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Lyu X, Ren X, Zhang W, Zhu H, Wang Y, Qiu J, Wu F, Xu S, Jin Z, Yang M. Association between the weight-adjusted-waist index and Familial hypercholesterolemia: a cross-sectional study. BMC Cardiovasc Disord 2024; 24:632. [PMID: 39523324 PMCID: PMC11552114 DOI: 10.1186/s12872-024-04293-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
OBJECTIVE The weight-adjusted-waist index (WWI) is a novel obesity measurement indicator, and this study aims to determine the relationship between WWI and Familial hypercholesterolemia (FH). METHODS Using data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to March 2020, cross-sectional data from 3698 participants were analyzed. The study examined the correlation between WWI and FH using multivariate logistic regression and smooth curve fitting, and conducted subgroup analysis and interaction tests. RESULTS The study sample consisted of 3698 subjects for whom the overall probable prevalence of FH was 5.43% and increased with WWI tertile (quantile 1: 4.00%; quantile 2: 4.94%; quantile 3: 7.34%); individuals with the highest WWI tertile were significantly more likely to have FH than those with the lowest tertile (OR = 4.60,95% CI: 2.00-10.60). Subgroup analysis and interaction tests showed significant significance between WWI and personal history of early Atherosclerotic cardiovascular disease (ASCVD), family history of early ASCVD and probable prevalence of FH (p < 0.05). CONCLUSION This study demonstrates a nonlinear positive correlation between WWI and FH. This may provide new ideas for the prevention and treatment of FH in the future.
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Affiliation(s)
- Xuan Lyu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Xuanxuan Ren
- Zhejiang Hospital, Hangzhou, Zhejiang, 310013, China
| | - Weiqing Zhang
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Hanqin Zhu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Yu Wang
- Hangzhou City University, Hangzhou, Zhejiang, 310015, China
| | - Jiarou Qiu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Fangying Wu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Sisi Xu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Zhaokai Jin
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Minchun Yang
- Zhejiang Hospital, Hangzhou, Zhejiang, 310013, China.
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Constantin AT, Delia C, Roșu LM, Roșca I, Streață I, Riza AL, Gherghina I. The Importance of Genetic Testing for Familial Hypercholesterolemia: A Pediatric Pilot Study. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1602. [PMID: 39459389 PMCID: PMC11509574 DOI: 10.3390/medicina60101602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/25/2024] [Accepted: 09/28/2024] [Indexed: 10/28/2024]
Abstract
Background and Objectives: Familial hypercholesterolemia (FH) is a genetic disease that is massively underdiagnosed worldwide. Affected patients are at high risk of cardiovascular events at young ages. Early intervention in childhood could help prevent heart attacks and cerebral strokes in these patients. Materials and Methods: We conducted an interventional study including 10 patients that previously underwent genetic testing for familial hypercholesterolemia. These patients received lifestyle and diet recommendations that they followed for a year before being reevaluated. Results: Patients with negative genetic testing were able to achieve lower levels in their lipid panel values compared to the patients with positive genetic testing, with lifestyle changes alone. LDL-cholesterol levels decreased by 18.5% in patients without FH while patients genetically confirmed with FH failed to achieve lower LDL-cholesterol levels without medication. Conclusions: Genetic testing for FH is not always part of screening algorithms for FH. Some studies even advise against it. Our study proved the importance of genetic testing for FH when suspecting this disorder and choosing the treatment course for patients.
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Affiliation(s)
- Andreea Teodora Constantin
- Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania; (A.T.C.)
- Pediatrics Department, National Institute for Mother and Child Health “Alessandrescu-Rusescu”, 020395 Bucharest, Romania
| | - Corina Delia
- Pediatrics Department, National Institute for Mother and Child Health “Alessandrescu-Rusescu”, 020395 Bucharest, Romania
- Faculty of Biology, University of Bucharest, 030018 Bucharest, Romania
| | - Lucia Maria Roșu
- Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania; (A.T.C.)
- Pediatrics Department, National Institute for Mother and Child Health “Alessandrescu-Rusescu”, 020395 Bucharest, Romania
| | - Ioana Roșca
- Faculty of Midwifery and Nursery, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania
- Neonatology Department, Clinical Hospital of Obstetrics and Gynecology ”Prof. Dr. P. Sârbu”, 060251 Bucharest, Romania
| | - Ioana Streață
- Genetics Department, University of Medicine and Pharmacy, 200349 Craiova, Romania
- Regional Center for Medical Genetics Dolj, 200642 Craiova, Romania
| | - Anca-Lelia Riza
- Genetics Department, University of Medicine and Pharmacy, 200349 Craiova, Romania
- Regional Center for Medical Genetics Dolj, 200642 Craiova, Romania
| | - Ioan Gherghina
- Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 020021 Bucharest, Romania; (A.T.C.)
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Raslova K, Donicova V, Gonova K, Klabnik A, Tichy L, Bridges I, Buckova D, Zachlederova M, Freiberger T, Vohnout B. Detecting familial hypercholesterolemia: An observational study leveraging mandatory universal pediatric total cholesterol screening in Slovakia. J Clin Lipidol 2024; 18:e537-e547. [PMID: 38955586 DOI: 10.1016/j.jacl.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 03/11/2024] [Accepted: 03/26/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND In Slovakia, a mandatory national universal pediatric total cholesterol (TC) screening program is in place to identify cases of familial hypercholesterolemia (FH). However, the program's effectiveness has not been systematically assessed. OBJECTIVE This study aimed to estimate the prevalence of FH among parents of children that had elevated TC levels identified during screening. METHODS This prospective, non-interventional, observational study enrolled parents of 11-year-old children who underwent TC screening in 23 selected pediatric outpatient clinics between 2017 and 2018. FH was diagnosed using the Dutch Lipid Clinic Network (DLCN) criteria and targeted next-generation sequencing. The primary objective was to estimate the proportion of children with a TC level of >188 mg/dL (>4.85 mmol/L) who had a parent with a confirmed diagnosis of FH. RESULTS A total of 112 parents of 56 children with an elevated TC level were enrolled. Five children (8.9%) had a parent in whom FH was genetically confirmed. Without genetic analysis, all five parents would only be diagnosed with "possible FH" by DLCN criteria. Of parents, 83.9% (n = 94/112) had an low-density lipoprotein cholesterol (LDL-C) level of >116 mg/dL (>3 mmol/L), but only 5.3% (n = 5/94) received lipid-lowering therapy. Among the five parents with genetically confirmed FH, all had an LDL-C level >116 mg/dL (>3 mmol/L), with a mean (±SD) of 191 (±24) mg/dL (4.94 [±0.61] mmol/L). Only two of these parents received lipid-lowering therapy. CONCLUSIONS The present study demonstrates the significance of mandatory universal pediatric TC screening in identifying families with FH and other at-risk families in need of lipid-lowering therapy.
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Affiliation(s)
- Katarina Raslova
- Metabolic Center, Ltd, Coordination for Familial Hyperlipidemias, Slovak Medical University, Bratislava, Slovakia (Dr Raslova).
| | - Viera Donicova
- Outpatient Department of Internal Medicine and Diabetology, Košice, Slovakia (Dr Donicova)
| | - Katarina Gonova
- Internal Outpatient Clinic, MedPed Lipid Clinic, Piestany, Slovakia (Dr Gonova); Faculty of Public Health, Slovak Medical University, Bratislava, Slovakia (Dr Gonova)
| | - Alexander Klabnik
- Cardiology Outpatient Clinic, MedPed Lipid Clinic, Namestovo, Slovakia (Dr Klabnik)
| | - Lukas Tichy
- Centre of Molecular Biology and Genetics, Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic (Dr Tichy); Medical Faculty, Masaryk University, Brno, Czech Republic (Drs Tichy and Freiberger)
| | - Ian Bridges
- Amgen UK Ltd, Uxbridge, United Kingdom (Dr Bridges)
| | - Dagmar Buckova
- Amgen Slovakia s.r.o., Bratislava, Slovakia (Dr Buckova)
| | | | - Tomas Freiberger
- Medical Faculty, Masaryk University, Brno, Czech Republic (Drs Tichy and Freiberger); Centre of Cardiovascular Surgery and Transplantation, Brno, Czech Republic (Dr Freiberger).
| | - Branislav Vohnout
- Diabetes and Lipid Outpatient Clinic, Diabeda s.r.o., Bratislava, Slovakia (Dr Vohnout); Coordination Center for Familial Hyperlipidemias, Institute of Nutrition, Department of Diabetes, Slovak Medical University, Bratislava, Slovakia (Dr Vohnout); Department of Epidemiology, School of Medicine, Comenius University, Bratislava, Slovakia (Dr Vohnout).
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Albuquerque J, Medeiros AM, Alves AC, Jannes CE, Mancina RM, Pavanello C, Chora JR, Mombelli G, Calabresi L, Pereira ADC, Krieger JE, Romeo S, Bourbon M, Antunes M. Generation and validation of a classification model to diagnose familial hypercholesterolaemia in adults. Atherosclerosis 2023; 383:117314. [PMID: 37813054 DOI: 10.1016/j.atherosclerosis.2023.117314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND AND AIMS The early diagnosis of familial hypercholesterolaemia is associated with a significant reduction in cardiovascular disease (CVD) risk. While the recent use of statistical and machine learning algorithms has shown promising results in comparison with traditional clinical criteria, when applied to screening of potential FH cases in large cohorts, most studies in this field are developed using a single cohort of patients, which may hamper the application of such algorithms to other populations. In the current study, a logistic regression (LR) based algorithm was developed combining observations from three different national FH cohorts, from Portugal, Brazil and Sweden. Independent samples from these cohorts were then used to test the model, as well as an external dataset from Italy. METHODS The area under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves was used to assess the discriminatory ability among the different samples. Comparisons between the LR model and Dutch Lipid Clinic Network (DLCN) clinical criteria were performed by means of McNemar tests, and by the calculation of several operating characteristics. RESULTS AUROC and AUPRC values were generally higher for all testing sets when compared to the training set. Compared with DLCN criteria, a significantly higher number of correctly classified observations were identified for the Brazilian (p < 0.01), Swedish (p < 0.01), and Italian testing sets (p < 0.01). Higher accuracy (Acc), G mean and F1 score values were also observed for all testing sets. CONCLUSIONS Compared to DLCN criteria, the LR model revealed improved ability to correctly classify observations, and was able to retain a similar number of FH cases, with less false positive retention. Generalization of the LR model was very good across all testing samples, suggesting it can be an effective screening tool if applied to different populations.
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Affiliation(s)
- João Albuquerque
- Departamento de Biomedicina, Unidade de Bioquímica, Faculdade de Medicina, Universidade do Porto, 4200-319, Porto, Portugal; Centro de Estatística e Aplicações, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal; Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisboa, Portugal.
| | - Ana Margarida Medeiros
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisboa, Portugal; Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
| | - Ana Catarina Alves
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisboa, Portugal; Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
| | - Cinthia Elim Jannes
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração, São Paulo, Brazil
| | - Rosellina M Mancina
- Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Sweden
| | - Chiara Pavanello
- Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, Italy
| | - Joana Rita Chora
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisboa, Portugal; Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
| | - Giuliana Mombelli
- Centro Dislipidemie, ASST Grande Ospedale Metropolitano Niguarda, 20162, Milano, Italy
| | - Laura Calabresi
- Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133, Milano, Italy
| | | | - José Eduardo Krieger
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração, São Paulo, Brazil
| | - Stefano Romeo
- Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Sweden; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Clinical and Surgical Sciences, Nutrition Unit, University Magna Graecia, Catanzaro, Italy
| | - Mafalda Bourbon
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisboa, Portugal; Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
| | - Marília Antunes
- Centro de Estatística e Aplicações, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal; Departamento de Estatística e Investigação Operacional, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
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5
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Ramli AS, Qureshi N, Abdul-Hamid H, Kamal A, Kanchau JD, Shahuri NS, Akyea RK, Silva L, Condon L, Abdul-Razak S, Al-Khateeb A, Chua YA, Mohamed-Yassin MS, Baharudin N, Badlishah-Sham SF, Abdul Aziz AF, Mohd Kasim NA, Sheikh Abdul Kadir SH, Kai J, Leonardi-Bee J, Nawawi H. Reducing Premature Coronary Artery Disease in Malaysia by Early Identification of Familial Hypercholesterolemia Using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT): Protocol for a Mixed Methods Evaluation Study. JMIR Res Protoc 2023; 12:e47911. [PMID: 37137823 PMCID: PMC10276320 DOI: 10.2196/47911] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 04/30/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND Familial hypercholesterolemia (FH) is predominantly caused by mutations in the 4 FH candidate genes (FHCGs), namely, low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB-100), proprotein convertase subtilisin/kexin type 9 (PCSK9), and the LDL receptor adaptor protein 1 (LDLRAP1). It is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels leading to premature coronary artery disease. FH can be clinically diagnosed using established clinical criteria, namely, Simon Broome (SB) and Dutch Lipid Clinic Criteria (DLCC), and can be identified using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT), a primary care screening tool. OBJECTIVE This study aims to (1) compare the detection rate of genetically confirmed FH and diagnostic accuracy between the FAMCAT, SB, and DLCC in the Malaysian primary care setting; (2) identify the genetic mutation profiles, including novel variants, in individuals with suspected FH in primary care; (3) explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing in primary care; and (4) evaluate the clinical utility of a web-based FH Identification Tool that includes the FAMCAT, SB, and DLCC in the Malaysian primary care setting. METHODS This is a mixed methods evaluation study conducted in 11 Ministry of Health primary care clinics located at the central administrative region of Malaysia. In Work stream 1, the diagnostic accuracy study design is used to compare the detection rate and diagnostic accuracy of the FAMCAT, SB, and DLCC against molecular diagnosis as the gold standard. In Work stream 2, the targeted next-generation sequencing of the 4 FHCGs is used to identify the genetic mutation profiles among individuals with suspected FH. In Work stream 3a, a qualitative semistructured interview methodology is used to explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing. Lastly, in Work stream 3b, a qualitative real-time observation of primary care physicians using the "think-aloud" methodology is applied to evaluate the clinical utility of a web-based FH Identification Tool. RESULTS The recruitment for Work stream 1, and blood sampling and genetic analysis for Work stream 2 were completed in February 2023. Data collection for Work stream 3 was completed in March 2023. Data analysis for Work streams 1, 2, 3a, and 3b is projected to be completed by June 2023, with the results of this study anticipated to be published by December 2023. CONCLUSIONS This study will provide evidence on which clinical diagnostic criterion is the best to detect FH in the Malaysian primary care setting. The full spectrum of genetic mutations in the FHCGs including novel pathogenic variants will be identified. Patients' perspectives while undergoing genetic testing and the primary care physicians experience in utilizing the web-based tool will be established. These findings will have tremendous impact on the management of patients with FH in primary care and subsequently reduce their risk of premature coronary artery disease. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/47911.
