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A Low-Frequency APOB p.(Pro955Ser) Variant Contributes to the Severity of/Variability in Familial Hypercholesterolemia 査読有り

Hori Mika, Takahashi Atsushi, Hosoda Kiminori, Ogura Masatsune, Harada-Shiba Mariko

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 108 巻 ( 2 ) 頁： 422 - 432 2023年1月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：The Journal of clinical endocrinology and metabolism

CONTEXT: Heterozygous familial hypercholesterolemia (HeFH) is caused by a rare pathogenic variant in the LDLR, APOB, and PCSK9 genes. However, the causative variants in these genes have not been identified in approximately 40% of HeFH patients. OBJECTIVE: Our aim was to identify novel (or additional) genes/variants that contribute to HeFH. METHODS: Whole-exome sequencing was performed for 215 family members from 122 families with HeFH without pathogenic variants in the LDLR or PCSK9 genes. RESULTS: We could not find novel causative familial hypercholesterolemia (FH) genes/variants by family analysis. Next, we examined all APOB variants. Twenty-four nonsynonymous APOB variants were identified. The allele frequencies of the c.2863C > T:p.(Pro955Ser) variant in the HeFH probands and the general Japanese population were 0.15 and 0.034, respectively [odds ratio 4.9 (95% CI 3.4-7.1); P = 6.9 × 10-13]. The patients harboring the c.2863C > T:p.(Pro955Ser) variant accounted for 9.8% (n = 63) of unrelated patients with HeFH (n = 645). The penetrance of the c.2863C > T:p.(Pro955Ser) variant was low in the pedigree-based genetic analysis. In an in vitro assay, low-density lipoprotein (LDL) uptake from patients with the homozygous c.2863C > T:p.(Pro955Ser) variant was 44% of the LDL uptake from control subjects, and it was similar to that of the LDL uptake from patients with the known pathogenic heterozygous p.(Arg3527Gln) variant. CONCLUSIONS: The low-frequency APOB c.2863C > T:p.(Pro955Ser) variant is not an FH-causative variant, but it has a moderate effect size in HeFH. These findings suggest that the combination of the APOB c.2863C > T:p.(Pro955Ser) variant and age, environmental factors, or other genetic factors contributes to the severity of or variability in the HeFH phenotype.

DOI： 10.1210/clinem/dgac572

Web of Science

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PubMed

The impact of gene variants on the thickness and softness of the Achilles tendon in familial hypercholesterolemia. 査読有り

Michikura M, Hori M, Ogura M, Hosoda K, Harada-Shiba M

Atherosclerosis 358 巻頁： 41 - 46 2022年10月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Atherosclerosis

Background and aims: Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL)-cholesterol, xanthoma of the Achilles tendon (AT), and premature coronary artery disease (CAD). Ultrasonography can assess AT thickness and softness, making it useful for evaluating AT in FH diagnosis. We aimed to clarify whether FH-causative LDLR or PCSK9 variants affect AT thickness or softness. Methods: In total, 248 FH and 60 non-familial hypercholesterolemia (non-FH) patients (total: 308) aged ≥30 years were enrolled. Patients with FH were classified according to genotype. AT thickness and elasticity index (EI) as softness were measured by ultrasonography. Results: In FH patients with LDLR variants, AT was significantly thicker and softer than it was in FH patients with PCSK9 variants, FH patients without LDLR or PCSK9 variants, and patients with non-FH. The proportion of patients harboring LDLR variants significantly increased with AT thickness (p = 2.0 × 10−31) and softness (p = 1.4 × 10−18). Among those with AT thickness>8.5 mm and EI < 3.9, patients with LDLR variants accounted for 89% and 83%, respectively. The odds of AT thickening, AT softening and CAD increased 13.3-fold, 4.9-fold, and 2.1-fold, adjusted for the LDL-C year score by the presence of LDLR variants compared with those of patients without LDLR or PCSK9 variants. PCSK9 variants did not influence AT thickening or softening or CAD prevalence. Conclusions: LDLR variants affected AT thickness and softness independent of the LDL-C year score, but PCSK9 variants did not. Evaluating AT is important for identifying FH patients with LDLR variants at high risk for CAD.

