Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020

Abstract

The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Original Article Aims: Familial hypercholesterolemia (FH) is currently a worldwide health issue. Understanding the characteristics of patients is important for proper diagnosis and treatment. This study aimed to analyze the phenotypic and genetic features, including threshold cholesterol levels, of Korean patients with FH. Methods: A total of 296 patients enrolled in the Korean FH registry were included, according to the following criteria: low-density lipoprotein-cholesterol (LDL-C) 190 mg/dL with tendon xanthoma or family history compatible with FH, or LDL-C 225 mg/dL. DNA sequences of three FH-associated genes were obtained using whole-exome or target exome sequencing. Threshold cholesterol levels for differentiating patients with FH/ pathogenic variant (PV) carriers and predictors of PVs were identified.Results: Of the 296 patients, 104 had PVs and showed more obvious clinical findings, including higher cholesterol levels. PV rates ranged from 30% to 64% when patients were categorized by possible or definite type according to the Simon Broome criteria. Frequent PV types included missense variants and copy number variations (CNVs), while the most frequent location of PVs was p.P685L in LDLR. The threshold LDL-C levels for patient differentiation and PV prediction were 177 and 225 mg/dL, respectively. Younger age, tendon xanthoma, and higher LDL-C levels were identified as independent predictors of PVs, while traditional cardiovascular risk factors were predictors of coronary artery disease.Conclusions: Korean patients with FH had variable PV rates depending on diagnostic criteria and distinctive PV locations. The reported threshold LDL-C levels pave the way for efficient patient care in this population.

2022 Consensus statement on the management of familial hypercholesterolemia in Korea

“…Due to gradual cost reduction, many institutes recently examine these three genes using next-generation sequencing and deletion/duplication analysis. Similar to data from other countries, copy number variations are found in approximately 10% of PV carriers, but this type of PV requires multiplex ligation-dependent probe amplification or the TaqMan method for validation [ 7 ]. When a PV is identified, it is critical to properly interpret whether it is a causative variant.…”

“…The Korean FH registry 2020 demonstrated that clinically diagnosed patients with FH had median total cholesterol and LDL-C levels of 306 and 221 mg/dL, respectively, and the prevalence of tendon xanthoma and CAD was 20% and 19%, respectively. Among registered patients, 60%, 36%, and 3% had a family history of severe hypercholesterolemia, premature CAD, and tendon xanthoma, respectively [ 7 ].…”

“…In Canada and Japan, they analyzed models including LDL-C levels, clinical findings, and family history, and determined criteria with optimal sensitivity and specificity [ 14 , 15 ]. The Korean FH registry 2020 revealed that the rates of PV carriers were 50% to 64% when the patients were classified as definite or probable types by the Dutch or Simon Broome criteria [ 7 ]. Not surprisingly, the sensitivity and specificity were inversely correlated according to the criteria used.…”

“…For PV carriers, the cut-off values of total cholesterol and LDL-C with optimal sensitivity and specificity were 325 and 225 mg/dL, respectively ( Fig. 3B ) [ 7 ]. Therefore, these values may be used when screening FH or cascade screening within a family in Korea.…”

“… (A) Frequency of pathogenic variant types in familial hypercholesterolemia-associated genes in Korean patients. (B) Location and characteristics of pathogenic variants presented on each gene [ 7 ]. CNV, copy number variation; EGF, epidermal growth factor.…”