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Affiliation(s)
- Anis Safura Ramli
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Nadeem Qureshi
- Centre of Academic Primary Care, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Hasidah Abdul-Hamid
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
- Centre of Academic Primary Care, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Aisyah Kamal
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Johanes Dedi Kanchau
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Nur Syahirah Shahuri
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Ralph Kwame Akyea
- Centre of Academic Primary Care, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Luisa Silva
- Centre of Academic Primary Care, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Laura Condon
- Centre of Academic Primary Care, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Suraya Abdul-Razak
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
- Cardio Vascular and Lungs Research Institute (CaVaLRI), Hospital Al-Sultan Abdullah, Universiti Teknologi MARA, Bandar Puncak Alam, Selangor, Malaysia
| | - Alyaa Al-Khateeb
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Yung-An Chua
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Mohamed-Syarif Mohamed-Yassin
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Noorhida Baharudin
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Siti Fatimah Badlishah-Sham
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | | | - Noor Alicezah Mohd Kasim
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Siti Hamimah Sheikh Abdul Kadir
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
| | - Joe Kai
- Centre of Academic Primary Care, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Jo Leonardi-Bee
- Centre of Academic Primary Care, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Hapizah Nawawi
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, Malaysia
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6
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Bassani Borges J, Fernandes Oliveira V, Dagli-Hernandez C, Monteiro Ferreira G, Kristini Almendros Afonso Barbosa T, da Silva Rodrigues Marçal E, Los B, Barbosa Malaquias V, Hernandes Bortolin R, Caroline Costa Freitas R, Akira Mori A, Medeiros Bastos G, Marques Gonçalves R, Branco Araújo D, Zatz H, Bertolami A, Arpad Faludi A, Chiara Bertolami M, Guerra de Moraes Rego Souza A, Ítalo Dias França J, Strelow Thurow H, Dominguez Crespo Hirata T, Takashi Imoto Nakaya H, Elim Jannes C, da Costa Pereira A, Nogueira Silbiger V, Ducati Luchessi A, Nayara Góes Araújo J, Arruda Nakazone M, Silva Carmo T, Rossi Silva Souza D, Moriel P, Yu Ting Wang J, Satya Naslavsky M, Gorjão R, Cristina Pithon-Curi T, Curi R, Moreno Fajardo C, Lin Wang HT, Regina Garófalo A, Cerda A, Ferraz Sampaio M, Dominguez Crespo Hirata R, Hiroyuki Hirata M. Identification of pathogenic variants in the Brazilian cohort with Familial Hypercholesterolemia using exon-targeted gene sequencing. Gene 2023; 875:147501. [PMID: 37217153 DOI: 10.1016/j.gene.2023.147501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 05/16/2023] [Accepted: 05/18/2023] [Indexed: 05/24/2023]
Abstract
Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n=210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows-Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Toolkit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regulatory regions (3'UTR and 5'UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown uncertain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort.
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Affiliation(s)
- Jéssica Bassani Borges
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil; Laboratory of Molecular Research in Cardiology, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil; Department of Teaching and Research, Real and Benemerita Associação Portuguesa de Beneficiencia, Sao Paulo 01323-001, Brazil
| | - Victor Fernandes Oliveira
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil
| | - Carolina Dagli-Hernandez
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil
| | - Glaucio Monteiro Ferreira
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil; Laboratory of Molecular Research in Cardiology, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil
| | | | - Elisangela da Silva Rodrigues Marçal
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil; Laboratory of Molecular Research in Cardiology, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil
| | - Bruna Los
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil
| | - Vanessa Barbosa Malaquias
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil
| | - Raul Hernandes Bortolin
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil; Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, United States
| | - Renata Caroline Costa Freitas
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil; Department of Cardiac Surgery, Boston Children's Hospital, Boston, MA 02115, United States
| | - Augusto Akira Mori
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil
| | - Gisele Medeiros Bastos
- Laboratory of Molecular Research in Cardiology, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil; Department of Teaching and Research, Real and Benemerita Associação Portuguesa de Beneficiencia, Sao Paulo 01323-001, Brazil
| | | | - Daniel Branco Araújo
- Medical Clinic Division, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil
| | - Henry Zatz
- Medical Clinic Division, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil
| | - Adriana Bertolami
- Medical Clinic Division, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil
| | - André Arpad Faludi
- Medical Clinic Division, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil
| | | | | | - João Ítalo Dias França
- Laboratory of Epidemiology and Statistics, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil
| | - Helena Strelow Thurow
- Department of Teaching and Research, Real and Benemerita Associação Portuguesa de Beneficiencia, Sao Paulo 01323-001, Brazil
| | - Thiago Dominguez Crespo Hirata
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil
| | - Helder Takashi Imoto Nakaya
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil
| | - Cinthia Elim Jannes
- Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo 05403-900, Brazil
| | - Alexandre da Costa Pereira
- Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo 05403-900, Brazil
| | - Vivian Nogueira Silbiger
- Department of Clinical and Toxicological Analysis, Federal University of Rio Grande do Norte, Natal 59078-900 Brazil; Northeast Biotechnology Network (RENORBIO), Graduate Program in Biotechnology, Federal University of Rio Grande do Norte, Natal 59078-900, Brazil
| | - André Ducati Luchessi
- Department of Clinical and Toxicological Analysis, Federal University of Rio Grande do Norte, Natal 59078-900 Brazil; Northeast Biotechnology Network (RENORBIO), Graduate Program in Biotechnology, Federal University of Rio Grande do Norte, Natal 59078-900, Brazil
| | - Jéssica Nayara Góes Araújo
- Northeast Biotechnology Network (RENORBIO), Graduate Program in Biotechnology, Federal University of Rio Grande do Norte, Natal 59078-900, Brazil
| | - Marcelo Arruda Nakazone
- Department of Cardiology and Cardiovascular Surgery, Faculdade de Medicina de São José do Rio Preto, Sao Jose do Rio Preto 15090-000, Brazil
| | - Tayanne Silva Carmo
- Department of Cardiology and Cardiovascular Surgery, Faculdade de Medicina de São José do Rio Preto, Sao Jose do Rio Preto 15090-000, Brazil
| | - Dorotéia Rossi Silva Souza
- Department of Biochemistry and Molecular Biology, Sao Jose do Rio Preto Medical School, Sao Jose do Rio Preto 15090-000, Brazil
| | - Patricia Moriel
- Department of Clinical Pathology, Faculty of Pharmaceutical Sciences, State University of Campinas-UNICAMP, Campinas 13083-871, Brazil
| | - Jaqueline Yu Ting Wang
- Human Genome and Stem-Cell Research Center, Biosciences Institute, University of Sao Paulo, Sao Paulo 05508-090, Brazil
| | - Michel Satya Naslavsky
- Human Genome and Stem-Cell Research Center, Biosciences Institute, University of Sao Paulo, Sao Paulo 05508-090, Brazil
| | - Renata Gorjão
- Interdisciplinary Post-graduate Program in Health Sciences, Cruzeiro do Sul University, Sao Paulo 01311-925, Brazil
| | - Tania Cristina Pithon-Curi
- Interdisciplinary Post-graduate Program in Health Sciences, Cruzeiro do Sul University, Sao Paulo 01311-925, Brazil
| | - Rui Curi
- Interdisciplinary Post-graduate Program in Health Sciences, Cruzeiro do Sul University, Sao Paulo 01311-925, Brazil
| | - Cristina Moreno Fajardo
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil
| | - Hui-Tzu Lin Wang
- Laboratory of Molecular Research in Cardiology, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil
| | - Adriana Regina Garófalo
- Laboratory of Molecular Research in Cardiology, Institute of Cardiology Dante Pazzanese, Sao Paulo 04012-909, Brazil
| | - Alvaro Cerda
- Department of Basic Sciences, Center of Excellence in Translational Medicine, BIOREN, Universidad de La Frontera, Temuco 4810296, Chile
| | - Marcelo Ferraz Sampaio
- Department of Cardiology, Real and Benemerita Associação Portuguesa de Beneficiencia, Sao Paulo 01323-001, Brazil
| | - Rosario Dominguez Crespo Hirata
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil
| | - Mario Hiroyuki Hirata
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000 SP, Brazil.
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7
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Heidarpour M, Rezvanian P, Sadri MA, Keshavarzrad P, Zakeri R, Vakilbashi O, Shafie D, Shekarchizadeh M, Zarfeshani S, Rabbanipour N, Najafian J, Vaseghi G, Sarrafzadegan N. The Association of Thyroid-Stimulating Hormone (TSH) Levels and Lipid Profile in Euthyroid Patients with Familial Hypercholesterolemia. BIOMED RESEARCH INTERNATIONAL 2023; 2023:4711275. [PMID: 37228643 PMCID: PMC10205407 DOI: 10.1155/2023/4711275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 03/13/2023] [Accepted: 05/03/2023] [Indexed: 05/27/2023]
Abstract
Previous studies reported a relationship between thyroid-stimulating hormone (TSH) and low-density lipoprotein cholesterol (LDL-C) levels. In this study, we aim to evaluate the impact of TSH levels on lipid profile in patients with familial hypercholesterolemia (FH) and euthyroid state. Patients were selected from the Isfahan FH registry. The Dutch Lipid Clinic Network (DLCN) criteria are used to detect FH. Patients were classified into no FH, possible FH, probable FH, and definite FH groups based on the DLCN scores. Patients with any cause of secondary hyperlipidemia, including hypothyroidism, were excluded from this study. The study group consisted of 103 patients with possible FH, 25 patients with definite FH, and 63 individuals with no FH. The mean TSH and LDL-C levels among participants were 2.10 ± 1.22 mU/l and 142.17 ± 62.56 mg/dl, respectively. No positive or negative correlation was found between serum TSH and total cholesterol (P value = 0.438), high-density lipoprotein cholesterol (P = 0.225), triglycerides (P value = 0.863), and LDL-C (P value = 0.203). We found no correlation between serum TSH levels and lipid profiles in euthyroid patients with FH.
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Affiliation(s)
- Maryam Heidarpour
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parastesh Rezvanian
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Amin Sadri
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parsa Keshavarzrad
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rezvan Zakeri
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Davood Shafie
- Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Masood Shekarchizadeh
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sonia Zarfeshani
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Najmeh Rabbanipour
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jamshid Najafian
- Hypertension Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Golnaz Vaseghi
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nizal Sarrafzadegan
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
- School of Population & Public Health, University of British Columbia, Vancouver, BC, Canada
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8
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Abstract
Atherosclerotic cardiovascular disease is the leading cause of death globally. Despite its important risk of premature atherosclerosis and cardiovascular disease, familial hypercholesterolemia (FH) is still largely underdiagnosed worldwide. It is one of the most frequently inherited diseases due to mutations, for autosomal dominant forms, in either of the LDLR, APOB, and PCSK9 genes or possibly a few mutations in the APOE gene and, for the rare autosomal forms, in the LDLRAP1 gene. The discovery of the genes implicated in the disease has largely helped to improve the diagnosis and treatment of FH from the LDLR by Brown and Goldstein, as well as the introduction of statins, to PCSK9 discovery in FH by Abifadel et al., and the very rapid availability of PCSK9 inhibitors. In the last two decades, major progress has been made in clinical and genetic diagnostic tools and the therapeutic arsenal against FH. Improving prevention, diagnosis, and treatment and making them more accessible to all patients will help reduce the lifelong burden of the disease.
