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Background: Familial hypercholesterolemia (FH) is a frequently underdiagnosed genetic disorder characterized by elevated low-density lipoprotein (LDL) levels. Genetic testing of LDLR, APOB, and PCSK9 genes can identify variants in up to 80% of clinically diagnosed patients. However, limitations in time, scalability, and cost have hindered effective next-generation sequencing of these genes. Additionally, pharmacogenomic variants are associated with statin-induced adverse effects in FH patients. To address these challenges, we developed a multiplex primer-based amplicon sequencing approach for FH genetic testing.
Methods: Multiplex primers were designed for the exons of the LDLR, APOB, and PCSK9 genes, as well as for pharmacogenomic variants rs4149056 (SLCO1B1:c.521T > A), rs2306283 (SLCO1B1:c.388A > G), and rs2231142 (ABCG2:c.421C > A). Analytical validation using samples with known pathogenic variants and clinical validation with 12 FH-suspected probands were conducted. Library preparation was based on a bead-based tagmentation method, and sequencing was conducted on the NovaSeq 6000 platform.
Results: Our approach ensured no amplicon dropouts, with over 100× coverage on each amplicon. Known variants in 2 samples were successfully detected. Further, we identified one heterozygous LDLR (p.Glu228Ter) variant and 2 homozygous cases of LDLR (p.Lys294Ter) and LDLR (p.Ser177Leu) variants in patients. Pharmacogenomic analysis revealed that overall 3 patients may require reduced statin doses. Our approach offered reduced library preparation time (approximately 3 h), greater scalability, and lower costs (under $50) for FH genetic testing.
Conclusions: Our method effectively sequences LDLR, APOB, and PCSK9 genes including pharmacogenomic variants that will guide appropriate screening and statin dosing, thus increasing both efficiency and affordability.
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http://dx.doi.org/10.1093/jalm/jfae089 | DOI Listing |
BMC Cardiovasc Disord
December 2024
Heart Center & Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China.
Background: Familial hypercholesterolemia (FH) is a genetically inherited disorder caused by monogenic mutations or polygenic deleterious variants. Patients with FH innate with significantly elevated risks for coronary heart disease (CHD). FH prevalence based on genetic testing in Chinese CHD patients is missing.
View Article and Find Full Text PDFMayo Clin Proc
November 2024
Center for Individualized Medicine, College of Medicine, Mayo Clinic, Rochester, MN, USA; Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN, USA. Electronic address:
Objective: To execute a large-scale, decentralized, clinical-grade whole exome sequencing study, coined Tapestry, for clinical practice, research discovery, and genomic education.
Patients And Methods: Between July 1, 2020, and May 31, 2024, we invited 1,287,608 adult Mayo Clinic patients to participate in Tapestry. Of those contacted, 114,673 patients were consented and 98,222 (65.
Bioinform Biol Insights
November 2024
Faculty of Medicine, Phenikaa University, Hanoi, Vietnam.
Atherosclerotic cardiovascular diseases (CVDs) are closely linked to factors such as familial hypercholesterolemia (FH), often caused by mutations in low-density lipoprotein receptor () and apolipoprotein B (). Through a comprehensive bioinformatic analysis, we identified novel and mutations and their cardiovascular disease (CVD) implications, focusing on unique variants in the Vietnamese population. We used homology modeling to predict protein structures; in addition, through protein-protein molecular docking, we assessed how these mutations affect binding affinities.
View Article and Find Full Text PDFImmunotargets Ther
November 2024
Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, People's Republic of China.
Background: Dyslipidemia has been implicated in the pathogenesis of several diseases, including thyroid dysfunction and immune disorders. However, whether circulating lipids and long-term use of lipid-lowering drugs influence the development of autoimmune thyroid disease (AITD) remains unclear. This study aims to evaluate the effects of lipid-lowering drugs on AITD and explore their potential mechanisms.
View Article and Find Full Text PDFFront Cardiovasc Med
November 2024
Preventive Treatment Center, The First Hospital of Hunan University of Chinese Medicine, Changsha, China.
Background: Previous studies have shown an association between lipid-lowering drugs, circulating inflammatory factors, and atrial fibrillation (AF), but the specific effects of lipid-lowering drugs on AF and whether they can be mediated by circulating inflammatory factors remain unclear.
Methods: We collected 10 genetic variants encoding lipid-lowering drug targets (LDLR, HMGCR, PCSK9, NPC1L1, APOB, APOB, ABCG5, ABCG8, LPL, APOC3, and PPARA) and AF based on genome-wide association study (GWAS) summary statistics. Drug target Mendelian randomization (MR) was used to explore the causal relationship between lipid-lowering drugs and AF.
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