DOI： 10.1016/j.atherosclerosis.2022.08.014

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PubMed

Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. 査読有り

Hori M, Ohta N, Takahashi A, Masuda H, Isoda R, Yamamoto S, Son C, Ogura M, Hosoda K, Miyamoto Y, Harada-Shiba M

Atherosclerosis 289 巻頁： 101-108 2019年10月

Humoral factors secreted from adipose tissue-derived mesenchymal stem cells ameliorate atherosclerosis in Ldlr-/- mice. 査読有り

Takafuji Y, Hori M, Mizuno T, Harada-Shiba M

Cardiovascular research 115 巻 ( 6 ) 頁： 1041-1051 2019年5月

Proprotein convertase subtilisin/kexin 9 V4I variant with LDLR mutations modifies the phenotype of familial hypercholesterolemia. 査読有り

Ohta N, Hori M, Takahashi A, Ogura M, Makino H, Tamanaha T, Fujiyama H, Miyamoto Y, Harada-Shiba M

Journal of clinical lipidology 10 巻 ( 3 ) 頁： 547 - 555.e5 2016年5月

Removal of plasma mature and furin-cleaved proprotein convertase subtilisin/kexin 9 by low-density lipoprotein-apheresis in familial hypercholesterolemia: development and application of a new assay for PCSK9. 査読有り

Hori M, Ishihara M, Yuasa Y, Makino H, Yanagi K, Tamanaha T, Kishimoto I, Kujiraoka T, Hattori H, Harada-Shiba M

The Journal of clinical endocrinology and metabolism 100 巻 ( 1 ) 頁： E41 - 9 2015年1月

Association of Achilles Tendon Thickness with Lipid Profile and Carotid IMT in Patients with Familial Hypercholesterolemia 査読有り

Michikura M, Ogura M, Hori M, Matsuki K, Makino H, Fujioka S, Shishikura D, Hoshiga M, Harada-Shiba M:

Atherosclerosis 2025年3月

[Mechanism of the Molecular Pathophysiology for Familial Hypercholesterolemia]. 招待有り査読有り Open Access

Hori M

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 145 巻 ( 3 ) 頁： 195 - 200 2025年3月

担当区分：筆頭著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Yakugaku Zasshi

Familial hypercholesterolemia (FH) is characterized by high serum low-density lipoprotein cholesterol (LDL-C) levels from birth, tendon/skin xanthomas, and premature coronary artery disease. The prevalence of FH is 1 per 300 individuals in the general population. FH is caused by a pathogenic (rare) variant in the LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. In Japan, there has been only one reported case of a family with FH caused by the known APOB p.(Arg3527Gln) variant. Those without pathogenic variants in the LDLR or PCSK9 genes account for approximately 36% of patients with FH. Novel causative genes/variants of FH have been explored in patients with FH worldwide, but no gene variants with a large effect size have been found. Polygenic hypercholesterolemia accounts for approximately 10% of patients with clinical FH. We performed whole-exome sequencing in 122 families without pathogenic variants in the LDLR and PCSK9 genes. However, we could not find novel causative genes/variants of FH via family analysis. We examined all the APOB variants and showed that the low-frequency APOB p.(Pro955Ser) variant has a moderate effect size in FH patients via functional analysis of hepatocytes. We also reported that low-frequency PCSK9 variants contribute to the severity of the FH phenotype in patients with FH harboring an LDLR pathogenic variant. Thus, the combination of low-frequency variants and age, environmental factors such as diet, or other genetic factors contribute to the severity of or variability in the FH phenotype.