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Affiliation(s)
- Marianne Abifadel
- UMR1148, Inserm, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, F-75018 Paris, France.,Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy, Pôle Technologie-Santé, Saint Joseph University of Beirut, Beirut, Lebanon
| | - Catherine Boileau
- UMR1148, Inserm, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, F-75018 Paris, France.,Département de Génétique, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France
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9
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Luo J, Wang JK, Song BL. Lowering low-density lipoprotein cholesterol: from mechanisms to therapies. LIFE METABOLISM 2022; 1:25-38. [PMID: 39872686 PMCID: PMC11749099 DOI: 10.1093/lifemeta/loac004] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/31/2022] [Accepted: 05/13/2022] [Indexed: 01/30/2025]
Abstract
Low-density lipoprotein (LDL) is the main carrier of cholesterol and cholesteryl ester in circulation. High plasma levels of LDL cholesterol (LDL-C) are a major risk factor of atherosclerotic cardiovascular disease (ASCVD). LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD. Statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy. Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments. Here, we review the most recent advances on LDL-C-lowering drugs, focusing on the mechanisms by which they act to reduce LDL-C levels. The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD. Special treatments for those with little or no LDL receptor function then follow. The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein, which are recently approved and still under investigation for LDL-C lowering, respectively, are also included. Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.
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Affiliation(s)
- Jie Luo
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Jin-Kai Wang
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
| | - Bao-Liang Song
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China
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10
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Albuquerque J, Medeiros AM, Alves AC, Bourbon M, Antunes M. Comparative study on the performance of different classification algorithms, combined with pre- and post-processing techniques to handle imbalanced data, in the diagnosis of adult patients with familial hypercholesterolemia. PLoS One 2022; 17:e0269713. [PMID: 35749402 PMCID: PMC9231719 DOI: 10.1371/journal.pone.0269713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 05/26/2022] [Indexed: 11/27/2022] Open
Abstract
Familial Hypercholesterolemia (FH) is an inherited disorder of cholesterol metabolism. Current criteria for FH diagnosis, like Simon Broome (SB) criteria, lead to high false positive rates. The aim of this work was to explore alternative classification procedures for FH diagnosis, based on different biological and biochemical indicators. For this purpose, logistic regression (LR), naive Bayes classifier (NB), random forest (RF) and extreme gradient boosting (XGB) algorithms were combined with Synthetic Minority Oversampling Technique (SMOTE), or threshold adjustment by maximizing Youden index (YI), and compared. Data was tested through a 10 × 10 repeated k-fold cross validation design. The LR model presented an overall better performance, as assessed by the areas under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves, and several operating characteristics (OC), regardless of the strategy to cope with class imbalance. When adopting either data processing technique, significantly higher accuracy (Acc), G-mean and F1 score values were found for all classification algorithms, compared to SB criteria (p < 0.01), revealing a more balanced predictive ability for both classes, and higher effectiveness in classifying FH patients. Adjustment of the cut-off values through pre or post-processing methods revealed a considerable gain in sensitivity (Sens) values (p < 0.01). Although the performance of pre and post-processing strategies was similar, SMOTE does not cause model’s parameters to loose interpretability. These results suggest a LR model combined with SMOTE can be an optimal approach to be used as a widespread screening tool.
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Affiliation(s)
- João Albuquerque
- Departamento de Biomedicina, Unidade de Bioquímica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
- Centro de Estatística e Aplicações, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal
- * E-mail:
| | - Ana Margarida Medeiros
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal
- Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Ana Catarina Alves
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal
- Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Mafalda Bourbon
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal
- Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
| | - Marília Antunes
- Centro de Estatística e Aplicações, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
- Departamento de Estatística e Investigação Operacional, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
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11
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Yu Y, Chen L, Zhang H, Fu Z, Liu Q, Zhao H, Liu Y, Chen Y. Association Between Familial Hypercholesterolemia and Risk of Cardiovascular Events and Death in Different Cohorts: A Meta-Analysis of 1.1 Million Subjects. Front Cardiovasc Med 2022; 9:860196. [PMID: 35800161 PMCID: PMC9253470 DOI: 10.3389/fcvm.2022.860196] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 05/20/2022] [Indexed: 11/15/2022] Open
Abstract
Background and Aims The association of familial hypercholesterolemia (FH) with risk of cardiovascular events (CVE) and death in different cohorts is controversial. We aimed to assess the risk of CVE and death in patients with FH in different cohorts, including CHD and ACS patients, White and Asian, different diagnostic criteria. Methods We searched PubMed, MEDLINE, and Web of Science electronic databases through May 2021 to identify cohort studies of CVE and death in patients with FH. Results We found 18 eligible studies with 1,139,788 participants, including 34,261 patients. There were 31,287 ACS patients, of whom 2,338 were combined with FH. Randomized-effects meta-analysis showed that in patients with FH, relative risk (RR) of CVE and death was 1.87 (95% CI 1.21–2.88), among which CVE was 2.14 (95%CI 1.26–3.64), all-cause of death RR = 1.12 (95% CI 0.89–1.41), and cardiac death RR = 1.03 (95% CI 0.59–1.79). Risk of CVE and death in general population with FH was 2.85 (95% CI 0.72–11.21), hyperlipidemia population RR = 1.59 (95% CI 1.05–2.41), coronary heart disease patients (CHD) RR = 1.46 (95% CI 1.24–1.72), and acute coronary syndrome patients (ACS) RR = 1.71 (95% CI 1.19–2.46). Among ACS patients, the RR of CVE in patients with FH was 1.91 (95% CI 1.55–2.35), the RR of all-cause of death was 1.03 (95% CI 0.80–1.32), and the RR of cardiac death was 1.03 (95% CI 0.59–1.79). The risk of CVE and death in ACS patients with FH in White was 1.69 (95% CI 1.09–2.64) and Asian 1.90 (95% CI 1.31–2.75). RR in patients with Dutch Lipid Network criteria (DLCN) ≥6 vs. <3 points was higher (RR = 2.24, 95% CI 1.69–2.97). RR for long-term follow-up was 1.68 (95% CI 1.09–2.61) and for short-term follow-up was 1.80 (95% CI 1.16–2.78). The results of the overall population were similar, but RR for overall population during a short-term follow-up was 1.49 (95% CI 0.81–2.73). We followed PRISMA checklist to complete meta-analysis. Conclusions The risk of CVE and death was increased in patients with CHD, especially in patients with ACS. DLCN ≥ 6 points was suggested for clinical diagnosis of FH. The risk of long-term and short-term CVE and death increased in ACS patients with FH. Registration Number INPLASY2021110010.
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Affiliation(s)
- Yani Yu
- Medical College of Nankai University, Tianjing, China
- Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lei Chen
- Medical College of Nankai University, Tianjing, China
- Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Honghong Zhang
- Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zihao Fu
- Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qi Liu
- Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Haijing Zhao
- Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuqi Liu
- Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
- *Correspondence: Yuqi Liu
| | - Yundai Chen
- Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
- Yundai Chen
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12
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Gazzotti M, Casula M, Bertolini S, Capra ME, Olmastroni E, Catapano AL, Pederiva C, the LIPIGEN Paediatric Group. The Role of Registers in Increasing Knowledge and Improving Management of Children and Adolescents Affected by Familial Hypercholesterolemia: the LIPIGEN Pediatric Group. Front Genet 2022; 13:912510. [PMID: 35795214 PMCID: PMC9251337 DOI: 10.3389/fgene.2022.912510] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 04/28/2022] [Indexed: 11/13/2022] Open
Abstract
Pathology registers can be a useful tool to overcome obstacles in the identification and management of familial hypercholesterolemia since childhood. In 2018, the LIPIGEN pediatric group was constituted within the Italian LIPIGEN study to focus on FH subjects under 18 years. This work aimed at discussing its recent progress and early outcomes. Demographic, biochemical, and genetic baseline characteristics were collected, with an in-depth analysis of the genetic defects. The analysis was carried out on 1,602 children and adolescents (mean age at baseline 9.9 ± 4.0 years), and almost the whole cohort underwent the genetic test (93.3%). Overall, the untreated mean value of LDL-C was 220.0 ± 97.2 mg/dl, with an increasing gradient from subjects with a negative (N = 317; mean untreated LDL-C = 159.9 ± 47.7 mg/dl), inconclusive (N = 125; mean untreated LDL-C = 166.4 ± 56.5 mg/dl), or positive (N = 1,053; mean untreated LDL-C = 246.5 ± 102.1 mg/dl) genetic diagnosis of FH. In the latter group, the LDL-C values presented a great variability based on the number and the biological impact of involved causative variants. The LIPIGEN pediatric group represents one of the largest cohorts of children with FH, allowing the deepening of the characterization of their baseline and genetic features, providing the basis for further longitudinal investigations for complete details.
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Affiliation(s)
| | - Manuela Casula
- IRCCS MultiMedica, Sesto San Giovanni(Milan), Italy
- Department of Pharmacological and Biomolecular Sciences, Epidemiology and Preventive Pharmacology Service (SEFAP), University of Milan, Milan, Italy
- *Correspondence: Manuela Casula,
| | - Stefano Bertolini
- Department of Internal Medicine, University of Genova, Genova, Italy
| | - Maria Elena Capra
- Centre for Paediatric Dyslipidaemias, Paediatrics and Neonatology Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy
| | - Elena Olmastroni
- Department of Pharmacological and Biomolecular Sciences, Epidemiology and Preventive Pharmacology Service (SEFAP), University of Milan, Milan, Italy
| | - Alberico Luigi Catapano
- IRCCS MultiMedica, Sesto San Giovanni(Milan), Italy
- Department of Pharmacological and Biomolecular Sciences, Epidemiology and Preventive Pharmacology Service (SEFAP), University of Milan, Milan, Italy
| | - Cristina Pederiva
- Clinical Service for Dyslipidaemias, Study and Prevention of Atherosclerosis in Childhood, Paediatrics Unit, ASST-Santi Paolo e Carlo, Milan, Italy
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13
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Winchester B, Cragun D, Redlinger-Grosse K, Walters ST, Ash E, Baldry E, Zierhut H. Application of motivational interviewing strategies with the extended parallel process model to improve risk communication for parents of children with familial hypercholesterolemia. J Genet Couns 2022; 31:847-859. [PMID: 35150174 DOI: 10.1002/jgc4.1554] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 01/10/2021] [Accepted: 01/14/2021] [Indexed: 12/30/2022]
Abstract
Current genetic counseling practice has not been found to significantly increase risk communication between family members. A more diverse set of genetic counseling approaches may be needed. A genetic counseling intervention based on motivational interviewing principles and the extended parallel process model was utilized to increase cascade outcomes within families with familial hypercholesterolemia, a common, underdiagnosed, and treatable condition. Parents of children with familial hypercholesterolemia were invited to participate in an online pre-survey, single-session genetic counseling intervention, and post-intervention surveys as a part of the CHEERS (Cholesterol Evaluation to Explore Risk Screening) intervention. This study investigated the efficacy of a genetic counselor delivered motivational interviewing intervention and how parents of children with familial hypercholesterolemia react by assessing family member cholesterol screening and risk communication to at-risk relatives. Transcripts were audio-recorded, transcribed, and analyzed for change talk using the Motivational Interviewing Skill Code version 2.1. Participant surveys were analyzed for self-reported extended parallel process constructs and motivations. Coincidence analysis was conducted to explore differences between those with and without positive cascade outcomes within 12 months after the intervention. On average, change talk increased during the session in order of the extended parallel process constructs (perceived severity, susceptibility, response efficacy, self-efficacy). Coincidence analysis revealed that 6 of the 7 cases with positive cascade outcomes were explained by either the presence of high change talk during the intervention or presence of positive motivations shortly after, while 5 of the 5 cases without a positive outcome lacked both of these key factors that were associated with cascade outcomes. Results of this study suggest that incorporating motivational interviewing and the extended parallel process model increases change talk and that the presence of either high levels of change talk or positive motivations is associated with positive cascade outcomes.
