Identification of a novel LDLR p.Glu179Met variant in Thai families with familial hypercholesterolemia and response to treatment with PCSK9 inhibitor.

Familial hypercholesterolemia (FH) is a genetic disease characterized by elevated LDL-C levels. In this study, two FH probands and 9 family members from two families from northeastern Thailand were tested for LDLR, APOB, and PCSK9 variants by whole-exome sequencing, PCR-HRM, and Sanger sequencing. In silico analysis of LDLR was performed to analyse its structure‒function relationship. A novel variant of LDLR (c.535_536delinsAT, p.Glu179Met) was detected in proband 1 and proband 2 in homozygous and heterozygous forms, respectively. A total of 6 of 9 family members were heterozygous for LDLR p.Glu179Met variant. Compared with proband 2, proband 1 had higher baseline TC and LDL-C levels and a poorer response to lipid-lowering therapy combined with a PCSK9 inhibitor. Multiple sequence alignment showed that LDLR p.Glu179Met was located in a fully conserved region. Homology modelling demonstrated that LDLR p.Glu179Met variant lost one H-bond and a negative charge. In conclusion, a novel LDLR p.Glu179Met variant was identified for the first time in Thai FH patients. This was also the first report of homozygous FH patient in Thailand. Our findings may expand the knowledge of FH-causing variants in Thai population, which is beneficial for cascade screening, genetic counselling, and FH management to prevent coronary artery disease.

The prevalence and treatment patterns of familial hypercholesterolemia among Thai patients with premature coronary artery disease.

OBJECTIVES: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that is characterized by severe hypercholesterolemia. The prevalence of FH in Thailand has not been reported. Therefore, this study aimed to investigate the prevalence of FH and treatment patterns among Thai patients with premature coronary artery disease (pCAD). METHODS: A total of 1,180 pCAD patients at two heart centers from northeastern and southern Thailand between October 2018 and September 2020 were enrolled. FH was diagnosed using the Dutch Lipid Clinic Network (DLCN) criteria. pCAD was diagnosed in men aged < 55 years and women aged < 60 years. RESULTS: The prevalence of definite/probable FH, possible FH, and unlikely FH in pCAD patients was 1.36% (n = 16), 24.83% (n = 293), and 73.81% (n = 871), respectively. Definite/probable FH in pCAD patients had a significantly higher frequency of STEMI but a lower frequency of hypertension than those with unlikely FH. After discharge, most pCAD patients (95.51%) received statin therapy. Definite/probable FH patients had a higher frequency of high-intensity statin therapy than those with possible FH and unlikely FH. After follow-up for 3-6 months, approximately 54.72% of pCAD patients with DLCN scores ≥ 5 had a reduction in LDL-C > 50% from baseline. CONCLUSIONS: The prevalence of definite/probable FH, particularly possible FH, was high among pCAD patients in this study. The early diagnosis of FH among Thai pCAD patients should be performed for the early treatment and prevention of CAD.