DOI： 10.1248/yakushi.24-00177-5

Superoxide dismutase 2 deficiency in mesenchymal stromal cells induces sympathetic denervation and functional impairment of brown adipose tissue. 査読有り

Urano Y, Mii S, Asai S, Esaki N, Ando R, Shiraki Y, Iida T, Kato K, Hori M, Hayashi Y, Shimizu T, Enomoto A

Pathology international 75 巻 ( 2 ) 頁： 69 - 81 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pathology International

Brown adipose tissue (BAT) is an energy-consuming organ, and its functional dysregulation contributes to the development of metabolic diseases and obesity. BAT function is regulated by the sympathetic nervous system but declines with age, which is partly caused by reduced sympathetic nerve fibers innervating BAT. Thus far, the role of mesenchymal stromal/stem cells in age-related BAT dysfunction remains unknown. Here, we show that BAT dysfunction may be induced by a defect in the antioxidant capacity of stromal cells that localize in and around the nerve fibers (perineurial cells) of BAT. These cells express Meflin, a marker of mesenchymal stromal/stem cells. Specific deletion of the antioxidant enzyme superoxide dismutase 2 in Meflin-lineage cells caused sympathetic denervation and whitening of BAT and its functional impairment, as exemplified by a decline in the fat oxidation rate during the daytime. This phenotype was accompanied by overexpression of the neurorepulsive factor semaphorin 3A in perineurial cells. Notably, Meflin-deficient mice exhibited resistance to doxorubicin-induced BAT dysfunction. These results highlight the role of Meflin+ stromal cells, including perineurial cells, in maintaining BAT function and suggest that targeting BAT stromal cells provides a new avenue for improving BAT function.

DOI： 10.1111/pin.13503

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PubMed

Asymptomatic Intracranial Artery Stenosis/Occlusion in Heterozygous Familial Hypercholesterolemia: Its Frequency and Implications for Cerebrovascular and Cardiovascular Events. 査読有り国際誌

Funabashi S, Kataoka Y, Hori M, Ogura M, Doi T, Morita Y, Kiyoshige E, Nishimura K, Noguchi T, Harada-Shiba M

Journal of the American Heart Association 13 巻 ( 15 ) 頁： e033972 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of the American Heart Association

BACKGROUND: The atherogenic characteristics of heterozygous familial hypercholesterolemia (HeFH) increase the risk of premature atherosclerotic cardiovascular disease including not only coronary artery disease but ischemic stroke. Asymptomatic intracranial artery stenosis/occlusion (IASO) is a major cause of ischemic stroke, but it has not yet been fully characterized in patients with HeFH. METHODS AND RESULTS: This study analyzed 147 clinically diagnosed subjects with HeFH who underwent magnetic resonance imaging/magnetic resonance angiography imaging for evaluation of IASO (≥50% diameter stenosis). Major adverse cerebrovascular and cardiovascular events (cardiac death, ischemic stroke, and acute coronary syndrome) were compared in patients with HeFH with and without asymptomatic IASO. Asymptomatic IASO was observed in 13.6% of patients with HeFH. The untreated low-density lipoprotein cholesterol level (240±95 versus 244±75 mg/dL; P=0.67) did not differ between the 2 groups. Despite the use of lipid-lowering therapies (statin, P=0.71; high-intensity statin, P=0.81; ezetimibe, P=0.33; proprotein convertase subxilisin/kexin type 9 inhibitor, P=0.39; low-density lipoprotein apheresis, P=0.14), on-treatment low-density lipoprotein cholesterol level in patients with both HeFH and IASO was still suboptimally controlled (97±62 versus 105±50 mg/ dL; P=0.17), accompanied by a higher triglyceride level (median, 109 versus 79 mg/dL; P=0.001). During the 12.4-year observational period (interquartile range, 6.2-24.6 years), asymptomatic IASO exhibited a 4.04-fold greater likelihood of experiencing a major adverse cardiovascular event (95% CI, 1.71-9.55; P=0.001) in patients with HeFH. This increased risk of a major adverse cardiovascular event was consistently observed in a multivariate Cox proportional hazards model adjusting clinical characteristics (hazard ratio, 4.32 [95% CI, 1.71-10.9]; P=0.002). CONCLUSIONS: A total of 13.6% of Japanese subjects with HeFH presented with asymptomatic IASO. Despite lipid-lowering therapies, patients with both HeFH and IASO more likely had elevated risk of cerebrovascular and cardiovascular events. Our findings highlight asymptomatic IASO as a phenotypic feature of HeFH-related atherosclerosis, which ultimately affects future outcomes.