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Affiliation(s)
- Bridget Winchester
- Department of Genetics, Cell Biology, & Development, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA
| | - Deborah Cragun
- College of Public Health, University of South Florida, Tampa, Florida, USA
| | - Krista Redlinger-Grosse
- Department of Genetics, Cell Biology, & Development, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA
| | - Scott T Walters
- School of Public Health, University of North Texas Health Science Center, Fort Worth, Texas, USA
| | - Erin Ash
- Genetic Counseling Program, Sarah Lawrence College, Bronxville, New York, USA
| | - Emma Baldry
- Department of Genetics, Cell Biology, & Development, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA
| | - Heather Zierhut
- Department of Genetics, Cell Biology, & Development, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA
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14
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Albuquerque J, Medeiros AM, Alves AC, Bourbon M, Antunes M. Performance comparison of different classification algorithms applied to the diagnosis of familial hypercholesterolemia in paediatric subjects. Sci Rep 2022; 12:1164. [PMID: 35064162 PMCID: PMC8782861 DOI: 10.1038/s41598-022-05063-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 12/28/2021] [Indexed: 12/03/2022] Open
Abstract
Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, characterized by increased low density lipoprotein cholesterol (LDLc) levels. The main purpose of the current work was to explore alternative classification methods to traditional clinical criteria for FH diagnosis, based on several biochemical and biological indicators. Logistic regression (LR), decision tree (DT), random forest (RF) and naive Bayes (NB) algorithms were developed for this purpose, and thresholds were optimized by maximization of Youden index (YI). All models presented similar accuracy (Acc), specificity (Spec) and positive predictive values (PPV). Sensitivity (Sens) and G-mean values were significantly higher in LR and RF models, compared to the DT. When compared to Simon Broome (SB) biochemical criteria for FH diagnosis, all models presented significantly higher Acc, Spec and G-mean values (p < 0.01), and lower negative predictive value (NPV, p < 0.05). Moreover, LR and RF models presented comparable Sens values. Adjustment of the cut-off point by maximizing YI significantly increased Sens values, with no significant loss in Acc. The obtained results suggest such classification algorithms can be a viable alternative to be used as a widespread screening method. An online application has been developed to assess the performance of the LR model in a wider population.
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Affiliation(s)
- João Albuquerque
- Departamento de Biomedicina, Unidade de Bioquímica, Faculdade de Medicina, Universidade do Porto, 4200-319, Porto, Portugal.
- Centro de Estatística e Aplicações, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal.
| | - Ana Margarida Medeiros
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisboa, Portugal
- Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
| | - Ana Catarina Alves
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisboa, Portugal
- Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
| | - Mafalda Bourbon
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisboa, Portugal
- Instituto de Biossistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
| | - Marília Antunes
- Centro de Estatística e Aplicações, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
- Departamento de Estatística e Investigação Operacional, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal
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15
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Chetruengchai W, Shotelersuk V. Actionable secondary findings in the 73 ACMG-recommended genes in 1559 Thai exomes. J Hum Genet 2021; 67:137-142. [PMID: 34621001 PMCID: PMC9022721 DOI: 10.1038/s10038-021-00982-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 12/25/2022]
Abstract
High-throughput DNA sequencing provides not only primary diagnosis but also makes available other genetic variants with potential health implications. the American College of Medical Genetics and Genomics (ACMG) has recommended a list of medically actionable genes since 2013 and very recently released an updated ACMG SF v3.0 list comprising 73 genes. Here, we analyzed exome data of 1559 unrelated Thai individuals to determine the frequency and spectrum of pathogenic (P) or likely pathogenic (LP) variants in the 73 genes. Based on the ACMG guidelines for the interpretation of sequence variants, 68 different P/LP variants in 26 genes associated with 18 diseases inherited in an autosomal-dominant manner of 186 individuals (11.9%; 186/1559) were identified. Of these, 22 P/LP variants in 15 genes associated with 13 diseases of 85 individuals (5.5%; 85/1559) were also reported as P/LP in the ClinVar archive. The majority harbored variants in genes related to cardiovascular diseases (4.7%; 74/1559), followed by cancer phenotypes (0.5%; 8/1559). None of the individuals in our cohort harbored biallelic variants in genes responsible for diseases inherited in an autosomal recessive manner. The results would serve as a basis for precision medicine practice at individual and population levels.
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Affiliation(s)
- Wanna Chetruengchai
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand.,Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Interdisciplinary Program of Biomedical Sciences, Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Vorasuk Shotelersuk
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand. .,Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
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16
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Baldry E, Redlinger-Grosse K, MacFarlane I, Walters ST, Ash E, Steinberger J, Murdy K, Cragun D, Allen-Tice C, Zierhut H. Outcomes from a pilot genetic counseling intervention using motivational interviewing and the extended parallel process model to increase cascade cholesterol screening. J Genet Couns 2021; 31:164-175. [PMID: 34260792 DOI: 10.1002/jgc4.1466] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 06/01/2021] [Accepted: 06/14/2021] [Indexed: 12/26/2022]
Abstract
Familial hypercholesterolemia (FH) is an inherited condition resulting in increased risk of premature cardiovascular disease. This risk can be reduced with early diagnosis and treatment, but it can be challenging to identify individuals with FH. Cascade screening, the most efficient and cost-effective identification method, requires FH patients to communicate with their at-risk family and encourage them to pursue screening. Beyond FH, patients with conditions increasing disease risk to family members report barriers to the communication process such as insufficient knowledge of the condition and discomfort informing relatives. We conducted a pilot study of a genetic counseling intervention incorporating behavior-change principles from motivational interviewing (MI) and the extended parallel process model (EPPM) to help parents of children with FH overcome these barriers and improve cascade screening rates for FH. Of the 13 participants who completed the intervention and post-intervention surveys, 6 reported contacting and/or screening additional relatives. A large effect size in increasing communication and screening was observed (η2 = 0.20), with the mean percent of at-risk relatives contacted rising from 33% to 45%, and the mean percent screened rising from 32% to 42%. On average, 2.23 new relatives were contacted and 2.46 were screened, per participant, by the end of the study. Direct content analysis revealed that despite the open-ended nature of the goal-setting process, participant goals fell into two categories including those who set goals focused on communicating with and screening family members (n = 9) and those who set goals only focused on managing FH (n = 4). Overall, the communication and screening rates reported after the intervention were higher than previous observations in adult FH populations. These results suggest this EPPM/MI genetic counseling intervention could be a useful tool for increasing communication and cascade screening for FH. With further research on goal-setting techniques, the intervention could be refined and replicated to identify more individuals affected by FH or modified for use with other actionable genetic conditions.
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Affiliation(s)
- Emma Baldry
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
| | - Krista Redlinger-Grosse
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
| | - Ian MacFarlane
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
| | - Scott T Walters
- Health Sciences Center, University of North Texas, Fort Worth, TX, USA
| | - Erin Ash
- Sarah Lawrence College, Broxville, NY, USA
| | - Julia Steinberger
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Kari Murdy
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Deborah Cragun
- College of Public Health, University of South Florida, Tampa, FL, USA
| | - Carly Allen-Tice
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
| | - Heather Zierhut
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
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17
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Borges JB, Oliveira VFD, Ferreira GM, Los B, Barbosa TKAA, Marçal EDSR, Dagli-Hernandez C, de Freitas RCC, Bortolin RH, Mori AA, Hirata TDC, Nakaya HTI, Bastos GM, Thurow HS, Gonçalves RM, Araujo DBD, Zatz HP, Bertolami A, Faludi AA, Bertolami MC, Sousa AGDMR, França JÍD, Jannes CE, Pereira ADC, Nakazone MA, Souza DRS, Carmo TS, Sampaio MF, Gorjão R, Pithon-Curi TC, Moriel P, Silbiger VN, Luchessi AD, de Araújo JNG, Naslavsky MS, Wang JYT, Kronenberger T, Cerda A, Lin-Wang HT, Garofalo AR, Fajardo CM, Hirata RDC, Hirata MH. Genomics, epigenomics and pharmacogenomics of familial hypercholesterolemia (FHBGEP): A study protocol. Res Social Adm Pharm 2021; 17:1347-1355. [DOI: 10.1016/j.sapharm.2020.10.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 10/08/2020] [Indexed: 02/08/2023]
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18
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Azraii AB, Ramli AS, Ismail Z, Abdul-Razak S, Badlishah-Sham SF, Mohd-Kasim NA, Ali N, Watts GF, Nawawi H. Validity and reliability of an adapted questionnaire measuring knowledge, awareness and practice regarding familial hypercholesterolaemia among primary care physicians in Malaysia. BMC Cardiovasc Disord 2021; 21:39. [PMID: 33468051 PMCID: PMC7814747 DOI: 10.1186/s12872-020-01845-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 12/30/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Primary care physicians (PCP) play an important role in detecting Familial Hypercholesterolaemia (FH) early. However, knowledge, awareness and practice (KAP) regarding FH among Malaysian PCP are not well established, and there was no validated tool to assess their FH KAP. Thus, the aim of this study was to adapt an FH KAP questionnaire and determine its validity and reliability among Malaysian PCP. METHODS This cross-sectional validation study involved Malaysian PCP with ≥ 1-year work experience in the primary care settings. In Phase 1, the original 19-item FH KAP questionnaire underwent content validation and adaptation by 7 experts. The questionnaire was then converted into an online survey instrument and was face validated by 10 PCP. In Phase 2, the adapted questionnaire was disseminated through e-mail to 1500 PCP. Data were collected on their KAP, demography, qualification and work experience. The construct validity was tested using known-groups validation method. The hypothesis was PCP holding postgraduate qualification (PCP-PG-Qual) would have better FH KAP compared with PCP without postgraduate qualification (PCP-noPG-Qual). Internal consistency reliability was calculated using Kuder Richardson formula-20 (KR-20) and test-retest reliability was tested on 26 PCP using kappa statistics. RESULTS During content validation and adaptation, 10 items remained unchanged, 8 items were modified, 1 item was moved to demography and 7 items were added. The adapted questionnaire consisted of 25 items (11 knowledge, 5 awareness and 9 practice items). A total of 130 out of 1500 PCP (response rate: 8.7%) completed the questionnaire. The mean percentage knowledge score was found to be significantly higher in PCP-PG-Qual compared with PCP-noPG-Qual (53.5, SD ± 13.9 vs. 35.9, SD ± 11.79), t(128) = 6.90, p < 0.001. The median percentage awareness score was found to be significantly higher in PCP-PG-Qual compared with PCP-noPG-Qual (15.4, IqR ± 23.08 vs. 7.7, IqR ± 15.38), p = 0.030. The mean percentage practice score was significantly higher in PCP-PG-Qual compared with PCP-noPG-Qual (69.2, SD ± 17.62 vs. 54.4, SD ± 19.28), t(128) = 3.79, p < 0.001. KR-20 value was 0.79 (moderate reliability) and average Kappa was 0.796 (substantial agreement). CONCLUSION This study has proven that the 25-item adapted FH KAP questionnaire is valid and reliable. It can be used to measure and establish FH KAP among PCP in Malaysia.
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Affiliation(s)
- Ahmad Baihaqi Azraii
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Selayang Campus, Jalan Prima Selayang 7, 68100 Batu Caves, Selangor Malaysia
| | - Anis Safura Ramli
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Selayang Campus, Jalan Prima Selayang 7, 68100 Batu Caves, Selangor Malaysia
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor Malaysia
| | - Zaliha Ismail
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor Malaysia
- Department of Public Health Medicine, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor Malaysia
| | - Suraya Abdul-Razak
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Selayang Campus, Jalan Prima Selayang 7, 68100 Batu Caves, Selangor Malaysia
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor Malaysia
| | - Siti Fatimah Badlishah-Sham
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Selayang Campus, Jalan Prima Selayang 7, 68100 Batu Caves, Selangor Malaysia
| | - Noor Alicezah Mohd-Kasim
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor Malaysia
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor Malaysia
| | - Norsiah Ali
- Klinik Kesihatan Masjid Tanah, 78300 Masjid Tanah, Melaka Malaysia
| | - Gerald F. Watts
- School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, GPO Box X2213, Perth, WA 6827 Australia
- Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, WA 6827 Australia
| | - Hapizah Nawawi
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor Malaysia
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor Malaysia
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Mehta R, Martagon AJ, Galan Ramirez GA, Antonio-Villa NE, Vargas-Vázquez A, Elias-Lopez D, Gonzalez-Retana G, Rodríguez-Encinas B, Ceballos-Macías JJ, Romero-Zazueta A, Martinez-Alvarado R, Morales-Portano JD, Alvarez-Lopez H, Sauque-Reyna L, Gomez-Herrera LG, Simental-Mendia LE, Garcia-Aguilar H, Ramirez-Cooremans E, Peña-Aparicio B, Mendoza-Zubieta V, Carrillo-Gonzalez PA, Ferreira-Hermosillo A, Caracas-Portilla N, Jimenez-Dominguez G, Ruiz-Garcia AY, Arriaga-Cazares HE, Gonzalez-Gonzalez JR, Mendez-Valencia CV, Padilla FG, Madriz-Prado R, De Los Rios-Ibarra MO, Vazquez-Cardenas A, Arjona-Villicaña RD, Acevedo-Rivera KJ, Allende-Carrera R, Alvarez JA, Amezcua-Martinez JC, de Los Reyes Barrera-Bustillo M, Carazo-Vargas G, Contreras-Chacon R, Figueroa-Andrade MH, Flores-Ortega A, Garcia-Alcala H, Garcia de Leon LE, Garcia-Guzman B, Garduño-Garcia JJ, Garnica-Cuellar JC, Gomez-Cruz JR, Hernandez-Garcia A, Holguin-Almada JR, Juarez-Herrera U, Lugo-Sobrevilla F, Marquez-Rodriguez E, Martinez-Sibaja C, Medrano-Rodriguez AB, Morales-Oyervides JC, Perez-Vazquez DI, Reyes-Rodriguez EA, Robles-Osorio ML, Rosas-Saucedo J, Torres-Tamayo M, Valdez-Talavera LA, Vera-Arroyo LE, Zepeda-Carrillo EA, Aguilar-Salinas CA. Familial hypercholesterolemia in Mexico: Initial insights from the national registry. J Clin Lipidol 2021; 15:124-133. [PMID: 33422452 DOI: 10.1016/j.jacl.2020.12.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 11/18/2020] [Accepted: 12/04/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated. OBJECTIVE Report the results of the first years (2017-2019) of the Mexican FH registry. METHODS There are 60 investigators, representing 28 federal states, participating in the registry. The variables included are in accordance with the European Atherosclerosis Society (EAS) FH recommendations. RESULTS To date, 709 patients have been registered, only 336 patients with complete data fields are presented. The mean age is 50 (36-62) years and the average time since diagnosis is 4 (IQR: 2-16) years. Genetic testing is recorded in 26.9%. Tendon xanthomas are present in 43.2%. The prevalence of type 2 diabetes is 11.3% and that of premature CAD is 9.8%. Index cases, male gender, hypertension and smoking were associated with premature CAD. The median lipoprotein (a) level is 30.5 (IQR 10.8-80.7) mg/dl. Statins and co-administration with ezetimibe were recorded in 88.1% and 35.7% respectively. A combined treatment target (50% reduction in LDL-C and an LDL-C <100 mg/dl) was achieved by 13.7%. Associated factors were index case (OR 3.6, 95%CI 1.69-8.73, P = .002), combination therapy (OR 2.4, 95%CI 1.23-4.90, P = .011), type 2 diabetes (OR 2.8, 95%CI 1.03-7.59, P = .036) and age (OR 1.023, 95%CI 1.01-1.05, P = .033). CONCLUSION The results confirm late diagnosis, a lower than expected prevalence and risk of ASCVD, a higher than expected prevalence of type 2 diabetes and undertreatment, with relatively few patients reaching goals. Recommendations include, the use of combination lipid lowering therapy, control of comorbid conditions and more frequent genetic testing in the future.
