABCG5, ABCG8 and APOE] was performed among 104 clinically diagnosed FH patients with PCAD who agreed to participate. The prevalence of PCAD was about 9-40%, depending on age cut-off groups. The top three coronary risk factors that mostly influenced PCAD were LDL-c level, TC level and hypertension. The prevalence of clinically diagnosed FH among AP-PCAD was 45.5%; with 16.0% Potential FH (Definite/Probable). Overall, 26.9% (28/104) patients have ≥1 pathogenic variant (PV) in any of the seven genes and 19.2% (20/104) have ≥1 PV in FHCG. Twenty seven percent of Potential FH patients and 17.8% Possible FH patients carry ≥1 PV. Out of 233 variants reported, 11.2% (26/233) were PVs. LDLR gene shows the most various types of PVs in this cohort, but APOB gene PVs was the most frequently to be reported in this cohort. In conclusion, the prevalence of PCAD was high and nearly half AP-PCAD patients were clinically diagnosed as FH. Almost 27% of the clinically diagnosed FH patients with PCAD were genetically confirmed FH.