DOI： 10.1161/JAHA.123.033972

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PubMed

A Case of Multiple Intracranial Major Artery Stenoses With Coexisting PCSK9 p.E32K and RNF213 p.R4810K Variants. 査読有り国際誌

Noda K, Hattori Y, Hori M, Harada-Shiba M, Ihara M

Neurology. Genetics 9 巻 ( 5 ) 頁： e200099 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Neurology: Genetics

ObjectivesFamilial hypercholesterolemia (FH), caused by PCSK9 p.E32K, is characterized by early-onset coronary artery disease. However, the relationship between PCSK9 p.E32K and cerebrovascular disease is unclear. One of our patients with the PCSK9 p.E32K had several intracranial artery stenoses (ICAS). The objective of this case series was to identify factors that may be associated with ICAS in the variant carriers.MethodsA 75-year-old Japanese woman with FH carrying PCSK9 p.E32K was found to have 5 asymptomatic ICAS when brain magnetic resonance angiography (MRA) was performed. We retrospectively investigated additional patients with FH who underwent brain MRA at our institution to explore the unknown factors accelerating ICAS.ResultsWe investigated an additional 5 patients with FH who underwent brain MRA. Of them, only one had mild ICAS. The RNF213 p.R4810K that is an established genetic risk for ICAS, particularly in East Asians, was identified only in the patient with 5 ICAS.DiscussionPCSK9 and RNF213 play an important role in lipid metabolism and endothelial integrity. Therefore, together, these variants could be involved in the development of multiple ICAS. Our case series indicated that PCSK9 p.E32K carriers should undergo early brain screening to obtain appropriate stroke prevention measures in the asymptomatic stage.

DOI： 10.1212/NXG.0000000000200099

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PubMed

Amplified Risk of Intracranial Artery Stenosis/Occlusion Associated With RNF213 p.R4810K in Familial Hypercholesterolemia. 査読有り

Noda K, Hattori Y, Hori M, Nakaoku Y, Tanaka A, Yoshimoto T, Nishimura K, Yokota T, Harada-Shiba M, Ihara M

JACC. Asia 3 巻 ( 4 ) 頁： 625 - 633 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JACC: Asia

Background: The RNF213 p.R4810K variant is associated with moyamoya disease in East Asian individuals and increases the risk of developing intracranial major artery stenosis/occlusion (ICASO) that affects anterior circulation. Meanwhile, 0.5% to 2.5% of asymptomatic East Asian individuals also carry this variant. As such, additional factors are likely required to develop ICASO in variant carriers. Familial hypercholesterolemia (FH) is a common genetic disorder in Japan that has a significant associated risk of developing premature coronary atherosclerosis; however, the relationship between ICASO and FH remains unknown. Objectives: This study aimed to determine if FH facilitates RNF213 p.R4810K carriers to develop ICASO. Methods: We enrolled patients with FH who had undergone brain magnetic resonance angiography at our hospital from May 2005 to March 2020. The RNF213 p.R4810K variant, and LDLR and PCSK9 mutations were genotyped. ICASO lesions in the brain magnetic resonance angiogram were analyzed. Results: Six RNF213 p.R4810K variant carriers were identified among 167 patients with FH (LDLR, n = 104; PCSK9, n = 22). Five of the carriers (83.3%) exhibited ICASO in the anterior circulation; a significant difference in ICASO frequency was observed between the variant carriers and noncarriers (P = 0.025). The median number of stenotic or occluded arteries in the anterior circulation was also significantly larger in the variant carriers (3 vs 1, P = 0.01); however, did not differ between patients with FH with LDLR and PCSK9 mutations. Conclusions: Patients with FH exhibit increased prevalence and severity of ICASO associated with RNF213 p.R4810K. Gene mutations for FH may confer an increased risk of ICASO in RNF213 p.R4810K carriers.