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Affiliation(s)
- Roopa Mehta
- Unidad de Investigación de Enfermedades Metabolicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, México City, Mexico; Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Alexandro J Martagon
- Unidad de Investigación de Enfermedades Metabolicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, México City, Mexico; Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico
| | - Gabriela A Galan Ramirez
- Unidad de Investigación de Enfermedades Metabolicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, México City, Mexico
| | - Neftali Eduardo Antonio-Villa
- Unidad de Investigación de Enfermedades Metabolicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, México City, Mexico
| | - Arsenio Vargas-Vázquez
- Unidad de Investigación de Enfermedades Metabolicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, México City, Mexico
| | - Daniel Elias-Lopez
- Unidad de Investigación de Enfermedades Metabolicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, México City, Mexico; Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Gustavo Gonzalez-Retana
- Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Bethsabel Rodríguez-Encinas
- Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Guadalupe Jimenez-Dominguez
- Hospital General Zona #46 IMSS, Villahermosa, Tabasco, Mexico; Hospital Angeles de Villahermosa, Tabasco, Mexico
| | | | - Hector E Arriaga-Cazares
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico; Centro Medico Nacional del Noreste IMSS, Monterrey, Nuevo Leon, Mexico
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Carlos A Aguilar-Salinas
- Unidad de Investigación de Enfermedades Metabolicas, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, México City, Mexico; Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutricion Salvador Zubiran, Mexico City, Mexico; Direccion de Nutricion, Instituto Nacional de Ciencias Médicas y Nutricion Salvador Zubiran, Mexico City, Mexico; Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico.
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20
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Sarrafzadegan N, Vaseghi G, Malakoutikhah Z, Shafiee Z, Gharipour M, Shariati L, Sadeghian L, Khosravi E, Javanmard S, Pourmoghaddas A, Laher I, Zarfeshani S. Apolipoprotein B gene mutation related to familial hypercholesterolemia in an Iranian population: With or without hypothyroidism. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2021; 26:94. [PMID: 34899932 PMCID: PMC8607183 DOI: 10.4103/jrms.jrms_970_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/07/2021] [Accepted: 05/24/2021] [Indexed: 11/16/2022]
Abstract
Background: Familial hypercholesterolemia (FH) leads to elevated low-density lipoprotein cholesterol (LDL-C) levels in plasma. Mutations of its related gene; apolipoprotein B (APOB) is seen in about two percent of the patient with FH. Thyroid disease is usually part of the exclusion criteria for the detection of FH which alters the lipid profile. We evaluated mutations in the APOB gene in patients with high LDL-C levels. Materials and Methods: Patients aged between 2 and 80 years with at least one LDL-C level of more than 190 mg/dl were selected (120 patients) from Isfahan Laboratories. Blood samples were obtained from all patients. Genomic DNA was extracted. Primer sequences were designed by Oligo 7.60 to amplify the desired 844 bp region of exon 26 of the APOB gene containing R3500Q and R3500W variants associated with FH. Results: Overall, two patients showed a heterozygous form of a common pathogenic variant in exon 26 named c. 10579 C > T (R3500W, cDNA.10707), and one patient was hypothyroidism. We also recognized another nonpathognomonic variant c. 10913G > A (rs1801701, cDNA.11041) in 13 patients, two of them were hypothyroidism. Conclusion: This study for the first time shows the coexistence of APOB mutation in hypothyroidism, which emphasis screening of patients with hypothyroid for FH detection.
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21
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Abstract
CME: Primary and Secondary Hypercholesterolemia Abstract. In patients with hypercholesterolemia and an LDL-cholesterol level >5 mmol/l, familial hypercholesterolemia (primary hypercholesterolemia) should be considered. This genetically determined illness should lead to medical therapy and screening for hypercholesterinemia in close relatives. Beside the superelevated LDL-cholesterol levels, additional clinically diagnostic findings and family anamnesis can support the diagnosis of familial hypercholesterolemia. The likelihood of familial hypercholesterolemia can be estimated using the Lipid Clinic Network Score. Additionally, a variety of exogenous factors may have an impact on lipoprotein metabolism and may lead to secondary hypercholesterolemia. Hypothyroidism, cholestasis, nephrotic syndrome or specific medications, among others, should be considered as potential factors leading to high cholesterol levels before familial hypercholesterolemia is suspected or lipid-lowering treatment is started.
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Affiliation(s)
| | - Peter Wiesli
- Endokrinologie/Diabetologie, Kantonsspital Frauenfeld
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22
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Bianconi V, Banach M, Pirro M. Why patients with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels. Trends Cardiovasc Med 2020; 31:205-215. [PMID: 32205033 DOI: 10.1016/j.tcm.2020.03.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/03/2020] [Accepted: 03/06/2020] [Indexed: 01/07/2023]
Abstract
Familial hypercholesterolemia (FH) is a common genetic cause of elevated low-density lipoprotein cholesterol (LDL-C) due to defective clearance of circulating LDL particles. All FH patients are at high risk for premature cardiovascular disease (CVD) events due to their genetically determined lifelong exposure to high LDL-C levels. However, different rates of CVD events have been reported in FH patients, even among those with the same genetic mutations and comparable LDL-C levels. Hence, additional CVD risk modifiers, beyond LDL-C, may contribute to increase CVD risk in the FH population. In this review, we discuss the overall CVD risk burden of the FH population. Additionally, we revise the prognostic impact of several traditional and emerging predictors of CVD risk and we provide an overview of the role of specific tools to stratify CVD risk in FH patients in order to ensure them a more personalized treatment approach.
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Affiliation(s)
- Vanessa Bianconi
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Hospital "Santa Maria della Misericordia", Piazzale Menghini, 1, 06129 Perugia, Italy
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
| | - Matteo Pirro
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Hospital "Santa Maria della Misericordia", Piazzale Menghini, 1, 06129 Perugia, Italy.
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23
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CRISPR Diagnosis and Therapeutics with Single Base Pair Precision. Trends Mol Med 2019; 26:337-350. [PMID: 31791730 DOI: 10.1016/j.molmed.2019.09.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 12/11/2022]
Abstract
Clustered regularly interspaced short palindromic repeats, or CRISPR, has been widely accepted as a versatile genome editing tool with significant potential for medical application. Reliable allele specificity is one of the most critical elements for successful application of this technology to develop high-precision therapeutics and diagnostics. CRISPR-based genome editing tools achieve high-fidelity distinction of single-base differences in target genomic loci by structural identification of CRISPR-associated (Cas) proteins and sequences of the guide RNAs. In this review, we describe the structural features of ribonucleoprotein complex formation by CRISPR proteins and guide RNAs that eventually recognize target DNA sequences. This structural understanding provides the basis for the recent applications of enhanced single-base precision genome editing technologies for effective distinction of specific alleles.
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Cephus CE, Qureshi AM, Sexson Tejtel SK, Alam M, Moodie DS. Coronary artery disease in a child with homozygous familial hypercholesterolemia: Regression after liver transplantation. J Clin Lipidol 2019; 13:880-886. [PMID: 31704104 DOI: 10.1016/j.jacl.2019.09.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 09/08/2019] [Accepted: 09/17/2019] [Indexed: 11/26/2022]
Abstract
Children with homozygous familial hypercholesterolemia are at risk for early cardiovascular events secondary to coronary artery disease. Current medical therapy does not ameliorate this risk. Liver transplantation offers the most effective option to reduce circulating levels of low-density lipoprotein cholesterol and thereby reduce risk of cardiovascular events. Angiographic evidence of regression of coronary artery disease is presented.
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Affiliation(s)
- Constance E Cephus
- Texas Children's Hospital Heart Center, Pediatric Cardiology, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX.
| | - Athar M Qureshi
- Texas Children's Hospital Heart Center, Pediatric Cardiology, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - S Kristen Sexson Tejtel
- Texas Children's Hospital Heart Center, Pediatric Cardiology, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - Mahboob Alam
- Margaret M and Albert B Alkek Department of Medicine, Cardiology, Baylor College of Medicine, Houston, TX
| | - Douglas S Moodie
- Texas Children's Hospital Heart Center, Pediatric Cardiology, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX
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Scaglione J, Diaz SF, Bonagura JD, Kohnken RA, Helms TH, Cianciolo RE. Ischemic necrosis of the digits and hyperlipidemia associated with atherosclerosis in a Miniature American Shepherd. J Am Vet Med Assoc 2019; 253:209-214. [PMID: 29963946 DOI: 10.2460/javma.253.2.209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
CASE DESCRIPTION A 2.5-year-old 12-kg (26.4-lb) castrated male Miniature American Shepherd was referred because of a 3-week history of a localized crusted skin lesion on the digital pad of digit 3 of the right hind limb. CLINICAL FINDINGS Skin lesions were noted on the digital pads of the right hind limb. Serum biochemical analyses indicated severe hypercholesterolemia and hypertriglyceridemia. Ultrasonography of the terminal portion of the aorta and other major arterial vessels revealed substantial arteriosclerotic change. TREATMENT AND OUTCOME Medical treatments included administration of atorvastatin calcium, a low-fat diet, and omega-3 fatty acids to reduce serum lipids concentration; clopidogrel to prevent thrombosis; pentoxifylline to improve microcirculatory blood flow; clomipramine hydrochloride and trazodone hydrochloride to help with the behavioral problems; and gabapentin to help with pain management and behavioral problems. Surgical management included amputation of the initial digit involved, then eventually the entire initial limb involved. The response to treatment was poor, and euthanasia was elected. Postmortem findings revealed severe, widespread, and chronic intimal atherosclerosis; mild, widespread, and degenerative changes in the cerebral cortex; and edema and vascular congestion in the meninges. CLINICAL RELEVANCE To the authors' knowledge, this was the first report of skin necrosis secondary to atherosclerosis in a dog. Although the incidence of atherosclerosis has been considered very low in dogs, it should be investigated in dogs with severe hyperlipidemia. Primary hyperlipidemia has not been previously described in Miniature American Shepherd dogs but was the suspected underlying metabolic disorder.
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Chen CC, Rane PB, Hines DM, Patel J, Harrison DJ, Wade RL. Low-density lipoprotein cholesterol outcomes post-non-PCSK9i lipid-lowering therapies in atherosclerotic cardiovascular disease and probable heterozygous familial hypercholesterolemia patients. Ther Clin Risk Manag 2018; 14:2425-2435. [PMID: 30587999 PMCID: PMC6296203 DOI: 10.2147/tcrm.s180783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background This study evaluated the proportion of patients with atherosclerotic cardiovascular disease (ASCVD) and probable heterozygous familial hypercholesterolemia (HeFH) achieving ≥50% reduction in low-density lipoprotein cholesterol (LDL-C) or reaching the LDL-C ≤70 mg/dL threshold, after initiating or modifying statin, and/or ezetimibe therapy. Materials and methods Adult ASCVD patients with baseline LDL-C >70 mg/dL (index) and a subset of patients with probable HeFH (proxied by LDL-C ≥190 mg/dL) were identified between January 1, 2012, and August 31, 2014, from the IQVIA electronic medical record database. Patients were followed for 12 months pre-index to examine baseline lipid-lowering therapy (LLT) use, and 12 months post index to evaluate treatment modifications and post-treatment LDL-C levels, stratified by type of treatment received and LDL-C levels at baseline. Results Of the sample of ASCVD patients who initiated treatment post-index (n=111,147), only 7.6% patients achieved a ≥50% reduction from baseline LDL-C and 19.1% of patients reached the LDL-C ≤70 mg/dL threshold. Among treated ASCVD patients who modified therapy post-index (n=75,523), 5.6% achieved a ≥50% reduction in LDL-C, and proportion of patients achieving LDL-C ≤70 mg/dL ranged from 6.9% to 26.7%, depending on the baseline LDL-C levels. Approximately 50% of the untreated probable HeFH patients (n=3,064) initiated LLT; however, the mean (SD) post-treatment LDL-C remained high (136.2 [47.8] mg/dL), with only 4.4% reaching LDL-C ≤70 mg/dL. Of the treated probable HeFH patients (n=1,073), 41.5% modified treatment; 22.1% achieved a ≥50% reduction in LDL-C and 1.1% reached LDL-C ≤70 mg/dL. Conclusion This study found that most patients had suboptimal LDL-C responses after initiating or modifying standard LLT (statin and/or ezetimibe). More frequent and aggressive lipid management, including increasing statin intensity and alternative therapies, may be needed in patients with ASCVD and probable HeFH to reduce their cardiovascular risk.
