Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia

Abstract

The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Original Article Aim: Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing into clinical practice. We aimed to report the spectrum of genetic mutations from patients with clinically diagnosed FH in Taiwan.Methods: Patients with LDL-C 190 mg/dL or those with probable or definite FH according to the Taiwan Lipid Guidelines underwent genetic testing. Samples from 750 index patients from the Taiwan FH registry were screened using custom-made mass spectrometry, followed by targeted next generation sequencing (NGS) and/or multiplex ligation-dependent probe amplification (MLPA) if found negative. Results: The mean age of the patients was 52.4 15.1 years and 40.9% were male. Mutations were detected in 445 patients (59.3%). The distribution of mutations was as follows: LDLR (n 395), APOB (n 58), PCSK9 (n 0), and ABCG5 (n 3). The most common mutations were APOB c.10579 C T (p.R3527W) (12.6%), LDLR c.986 G A (p.C329Y) (11.5%), and LDLR c.1747 C T (p.H583Y) (10.8%). LDLR c.1187-10 G A (IVS 8-10) and APOB c.10580 G A (p.R3527Q) were detected using targeted NGS in Taiwan for the first time. Four novel mutations were identified, including LDLR c.1060 2 T C (IVS 7 2), LDLR c.1139 A C (p.E380A), LDLR c.1322 T C (p.A431T) c.1867 A G (p.I623V), and ABCG5 c.1337 G A (p.R447Q). Conclusion:LDLR and APOB, but not PCSK9, mutations were the major genetic causes of FH. Four novel mutations in LDLR or ABCG5 were identified. This genetic screening method using mass spectrometry, targeted NGS, and MLPA analysis provided an efficient algorithm for genetic testing for clinically diagnosed FH in Taiwan.most commonly mutated is the gene coding for lowdensity lipoprotein receptor (LDLR), resulting in defective synthesis, assembly, transport, and recycling of the LDLR. Mutations in apolipoprotein B (APOB), encoding the ligand of the LDLR, cause a phenotypically identical condition 3) . Mutations in a third gene, Proprotein Convertase Subtilisin Kexin type 9 (PCSK9), which degrades the LDLR, haveCopyright©2021 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

Pleiotropic Effects of APOB Variants on Lipid Profiles, Metabolic Syndrome, and the Risk of Diabetes Mellitus

“…Table 1 lists the baseline characteristics, lipid profiles, metabolic syndrome, and DM of the participants selected from the TWB, including 115,088 participants with Axiom genome-wide CHB array data and 1478 participants with WGS data. Previous studies have revealed ethnic-specific APOB exonic mutations associated with LDL cholesterol levels, familial hypercholesterolemia, and HBLP [ 10 , 11 , 12 , 17 , 18 , 19 ]. We selected candidate APOB nonsynonymous mutations from our WGS data.…”

“…The APOB gene, located on chromosome 2p24.1, contains 29 exons and has a total length of 43 kb [ 9 ]. APOB variants have been extensively studied over the past three decades and more than 5000 polymorphic sites have been reported at the highly polymorphic APOB locus ( , accessed on 25 June 2022), which may be associated with familial hypercholesterolemia or hypobetalipoproteinemia (HBLP) [ 10 , 11 , 12 , 13 ]. However, the effects of APOB variants on lipid profiles, metabolic syndrome, and diabetes mellitus (DM) in Asian populations have not been fully elucidated.…”

Prevalence of genetically defined familial hypercholesterolemia and the impact on acute myocardial infarction in Taiwanese population: A hospital-based study

“…First, this study was a population-based investigation of the impact of different FH risk alleles on hyperlipidemia and cardiovascular diseases with a large sample size, which allowed enough power for analysis. In addition, we used the Axiom Genome-Wide TWB 2.0 Array Plate, which is a validated chip with tight quality control and it performed well in terms of the similarity of its results to those reported in another study in Taiwan using distinct methodology ( 27 ). The exploration of the effect of tailor-made hotspot genes was more feasible in clinical practice.…”

“…Despite the heterogeneous genetics of FH and the different detection rates of numerous genetic screening methods, our results are consistent with previously reported data. Huang CC and his colleagues determined the spectrum of FH genetic mutations in Taiwan in clinically diagnosed FH patients based on hyperlipidemia (LDL >190 mg/dL) and in those meeting the Taiwan FH diagnostic criteria ( 27 ). By using custom-made mass spectrometry, targeted next generation sequencing, or multiplex ligation-dependent probe amplification, the results revealed the distribution of FH variants in 445 patients in Taiwan was as follows: 86.6% LDLR mutations, 12.7% APOB mutations, and 0.7% ABCG5 mutations.…”

Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study

“…Both GOF and LOF mutations may occur as common or rare alternative allele frequencies, and through different mechanisms [ 23 , 24 , 27 ]. Research has also commonly observed differences in genetic variants in PCSK9 between Caucasian and East Asian populations, demonstrating the ethnic heterogeneity of such variants [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. In contrast, noncoding PCSK9 sequence variants are rarely reported [ 10 , 37 , 38 , 39 ].…”