DOI： 10.1016/j.jacasi.2023.03.011

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The Prevalence Of Intracranial Artery Stenosis And Ischemic Stroke In Familial Hypercholesterolemia: A Retrospective Cohort Study 査読有り

Kotaro Noda, Yorito Hattori, Mika Hori, Akito Tanaka, Atsushi Nagai, Mariko Harada-Shiba, Shuhei Yamaguchi, Masafumi Ihara

STROKE 54 巻 2023年2月

Association between Familial Hypercholesterolemia and Serum Levels of Cholesterol Synthesis and Absorption Markers: The CACHE Study FH Analysis. 査読有り

Matsuki K, Harada-Shiba M, Hori M, Ogura M, Akiyama Y, Fujii H, Ishibashi Y, Ishida T, Ishigaki Y, Kabata D, Kihara Y, Kotani K, Kurisu S, Masuda D, Matoba T, Matsumura T, Mori K, Nakagami T, Nakazato M, Taniuchi S, Ueno H, Yamashita S, Yoshida H, Yoshida H, Shoji T

Journal of atherosclerosis and thrombosis advpub 巻 ( 0 ) 2023年1月

Characterization of Polyvascular Disease in Heterozygous Familial Hypercholesterolemia: Its Association With Circulating Lipoprotein(a) Levels 査読有り国際誌

Funabashi Sayaka, Kataoka Yu, Hori Mika, Ogura Masatsune, Doi Takahito, Noguchi Teruo, Harada-Shiba Mariko

JOURNAL OF THE AMERICAN HEART ASSOCIATION 11 巻 ( 16 ) 頁： e025232 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of the American Heart Association

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) more likely exhibits extensive atherosclerotic disease at multiple vascular beds. Lipoprotein(a) (Lp(a)) is an atherogenic lipoprotein that elevates HeFH-related atherosclerotic cardiovascular disease risks. Whether circulating Lp(a) level associates with polyvascular propagation of atherosclerosis in subjects with HeFH remains uncertain. METHODS AND RESULTS: The current study analyzed 370 subjects with clinically diagnosed HeFH who received evaluation of systemic arteries. Polyvascular disease (polyVD) was defined as more than 2 coexisting atherosclerosis conditions including coronary artery disease, carotid stenosis, or peripheral artery disease. Clinical characteristics and lipid features were analyzed in subjects with HeFH and polyVD; 5.7% of patients with HeFH (21/370) had polyVD. They were more likely to have a clustering of risk factors, tendon (P<0.001) and skin xanthomas (P=0.004), and corneal arcus (P=0.026). Furthermore, an elevated Lp(a) level (P=0.006) and a greater frequency of Lp(a) level ≥50 mg/dL (P<0.001) were observed in subjects with HeFH and polyVD. On multivariable analysis adjusting risk factors and lipid-lowering agents, Lp(a) ≥50 mg/dL (odds ratio [OR], 5.66 [95% CI, 1.68– 19.0], P=0.005), age, and family history of premature coronary artery disease independently predicted polyVD in subjects with HeFH. Of note, the prevalence of polyVD rose to 33.3% in patients with HeFH and age >58 years old, family history of premature coronary artery disease, and Lp(a) ≥50 mg/dL (OR, 10.3 [95% CI, 3.12– 33.4], P<0.001). CONCLUSIONS: An increased level of circulating Lp(a) levels predicted concomitance of polyVD in patients with HeFH. The current findings suggest subjects with HeFH and Lp(a) ≥50 mg/dL as a high-risk category who require meticulous screening of systemic vascular beds.

DOI： 10.1161/JAHA.121.025232

Web of Science

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PubMed

Acute Cholesterol-Lowering Effect of Exendin-4 in Ldlr-/- and C57BL/6J Mice. 査読有り

Hori M, Hasegawa Y, Hayashi Y, Nakagami T, Harada-Shiba M

Journal of atherosclerosis and thrombosis advpub 巻 ( 0 ) 2022年3月

Identification of a novel large duplication (exon2_6dup): copy number variation in the LDLR gene in a large family with familial hypercholesterolemia by whole-genome sequencing. 査読有り国際誌

Hori M, Takahashi A, Hosoda K, Harada-Shiba M

Journal of clinical lipidology 16 巻 ( 2 ) 頁： 167 - 172 2022年3月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Clinical Lipidology