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Systematic prediction of familial hypercholesterolemia caused by low-density lipoprotein receptor missense mutations. Atherosclerosis 2018; 281:1-8. [PMID: 30583242 DOI: 10.1016/j.atherosclerosis.2018.12.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 11/26/2018] [Accepted: 12/04/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Familial hypercholesterolemia (FH) is a an autosomal dominant disorder characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). It is estimated that >85% of all FH-causing mutations involve genetic variants in the LDL receptor (LDLR). To date, 795 single amino acid LDLR missense mutations have been reported in the Leiden Open Variation Database (LOVD). However, the functional impact of these variants on the LDLR pathway has received little attention and remains poorly understood. We aim to establish a systematic functional prediction model for LDLR single missense mutations. METHODS Using a combined structural modeling and bioinformatics algorithm, we developed an in silico prediction model called "Structure-based Functional Impact Prediction for Mutation Identification" (SFIP-MutID) for FH with LDLR single missense mutations. We compared the pathogenicity and functional impact predictions of our model to those of other conventional tools with experimentally validated variants, as well as in vitro functional test results for patients with LDLR variants. RESULTS Our SFIP-MutID model systematically predicted 13,167 potential LDLR single amino acid missense substitutions with biological effects. The functional impact of 52 out of 54 specific mutations with reported in vitro experimental data was predicted correctly. Further functional tests on LDLR variants from patients were also consistent with the prediction of our model. CONCLUSIONS Our LDLR structure-based computational model predicted the pathogenicity of LDLR missense mutations by linking genotypes with LDLR functional phenotypes. Our model complements other prediction tools for variant interpretation and facilitates the precision diagnosis and treatment of FH and atherosclerotic cardiovascular diseases.
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Banach M, Mazidi M, Mikhailidis DP, Toth PP, Jozwiak J, Rysz J, Watts GF. Association between phenotypic familial hypercholesterolaemia and telomere length in US adults: results from a multi-ethnic survey. Eur Heart J 2018; 39:3635-3640. [PMID: 30165413 DOI: 10.1093/eurheartj/ehy527] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 08/09/2018] [Indexed: 12/24/2022] Open
Abstract
Aims Familial hypercholesterolaemia (FH) accelerates atherosclerotic cardiovascular disease (ASCVD) and accordingly is the most potent hereditary cause of premature coronary heart disease. The association between telomere length (TL), a biological index of ageing, and FH has not been hitherto investigated. We addressed this question using data from the US National Health and Education National Surveys (NHANES, 1999-2002). Methods and results We included individuals, who had TL measurements (with quantitative polymerase chain reaction method) and a phenotypic diagnosis of FH based on the Dutch Lipid Clinic Network (DLCN) criteria. Sample weights were applied for unequal probabilities of selection, non-response bias, and oversampling by complex sample analysis. The adult prevalence of FH in NHANES was 0.43% [95% confidence interval (95% CI) 0.33-0.57]. The frequencies of probable FH (mean DLCN score: 6.2) and definite FH (mean DLCN score: 8.9) were 0.42% (95% CI 0.32-0.48) and 0.03% (95% CI 0.02-0.06), respectively. Subjects with FH had a higher prevalence of non-communicable diseases (hypertension, diabetes 2 type, and obesity) and early atherosclerosis (2.9% in overall population vs. 42.2% in FH). Overall, the mean TL in the non-FH population was 1.09 (95% CI 1.06-1.12) (T/S ratio) and 1.09 (95% CI 1.03-1.12) [(T/S ratio) for total FH]. Telomere length adjusted for age, sex, race, and body mass index was shorter in FH compared with healthy subjects (FH 0.89, 95% CI 0.84-0.93 vs. healthy: 1.05, 95% CI 0.97-1.11 T/S ratio; P < 0.001). Subjects with longer TL (highest quartile) had 12% less chance of having FH compared with those with TL in the lowest quartile (Q1, 95% CI 0.78-0.93). Conclusions These preliminary data suggest an association between TL, an index of biological age, and the presence of FH, the most common inherited cause of premature ASCVD. Given our relatively low sample size, the findings need confirmation in larger studies.
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Affiliation(s)
- Maciej Banach
- Chair of Nephrology and Hypertension, Medical University of Lodz, Zeromskiego 113, Lodz, Poland
- Polish Mother's Memorial Hospital Research Institute, Rzgowska 281/289, Lodz, Poland
- Cardiovascular Research Centre, University of Zielona Gora, Zyty 28, Zielona Gora, Poland
| | - Mohsen Mazidi
- Department of Biology and Biological Engineering, Food and Nutrition Science, Chalmers University of Technology, Kemigarden 4, Gothenburg, Sweden
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), Pond Street, London, UK
| | - Peter P Toth
- The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, 600 N. Wolfe St, Carnegie 565-G, Baltimore, MD, USA
- Preventive Cardiology, CGH Medical Center, 01 East Miller Road, Sterling, IL, USA
| | - Jacek Jozwiak
- Department of Medicine and Public Health, University of Opole, Kopernika 11A, Opole, Poland
| | - Jacek Rysz
- Chair of Nephrology and Hypertension, Medical University of Lodz, Zeromskiego 113, Lodz, Poland
| | - Gerald F Watts
- Cardiometabolic Service, Department of Cardiology, Royal Perth Hospital, School of Medicine, University of Western Australia, 35 Stirling Highway, Crawley, WA, Australia
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Phuong Kim T, Thuan Duc L, Thuy Ai HL. The Major Molecular Causes of Familial Hypercholesterolemia. ASIAN JOURNAL OF PHARMACEUTICAL RESEARCH AND HEALTH CARE 2018. [DOI: 10.18311/ajprhc/2018/20031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Momtazi AA, Banach M, Pirro M, Stein EA, Sahebkar A. MicroRNAs: New Therapeutic Targets for Familial Hypercholesterolemia? Clin Rev Allergy Immunol 2018; 54:224-233. [PMID: 28534160 PMCID: PMC5874276 DOI: 10.1007/s12016-017-8611-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Familial hypercholesterolemia (FH) is the most common inherited form of dyslipidemia and a major cause of premature cardiovascular disease. Management of FH mainly relies on the efficiency of treatments that reduce plasma low-density lipoprotein (LDL) cholesterol (LDL-C) concentrations. MicroRNAs (miRs) have been suggested as emerging regulators of plasma LDL-C concentrations. Notably, there is evidence showing that miRs can regulate the post-transcriptional expression of genes involved in the pathogenesis of FH, including LDLR, APOB, PCSK9, and LDLRAP1. In addition, many miRs are located in genomic loci associated with abnormal levels of circulating lipids and lipoproteins in human plasma. The strong regulatory effects of miRs on the expression of FH-associated genes support of the notion that manipulation of miRs might serve as a potential novel therapeutic approach. The present review describes miRs-targeting FH-associated genes that could be used as potential therapeutic targets in patients with FH or other severe dyslipidemias.
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Affiliation(s)
- Amir Abbas Momtazi
- Nanotechnology Research Center, Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz (MUL), Zeromskiego 113, 90-549, Lodz, Poland. .,Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland. .,Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Evan A Stein
- Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran. .,School of Medicine, University of Western Australia, Perth, Australia. .,Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, P.O. Box: 91779-48564, Mashhad, Iran.
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Mytilinaiou M, Kyrou I, Khan M, Grammatopoulos DK, Randeva HS. Familial Hypercholesterolemia: New Horizons for Diagnosis and Effective Management. Front Pharmacol 2018; 9:707. [PMID: 30050433 PMCID: PMC6052892 DOI: 10.3389/fphar.2018.00707] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 06/12/2018] [Indexed: 12/11/2022] Open
Abstract
Familial hypercholesterolemia (FH) is a common genetic cause of premature cardiovascular disease (CVD). The reported prevalence rates for both heterozygous FH (HeFH) and homozygous FH (HoFH) vary significantly, and this can be attributed, at least in part, to the variable diagnostic criteria used across different populations. Due to lack of consistent data, new global registries and unified guidelines are being formed, which are expected to advance current knowledge and improve the care of FH patients. This review presents a comprehensive overview of the pathophysiology, epidemiology, manifestations, and pharmacological treatment of FH, whilst summarizing the up-to-date relevant recommendations and guidelines. Ongoing research in FH seems promising and novel therapies are expected to be introduced in clinical practice in order to compliment or even substitute current treatment options, aiming for better lipid-lowering effects, fewer side effects, and improved clinical outcomes.
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Affiliation(s)
- Maria Mytilinaiou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom.,Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, United Kingdom.,Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, Coventry, United Kingdom.,Centre of Applied Biological and Exercise Sciences, Faculty of Health and Life Sciences, Coventry University, Coventry, United Kingdom
| | - Mike Khan
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
| | - Dimitris K Grammatopoulos
- Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, Coventry, United Kingdom.,Institute of Precision Diagnostics and Translational Medicine, Coventry and Warwickshire Pathology Service, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
| | - Harpal S Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom.,Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, United Kingdom.,Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, Coventry, United Kingdom.,Centre of Applied Biological and Exercise Sciences, Faculty of Health and Life Sciences, Coventry University, Coventry, United Kingdom.,Institute of Precision Diagnostics and Translational Medicine, Coventry and Warwickshire Pathology Service, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
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Zamparini JM, Immelman AR, Raal FJ. Fibroblast growth factor-23 in patients with homozygous familial hypercholesterolemia. J Clin Lipidol 2018; 12:767-772. [PMID: 29550495 DOI: 10.1016/j.jacl.2018.02.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 02/10/2018] [Accepted: 02/13/2018] [Indexed: 11/18/2022]
Abstract
BACKGROUND Patients with homozygous familial hypercholesterolemia (HoFH) develop significant vascular calcification early in life, the cause of which is not yet fully understood. Patients with chronic kidney disease have similar vascular calcification, with fibroblast growth factor-23 (FGF23) implicated in these patients. OBJECTIVE To determine whether there was a difference in FGF23 between patients with HoFH and age- and gender-matched controls and whether there is a correlation between FGF23 and serum low-density lipoprotein, total cholesterol, and carotid intima-media thickness in patients with HoFH. METHODS The study was a cross-sectional review involving 30 patients with HoFH attending the Charlotte Maxeke Johannesburg Academic Hospital Lipid Clinic in Parktown, South Africa, as well as 30 age- and gender-matched healthy controls. FGF23, fasting lipid profiles, calcium, and phosphate were measured. B-mode ultrasonography of the carotid arteries was done to assess the extent and severity of arterial calcification. RESULTS There was no difference in mean FGF23 between the patient and control groups (62.07 ± 26.42 pg/mL vs 63.69 ± 19.84 pg/mL; P = .4621) nor was there any correlation between FGF23 and low-density lipoprotein cholesterol (P = .9483 and .8474) or total cholesterol (P = .9261 and .859). In the HoFH patients, FGF23 did not correlate significantly with any cardiovascular disease. CONCLUSIONS Serum FGF23 is not elevated in patients with HoFH when compared to non-familial hypercholesterolemia age- and gender-matched controls, and there is no correlation between serum FGF23 and cardiovascular disease in patients with HoFH. FGF23 does not appear to be a major factor for arterial calcification in HoFH.
