Rare and Deleterious Mutations in ABCG5/ABCG8 Genes Contribute to Mimicking and Worsening of Familial Hypercholesterolemia Phenotype

Tada, Hayato; Okada, Hirofumi; Nomura, Akihiro; Yashiro, Satoshi; Nohara, Atsushi; Ishigaki, Yasushi; Takamura, Masayuki; Kawashiri, Masa‐aki

doi:10.1253/circj.cj-19-0317

Cited by 58 publications

(56 citation statements)

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“…We expect to see that a portion of the clinical-FH patients have sitosterolemia and/or are carriers of the ABCG5 or ABCG8 gene mutation who have different aetiology as well as different prognosis from true FH. 19 Finally, this study will provide insights into the importance of clinical and genetic diagnosis of FH with extremely high cardiovascular risk.…”

Section: Discussionmentioning

confidence: 95%

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design

et al. 2020

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IntroductionFamilial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries. On the other hand, few data—and in particular multicentre data—exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds.Methods and analysisThe Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies.Ethics and disseminationThis study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal.Trial registration numberUMIN000038210.

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Section: Discussionmentioning

confidence: 95%

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design

et al. 2020

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“…We are now conducting a randomized, waiting list-controlled, open-label study to see if genetic testing and disclosure of the results will lead to a better prognosis 37) . Some patients with FH have additional rare mutations associated with LDL cholesterol elevation 38) . We have called this condition oligogenic FH; these patients have significantly higher LDL cholesterol levels than patients with pure monogenic FH (Fig.…”

Section: Fh As the Primary Model Of Precision Medicine For Ascvdmentioning

confidence: 99%

Challenges of Precision Medicine for Atherosclerotic Cardiovascular Disease Based on Human Genome Information

Tada

Usui

Sakata

et al. 2021

JAT

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The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Review Precision or personalized medicine is currently gaining a lot of attention. Clinical evidence for its effectiveness has been established based on randomized clinical trials accounting for classical risk factors, such as hypertension, diabetes, and serum lipids. However, besides such classical risk factors, the genetic background should be considered, at least for heritable traits, including atherosclerotic cardiovascular disease (ASCVD). Such classical risk factors are almost always incidents that have already occurred in which it may be too late to start treatment, instead of indicators of presymptomatic state. Human genome information is associated with most traits, including ASCVD. Two methods of implementing precision medicine for ASCVD using human genome information are currently being investigated: the use of rare genetic variations that have large effect sizes and polygenic risk scores that are composed of multiple common genetic variations. This review article emphasizes the importance of clinical as well as genetic diagnoses when implementing precision medicine. Precision medicine should be considered based on comprehensive genetic analyses, encompassing rare to common genetic variations. is strongly associated with premature ASCVD 4). A single loss-of-function genetic mutation in the LDL receptor gene is associated with ASCVD via elevation of LDL cholesterol because LDL cholesterol is one of the causal factors of ASCVD 5). However, there are a substantial number of people who are at extremely high risk for inherited ASCVD that is not associated with serum lipids. Causal links between biology and ASCVD development in such inherited risk factors exist. Aim The following review describes conditions beginning with FH in which precision medicine for ASCVD seems to be quite effective, to other conditions in which precision medicine for ASCVD is currently being rigorously examined.

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“…Accepted for publication: June 10, 2020 Published online: August 6, 2020 sterols and contributed to the development of the FH phenotype, leading to the misdiagnosis of FH in some sitosterolemia patients 30,31 . Tada et al had shown that there were substantial proportion of the patients with hypercholesterolemia caused by ABCG5 genetic mutation(s), and they suggested that rare mutations in ABCG5 may, at least in some patients, mimic FH or exacerbate the FH phenotype 32) . Furthermore, previous study revealed that patients with APOE mutations also had the same phenotype as that of FH patients 33) .…”

Section: Advance Publication Journal Of Atherosclerosis and Thrombosismentioning

confidence: 99%

Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia

Wang

Yang

Liu

et al. 2020

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The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Original Article Aim: Familial hypercholesterolemia (FH) is the most commonly encountered genetic condition that predisposes individuals to severe autosomal dominant lipid metabolism dysfunction. Although more than 75% of the European population has been scrutinized for FH-causing mutations, the genetic diagnosis proportion among Chinese people remains very low (less than 0.5%). The aim of this study was to identify genetic mutations and help make a precise diagnosis in Chinese FH patients. Methods: We designed a gene panel containing 20 genes responsible for FH and tested 208 unrelated Chinese possible/probable or definite FH probands. In addition, we called LDLR copy number variation (CNVs) with the panel data by panelcn.MOPS, and multiple ligation-dependent probe amplification (MLPA) was used to search for CNVs in LDLR, APOB, and PCSK9. Results: A total of 79 probands (38.0%) tested positive for a (likely) pathogenic mutation, most of which were LDLR mutations, and three LDLR CNVs called from the panel data were all successfully confirmed by MLPA analysis. In total, 48 different mutations were identified, including 45 LDLR mutations, 1 APOB mutation, 1 ABCG5 mutation, and 1 APOE mutation. Among them, the five most frequent mutations (LDLR c.1879G A, c.1747C T, c.313 1G A, c.400T C, and APOB c.10579C T) were detected. Moreover, we also found that patients with LDLR variants of CNVs and splicing and nonsense had increased low-density lipoprotein cholesterol levels when compared with those who carried missense variants. Conclusions: The spectrum of FH-causing mutations in the Chinese population is refined and expanded. Analyses of FH causal genes have been a great help in clinical diagnosis and have deep implications in disease treatment. These data can serve as a considerable dataset for next-generation sequencing analysis of the Chinese population with FH and contribute to the genetic diagnosis and counseling of FH patients. as 1 in 200-500 3) , with even higher frequencies in populations with founder effects 4). FH is also the first genetic disorder shown to cause myocardial infarction 5) , leading to premature heart disease and death in affected individuals. If untreated, men have a 50% chance of coronary heart disease before the age of 50 years, and women have a 30% risk by the age of 60 years 6, 7). Most FH cases are caused by mutations in three Copyright©2020 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

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Rare and Deleterious Mutations in ABCG5/ABCG8 Genes Contribute to Mimicking and Worsening of Familial Hypercholesterolemia Phenotype

Cited by 58 publications

References 20 publications

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design

Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design

Challenges of Precision Medicine for Atherosclerotic Cardiovascular Disease Based on Human Genome Information

Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia

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