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Affiliation(s)
- Jarrod M Zamparini
- Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa.
| | - Andrew R Immelman
- Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa; Carbohydrate & Lipid Metabolism Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
| | - Frederick J Raal
- Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa; Carbohydrate & Lipid Metabolism Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
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Ruel I, Aljenedil S, Sadri I, de Varennes É, Hegele RA, Couture P, Bergeron J, Wanneh E, Baass A, Dufour R, Gaudet D, Brisson D, Brunham LR, Francis GA, Cermakova L, Brophy JM, Ryomoto A, Mancini GBJ, Genest J. Imputation of Baseline LDL Cholesterol Concentration in Patients with Familial Hypercholesterolemia on Statins or Ezetimibe. Clin Chem 2018; 64:355-362. [DOI: 10.1373/clinchem.2017.279422] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 08/31/2017] [Indexed: 01/27/2023]
Abstract
Abstract
BACKGROUND
Familial hypercholesterolemia (FH) is the most frequent genetic disorder seen clinically and is characterized by increased LDL cholesterol (LDL-C) (>95th percentile), family history of increased LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) in the patient or in first-degree relatives, presence of tendinous xanthomas or premature corneal arcus, or presence of a pathogenic mutation in the LDLR, PCSK9, or APOB genes. A diagnosis of FH has important clinical implications with respect to lifelong risk of ASCVD and requirement for intensive pharmacological therapy. The concentration of baseline LDL-C (untreated) is essential for the diagnosis of FH but is often not available because the individual is already on statin therapy.
METHODS
To validate a new algorithm to impute baseline LDL-C, we examined 1297 patients. The baseline LDL-C was compared with the imputed baseline obtained within 18 months of the initiation of therapy. We compared the percent reduction in LDL-C on treatment from baseline with the published percent reductions.
RESULTS
After eliminating individuals with missing data, nonstandard doses of statins, or medications other than statins or ezetimibe, we provide data on 951 patients. The mean ± SE baseline LDL-C was 243.0 (2.2) mg/dL [6.28 (0.06) mmol/L], and the mean ± SE imputed baseline LDL-C was 244.2 (2.6) mg/dL [6.31 (0.07) mmol/L] (P = 0.48). There was no difference in response according to the patient's sex or in percent reduction between observed and expected for individual doses or types of statin or ezetimibe.
CONCLUSIONS
We provide a validated estimation of baseline LDL-C for patients with FH that may help clinicians in making a diagnosis.
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Affiliation(s)
- Isabelle Ruel
- Research Institute of the McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada
| | - Sumayah Aljenedil
- Research Institute of the McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada
| | - Iman Sadri
- Research Institute of the McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada
| | - Émilie de Varennes
- Research Institute of the McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada
| | - Robert A Hegele
- Departments of Medicine and Biochemistry, Schulich School of Medicine and Robarts Research Institute, Western University, London, ON, Canada
| | - Patrick Couture
- Lipid Research Centre, CHU de Québec-Université Laval, Quebec City, QC, Canada
| | - Jean Bergeron
- Lipid Research Centre, CHU de Québec-Université Laval, Quebec City, QC, Canada
| | - Eric Wanneh
- Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Alexis Baass
- Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
- Nutrition, Metabolism, and Atherosclerosis Clinic, Institut de recherches cliniques de Montréal, QC, Canada
- Division of Medical Biochemistry, Department of Medicine, McGill University, QC, Canada
| | - Robert Dufour
- Department of Nutrition, Université de Montréal, Montreal, QC, Canada
| | - Daniel Gaudet
- Lipidology Unit, Community Genomic Medicine Centre and ECOGENE-21, Department of Medicine, Université de Montréal, Saguenay, QC, Canada
| | - Diane Brisson
- Lipidology Unit, Community Genomic Medicine Centre and ECOGENE-21, Department of Medicine, Université de Montréal, Saguenay, QC, Canada
| | - Liam R Brunham
- Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, BC, Canada
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Centre for Heart Lung Innovation, Providence Health Care Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Gordon A Francis
- Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, BC, Canada
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
- Centre for Heart Lung Innovation, Providence Health Care Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Lubomira Cermakova
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - James M Brophy
- McGill University, Royal Victoria Hospital, Montreal, QC, Canada
| | - Arnold Ryomoto
- Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, BC, Canada
| | - G B John Mancini
- Department of Medicine, Division of Cardiology, University of British Columbia, Vancouver, BC, Canada
| | - Jacques Genest
- Research Institute of the McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada
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Ganjali S, Momtazi-Borojeni AA, Banach M, Kovanen PT, Gotto AM, Sahebkar A. HDL functionality in familial hypercholesterolemia: effects of treatment modalities and pharmacological interventions. Drug Discov Today 2018; 23:171-180. [DOI: 10.1016/j.drudis.2017.09.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 09/02/2017] [Accepted: 09/25/2017] [Indexed: 01/14/2023]
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Gupta N, Sharma N, Mathur SK, Chandra R, Nimesh S. Advancement in nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 46:188-197. [PMID: 29265888 DOI: 10.1080/21691401.2017.1417863] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Cardiovascular diseases have been the major cause of mortality and morbidity all over the world accounting for more than 80% of the deaths from heart attacks and strokes. Hypercholesterolemia, an autosomal disorder of lipoprotein metabolism is one of the foremost causes of CVDs. An increased level of low-density lipoprotein cholesterol (LDL-C) in the plasma results in the rise of incidence rates in disease patients. Several conventional and combinational therapies have been proposed for lowering the LDL-C levels in the blood. These therapeutic agents are designed to target some crucial molecules that participates in the lipid metabolism such as apolipoprotein B, HMGCoA reductase, proprotein convertase subtilisin/kexin 9, etc. Although these therapies are effective but are associated with certain side effects. This article presents an overview on different conventional and nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia. Numerous nanomaterial-based therapies including polymeric nanoparticles, cationic lipids, liposomes, dendrimers and inorganic nanoparticles have been discussed in lowering the cholesterol level along with recent advancement in diagnosis and imaging.
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Affiliation(s)
- Nidhi Gupta
- a Department of Biotechnology , The IIS University , Jaipur , India
| | - Nikita Sharma
- b Department of Biotechnology , Central University of Rajasthan , Ajmer , India
| | - Sandeep K Mathur
- c Department of Endocrinology , SMS Medical College and Hospitals , Jaipur , India
| | - Ramesh Chandra
- d Department of Chemistry , University of Delhi , Delhi , India
| | - Surendra Nimesh
- b Department of Biotechnology , Central University of Rajasthan , Ajmer , India
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DeBeasi LC. Optimizing Diet, Weight, and Exercise in Adults With Familial Hypercholesterolemia. J Nurse Pract 2017. [DOI: 10.1016/j.nurpra.2017.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Akioyamen LE, Genest J, Shan SD, Reel RL, Albaum JM, Chu A, Tu JV. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open 2017; 7:e016461. [PMID: 28864697 PMCID: PMC5588988 DOI: 10.1136/bmjopen-2017-016461] [Citation(s) in RCA: 234] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Heterozygous familial hypercholesterolaemia (FH) confers a significant risk for premature cardiovascular disease (CVD). However, the estimated prevalence of FH varies substantially among studies. We aimed to provide a summary estimate of FH prevalence in the general population and assess variations in frequency across different sociodemographic characteristics. SETTING, PARTICIPANTS AND OUTCOME MEASURES We searched MEDLINE, EMBASE, Global Health, the Cochrane Library, PsycINFO and PubMed for peer-reviewed literature using validated strategies. Results were limited to studies published in English between January 1990 and January 2017. Studies were eligible if they determined FH prevalence using clinical criteria or DNA-based analyses. We determined a pooled point prevalence of FH in adults and children and assessed the variation of the pooled frequency by age, sex, geographical location, diagnostic method, study quality and year of publication. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were investigated through subgroups, meta-regression and sensitivity analyses. RESULTS The pooled prevalence of FH from 19 studies including 2 458 456 unique individuals was 0.40% (95% CI 0.29% to 0.52%) which corresponds to a frequency of 1 in 250 individuals. FH prevalence was found to vary by age and geographical location but not by any other covariates. Results were consistent in sensitivity analyses. CONCLUSIONS Our systematic review suggests that FH is a common disorder, affecting 1 in 250 individuals. These findings underscore the need for early detection and management to decrease CVD risk.
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Affiliation(s)
- Leo E Akioyamen
- Faculty of Medicine, University of Toronto, Toronto, Canada
- Institute for Clinical Evaluative Sciences, Toronto, Canada
| | - Jacques Genest
- Faculty of Medicine, McGill University, Montreal, Canada
- MGill University Health Centre, Royal Victoria Hospital, Montreal, Canada
| | - Shubham D Shan
- Faculty of Medicine, University of Toronto, Toronto, Canada
- Institute for Clinical Evaluative Sciences, Toronto, Canada
| | - Rachel L Reel
- Faculty of Medicine, University of Toronto, Toronto, Canada
| | | | - Anna Chu
- Faculty of Medicine, University of Toronto, Toronto, Canada
- Institute for Clinical Evaluative Sciences, Toronto, Canada
| | - Jack V Tu
- Faculty of Medicine, University of Toronto, Toronto, Canada
- Institute for Clinical Evaluative Sciences, Toronto, Canada
- Schulich Heart Centre, Sunnybrook Health Sciences Centre, Toronto, Canada
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Ganjali S, Momtazi AA, Banach M, Kovanen PT, Stein EA, Sahebkar A. HDL abnormalities in familial hypercholesterolemia: Focus on biological functions. Prog Lipid Res 2017; 67:16-26. [DOI: 10.1016/j.plipres.2017.05.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 04/25/2017] [Accepted: 05/10/2017] [Indexed: 02/07/2023]
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Villa G, Wong B, Kutikova L, Ray KK, Mata P, Bruckert E. Prediction of cardiovascular risk in patients with familial hypercholesterolaemia. EUROPEAN HEART JOURNAL. QUALITY OF CARE & CLINICAL OUTCOMES 2017; 3:274-280. [DOI: 10.1093/ehjqcco/qcx011] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 05/28/2017] [Indexed: 01/10/2023]
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Li S, Wu NQ, Zhu CG, Zhang Y, Guo YL, Gao Y, Li XL, Qing P, Cui CJ, Xu RX, Sun J, Liu G, Dong Q, Li JJ. Significance of lipoprotein(a) levels in familial hypercholesterolemia and coronary artery disease. Atherosclerosis 2017; 260:67-74. [PMID: 28351002 DOI: 10.1016/j.atherosclerosis.2017.03.021] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 03/09/2017] [Accepted: 03/16/2017] [Indexed: 11/24/2022]
Abstract
BACKGROUND AND AIMS Patients with familial hypercholesterolemia (FH) are often characterized by premature coronary artery disease (CAD) with heterogeneity at onset. The aim of the present study was to investigate the associations of lipoprotein (a) [Lp(a)] with the FH phenotype, genotype and roles of Lp(a) in determining CAD risk among patients with and without FH. METHODS We enrolled 8050 patients undergoing coronary angiography, from our Lipid clinic. Clinical FH was diagnosed using the Dutch Lipid Clinic Network criteria. Mutational analysis (LDLR, APOB, PCSK9) in definite/probable FH was performed by target exome sequencing. RESULTS Lp(a) levels were increased, with a clinical FH diagnosis (unlikely, possible, definite/probable FH) independent of the patients status, with Lp(a)-hyperlipoproteinemia [Lp(a)-HLP] (median 517.70 vs. 570.98 vs. 604.65 mg/L, p < 0.001) or without (median 89.20 vs. 99.20 vs. 133.67 mg/L, p < 0.001). Patients with Lp(a)-HLP had a higher prevalence of definite/probable FH than those without (6.1% vs. 2.4%, p < 0.05). However, no significant difference in Lp(a) was observed in patients with definite/probable FH phenotype carrying LDLR or LDLR-independent (APOB, PCSK9) or neither mutations (p > 0.05). Multivariate analysis showed that Lp(a) and FH phenotype were both significant determinants in predicting the early onset and severity of CAD. Subsequently, patients with Lp(a)-HLP in definite/probable FH increased significantly the CAD risk (all p < 0.05). CONCLUSIONS Lp(a) levels were higher in patients with FH phenotype than in those without, but no difference were found in FH patients of different mutated backgrounds. Moreover, Lp(a) and FH played a synergistic role in predicting the early onset and severity of CAD.
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Affiliation(s)
- Sha Li
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Na-Qiong Wu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Cheng-Gang Zhu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Yan Zhang
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Yuan-Lin Guo
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Ying Gao
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Xiao-Lin Li
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Ping Qing
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Chuan-Jue Cui
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Rui-Xia Xu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Jing Sun
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Geng Liu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Qian Dong
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Jian-Jun Li
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China.
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Zhu CG, Li S, Wang ZF, Yin KL, Wu NQ, Guo YL, Gao Y, Li XL, Qing P, Liu G, Dong Q, Zhou Z, Li JJ. Homozygous familiar hypercholesterolemia in China: Case series from the national lipid clinics and literature review. IJC METABOLIC & ENDOCRINE 2017; 14:75-80. [DOI: 10.1016/j.ijcme.2017.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
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Du R, Fan LL, Lin MJ, He ZJ, Huang H, Chen YQ, Li JJ, Xia K, Zhao SP, Xiang R. Mutation detection in Chinese patients with familial hypercholesterolemia. SPRINGERPLUS 2016; 5:2095. [PMID: 28028493 PMCID: PMC5153400 DOI: 10.1186/s40064-016-3763-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 11/30/2016] [Indexed: 12/24/2022]
Abstract
Background Familial hypercholesterolemia (FH) is the first molecularly and clinically characterized genetic disease of lipid metabolism. It is an autosomal dominant disorder with significantly elevated levels of total cholesterol and low density of lipoprotein cholesterol in serum, which would lead to extensive xanthomas and premature coronary heart disease. Mutations in low density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 and Apo lipoprotein B-100 (APOB) have been identified to be the underlying cause of this disease. Methods Genetic testing and reports of the mutations in the Chinese population are still limited. In this study, 11 unrelated Chinese FH families were enrolled to detect the candidate gene variants by DNA direct sequencing. Results and conclusion We identified 12 mutations (11 in LDLR and one in APOB) in ten FH families. Three novel LDLR mutations (c.516C>A/p.D172E, c.1720C>A/p.R574S and c.760C>T/p.Q254X) were identified and co-segregated with the affected individuals in the families. Our discoveries not only further supports the significant role of LDLR in FH, but also expands the spectrum of LDLR mutations. These new insights will contribute to the genetic diagnosis and counseling of FH patients.
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Affiliation(s)
- Ran Du
- The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410013 China
| | - Liang-Liang Fan
- The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410013 China
| | - Min-Jie Lin
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011 China
| | - Zhi-Jian He
- The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410013 China
| | - Hao Huang
- The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410013 China
| | - Ya-Qin Chen
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011 China
| | - Jing-Jing Li
- The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410013 China
| | - Kun Xia
- The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410013 China
| | - Shui-Ping Zhao
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011 China
| | - Rong Xiang
- The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410013 China ; Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011 China
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Mehta R, Zubirán R, Martagón AJ, Vazquez-Cárdenas A, Segura-Kato Y, Tusié-Luna MT, Aguilar-Salinas CA. The panorama of familial hypercholesterolemia in Latin America: a systematic review. J Lipid Res 2016; 57:2115-2129. [PMID: 27777316 PMCID: PMC5321217 DOI: 10.1194/jlr.r072231] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Revised: 10/23/2016] [Indexed: 11/20/2022] Open
Abstract
The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified.
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Affiliation(s)
- Roopa Mehta
- Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - Rafael Zubirán
- Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | | | | | - Yayoi Segura-Kato
- Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico; Unidad de Biología Molecular y Medicina Genómica Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - María Teresa Tusié-Luna
- Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico; Unidad de Biología Molecular y Medicina Genómica Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Carlos A Aguilar-Salinas
- Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico.
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Mendelson MM, Regh T, Chan J, Baker A, Ryan HH, Palumbo N, Johnson PK, Griggs S, Boghani M, Desai NK, Yellen E, Buckley L, Gillman MW, Zachariah JP, Graham D, de Ferranti SD. Correlates of Achieving Statin Therapy Goals in Children and Adolescents with Dyslipidemia. J Pediatr 2016; 178:149-155.e9. [PMID: 27592099 PMCID: PMC5085848 DOI: 10.1016/j.jpeds.2016.08.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 06/30/2016] [Accepted: 08/02/2016] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To determine the real-world effectiveness of statins and impact of baseline factors on low-density lipoprotein cholesterol (LDL-C) reduction among children and adolescents. STUDY DESIGN We analyzed data prospectively collected from a quality improvement initiative in the Boston Children's Hospital Preventive Cardiology Program. We included patients ≤21 years of age initiated on statins between September 2010 and March 2014. The primary outcome was first achieving goal LDL-C, defined as <130 mg/dL, or <100 mg/dL with high-level risk factors (eg, diabetes, etc). Cox proportional hazards models were used to assess the impact of baseline clinical and lifestyle factors. RESULTS Among the 1521 pediatric patients evaluated in 3813 clinical encounters over 3.5 years, 97 patients (6.3%) were started on statin therapy and had follow-up data (median age 14 [IQR 7] years, 54% were female, and 24% obese, 62% with at least one lifestyle risk factor). The median baseline LDL-C was 215 (IQR 78) mg/dL, and median follow-up after starting statin was 1 (IQR 1.3) year. The cumulative probability of achieving LDL-C goal within 1 year was 60% (95% CI 47-69). A lower probability of achieving LDL-C goals was associated with male sex (HR 0.5 [95% CI 0.3-0.8]) and higher baseline LDL-C (HR 0.92 [95% CI 0.87-0.98] per 10 mg/dL), but not age, body mass index percentile, lifestyle factors, or family history. CONCLUSIONS The majority of pediatric patients started on statins reached LDL-C treatment goals within 1 year. Male patients and those with greater baseline LDL-C were less likely to be successful and may require increased support.
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Affiliation(s)
- Michael M Mendelson
- Department of Cardiology, Boston Children's Hospital, Boston, MA; Boston University School of Medicine, Boston University, Boston, MA.
| | - Todd Regh
- Institute for Relevant Clinical Data Analytics (IRCDA), Boston Children's Hospital, Boston, MA
| | - James Chan
- Institute for Relevant Clinical Data Analytics (IRCDA), Boston Children's Hospital, Boston, MA
| | - Annette Baker
- Department of Cardiology, Boston Children's Hospital, Boston, MA
| | | | - Nicole Palumbo
- Department of Cardiology, Boston Children's Hospital, Boston, MA
| | - Philip K Johnson
- Department of Cardiology, Boston Children's Hospital, Boston, MA
| | - Suzanne Griggs
- Department of Cardiology, Boston Children's Hospital, Boston, MA
| | - Meera Boghani
- Department of Cardiology, Boston Children's Hospital, Boston, MA; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA
| | - Nirav K Desai
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA
| | - Elizabeth Yellen
- Department of Cardiology, Boston Children's Hospital, Boston, MA; Boston University School of Medicine, Boston University, Boston, MA
| | - Lucy Buckley
- Department of Cardiology, Boston Children's Hospital, Boston, MA
| | - Matthew W Gillman
- Department of Cardiology, Boston Children's Hospital, Boston, MA; Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care, Boston, MA
| | | | - Dionne Graham
- Institute for Relevant Clinical Data Analytics (IRCDA), Boston Children's Hospital, Boston, MA
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Nemes K, Åberg F, Gylling H, Isoniemi H. Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications. World J Hepatol 2016; 8:924-932. [PMID: 27574546 PMCID: PMC4976211 DOI: 10.4254/wjh.v8.i22.924] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/07/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open
Abstract
The aim of this review is to enlighten the critical roles that the liver plays in cholesterol metabolism. Liver transplantation can serve as gene therapy or a source of gene transmission in certain conditions that affect cholesterol metabolism, such as low-density-lipoprotein (LDL) receptor gene mutations that are associated with familial hypercholesterolemia. On the other hand, cholestatic liver disease often alters cholesterol metabolism. Cholestasis can lead to formation of lipoprotein X (Lp-X), which is frequently mistaken for LDL on routine clinical tests. In contrast to LDL, Lp-X is non-atherogenic, and failure to differentiate between the two can interfere with cardiovascular risk assessment, potentially leading to prescription of futile lipid-lowering therapy. Statins do not effectively lower Lp-X levels, and cholestasis may lead to accumulation of toxic levels of statins. Moreover, severe cholestasis results in poor micellar formation, which reduces cholesterol absorption, potentially impairing the cholesterol-lowering effect of ezetimibe. Apolipoprotein B-100 measurement can help distinguish between atherogenic and non-atherogenic hypercholesterolemia. Furthermore, routine serum cholesterol measurements alone cannot reflect cholesterol absorption and synthesis. Measurements of serum non-cholesterol sterol biomarkers - such as cholesterol precursor sterols, plant sterols, and cholestanol - may help with the comprehensive assessment of cholesterol metabolism. An adequate cholesterol supply is essential for liver-regenerative capacity. Low preoperative and perioperative serum cholesterol levels seem to predict mortality in liver cirrhosis and after liver transplantation. Thus, accurate lipid profile evaluation is highly important in liver disease and after liver transplantation.
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Wong B, Kruse G, Kutikova L, Ray KK, Mata P, Bruckert E. Cardiovascular Disease Risk Associated With Familial Hypercholesterolemia: A Systematic Review of the Literature. Clin Ther 2016; 38:1696-709. [DOI: 10.1016/j.clinthera.2016.05.006] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 04/14/2016] [Accepted: 05/10/2016] [Indexed: 12/26/2022]
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Renner C, Connor WE, Steiner RD. Sitosterolemia Presenting as Pseudohomozygous Familial Hypercholesterolemia. Clin Med Res 2016; 14:103-8. [PMID: 27231115 PMCID: PMC5321287 DOI: 10.3121/cmr.2016.1294] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 02/05/2016] [Indexed: 12/30/2022]
Abstract
A young girl, age 8.5 years, presented with profound hypercholesterolemia and early xanthomatosis, suggesting homozygous familial (or type II) hypercholesterolemia. The patient's low density lipoprotein (LDL) receptor function and parental lipoprotein profiles were determined to be normal, prompting revision of the initial diagnosis to pseudohomozygous familial hypercholesterolemia. When she subsequently presented with giant platelets, the case was presented to colleagues on an electronic mailing list. It was recommended that plasma and sterol analysis be performed, which led to a diagnosis of sitosterolemia. The presentation of profound hypercholesterolomia in childhood that ultimately is not attributed as due to homozygous or compound heterozygous defects in the LDL receptor gene has been termed pseudohomozygous familial (or type II) hypercholesterolemia (PHT2HC). Patients diagnosed with PHT2HC subsequently confirmed to have sitosterolemia have been previously reported only rarely. The challenge of achieving accurate specific diagnosis and appropriate workup for these conditions in children is discussed in the context of this rare case and review of the historical literature concerning these conditions.
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Affiliation(s)
- Christian Renner
- Kinder und Jugendart Praxis, Pfleggasse 31, D-94469 Deggendorf, Germany
| | - William E Connor
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Robert D Steiner
- Department of Pediatrics and Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA Marshfield Clinic Research Foundation, Marshfield, USA
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Lückhoff HK, Kidd M, van Rensburg SJ, van Velden DP, Kotze MJ. Apolipoprotein E genotyping and questionnaire-based assessment of lifestyle risk factors in dyslipidemic patients with a family history of Alzheimer's disease: test development for clinical application. Metab Brain Dis 2016; 31:213-24. [PMID: 26481640 DOI: 10.1007/s11011-015-9737-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 09/21/2015] [Indexed: 01/14/2023]
Abstract
The cholesterol-raising properties of the apolipoprotein E (APOE) epsilon-4 (ε-4) allele has been validated in the South African population. Mounting evidence supports the added value of APOE genotyping for the evaluation of cardiovascular risk in dyslipidemic patients beyond its established role in the diagnosis of late-onset Alzheimer's disease (AD). The aim of this study was to determine the potential benefits of combining AD family history with questionnaire-based lifestyle assessment to facilitate the clinical interpretation of APOE genotyping results. A total of 580 unrelated South African individuals prospectively enrolled in a chronic disease screening program incorporating a genetic component (2010-2015) was selected for inclusion in this study based on the presence (75) or absence (505) of AD family history. Biochemical assessment of their lipid profiles was performed according to standard laboratory protocols. All study participants were genotyped for the APOE ε-2/ε-3/ε-4 alleles using allele-specific TaqMan real-time polymerase chain reaction technology. In patients without a family history of AD, APOE genotype modified the relationship between alcohol intake and body mass index (p = 0.026), with a significant positive correlation noted between these parameters being limited to ε-4 allele carriers. APOE genotype also modified the association between alcohol intake and total serum cholesterol in patients with a positive family history of AD (p = 0.026). We demonstrated the benefits of a questionnaire-based approach for assessment of lifestyle risk factors to facilitate clinical interpretation of APOE genotyping results for targeted intervention in a genetic subgroup of dyslipidemic patients at increased risk for AD.
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Abstract
PURPOSE OF REVIEW For the past 40 years, apheresis, in particular, lipoprotein apheresis, has been the therapy of choice to lower LDL-C for familial hypercholesterolemia patients with uncontrolled dyslipidemia and cardiovascular disease. With the advent of recent and future lipid-modifying agents and their ability to lower LDL-C, the question arises on what will be the future of lipoprotein apheresis. RECENT FINDINGS Lipoprotein apheresis lowers not only plasma levels of apolipoprotein B lipoproteins but also markers of vascular inflammation and blood rheology. Other vascular diseases, not necessarily associated with familial hypercholesterolemia, such as nephrotic syndrome and peripheral arterial disease have profited from lipoprotein apheresis therapy. In 2013, the Food and Drug Administration approved lipoprotein apheresis therapy for patients with focal segmental glomerulosclerosis. Since 2010, the German healthcare ministry has approved lipoprotein apheresis therapy for patients with an elevated lipoprotein(a) and ongoing cardiovascular disease irrespective of LDL-C levels. SUMMARY Recent and future lipid-modifying therapies will most likely reduce the practice of lipoprotein apheresis therapy for familial hypercholesterolemia patients. Future implications for lipoprotein apheresis will involve vascular diseases that are at present lacking clinically effective therapy, whereas acute and chronic reductions of lipids, vascular inflammation, and/or rheology may improve the clinical outcome.
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Affiliation(s)
- Patrick M Moriarty
- Atherosclerosis and Lipoprotein Apheresis Center, University of Kansas Medical Center, Kansas City, Kansas
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