Background: We found a large family with familial hypercholesterolemia (FH) that included 7 siblings who all developed myocardial infarction. Objective: The aim of this study was to identify the pathogenic gene underlying FH in the family. Methods: Whole-genome sequencing (WGS) was performed in 12 affected and 10 unaffected individuals in the family. Results: WGS identified a novel large duplication: copy number variation (CNV) in the LDLR gene, exon2_6dup (c.68-499_940+252dup), that was present in the 12 affected family members but not in any of the 10 unaffected family members. The exact extent and genomic breakpoint sequence of the duplication caused by nonallelic homologous recombination between Alu sequences were identified based on bioinformatic analysis of WGS data for the LDLR gene. Conclusions: A novel c.68-499_940+252dup variant in the LDLR gene was identified based on bioinformatic analysis of WGS data. WGS is a powerful tool that can be used to precisely identify CNVs in addition to small-scale variations in FH-related genes.

DOI： 10.1016/j.jacl.2022.01.007

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High Protein Diet Feeding Aggravates Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides 査読有り国際誌

Ueno, S; Seino, Y; Hidaka, S; Maekawa, R; Takano, Y; Yamamoto, M; Hori, M; Yokota, K; Masuda, A; Himeno, T; Tsunekawa, S; Kamiya, H; Nakamura, J; Kuwata, H; Fujisawa, H; Shibata, M; Takayanagi, T; Sugimura, Y; Yabe, D; Hayashi, Y; Suzuki, A

NUTRIENTS 14 巻 ( 5 ) 2022年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nutrients

(1) Background: Protein stimulates the secretion of glucagon (GCG), which can affect glucose metabolism. This study aimed to analyze the metabolic effect of a high-protein diet (HPD) in the presence or absence of proglucagon-derived peptides, including GCG and GLP-1. (2) Methods: The response to HPD feeding for 7 days was analyzed in mice deficient in proglucagon-derived peptides (GCGKO). (3) Results: In both control and GCGKO mice, food intake and body weight decreased with HPD and intestinal expression of Pepck increased. HPD also decreased plasma FGF21 levels, regardless of the presence of proglucagon-derived peptides. In control mice, HPD increased the hepatic expression of enzymes involved in amino acid metabolism without the elevation of plasma amino acid levels, except branched-chain amino acids. On the other hand, HPD-induced changes in the hepatic gene expression were attenuated in GCGKO mice, resulting in marked hyperaminoacidemia with lower blood glucose levels; the plasma concentration of glutamine exceeded that of glucose in HPD-fed GCGKO mice. (4) Conclusions: Increased plasma amino acid levels are a common feature in animal models with blocked GCG activity, and our results underscore that GCG plays essential roles in the homeostasis of amino acid metabolism in response to altered protein intake.

DOI： 10.3390/nu14050975

Web of Science

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Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study 査読有り国際共著

Tromp T.R., Hartgers M.L., Hovingh G.K., Vallejo-Vaz A.J., Ray K.K., Soran H., Freiberger T., Bertolini S., Harada-Shiba M., Blom D.J., Raal F.J., Cuchel M., Tromp T.R., Hovingh G.K., Ray K.K., Bertolini S.A., Pang J., Watts G.F., Greber-Platzer S., Mäser M., Stulnig T.M., Ebenbichler C.F., Bin Thani K., Cassiman D., Descamps O.S., Rymen D., Witters P., Santos R.D., Brunham L.R., Francis G.A., Genest J., Hegele R.A., Kennedy B.A., Ruel I., Sherman M.H., Jiang L., Wang L., Reiner Ž., Blaha V., Ceska R., Dvorakova J., Dlouhy L., Horak P., Soska V., Tichy L., Urbanek R., Vaverkova H., Vrablik M., Zemek S., Zlatohlavek L., Emil S., Naguib T., Reda A., Béliard S., Bruckert E., Gallo A., Elisaf M.S., Kolovou G., Cohen H., Durst R., Dann E.J., Elis A., Hussein O., Leitersdorf E., Schurr D., Setia N., Verma I.C., Alareedh M.D., Al-Khnifsawi M., Abdalsahib Al-Zamili A.F., Rhadi S.H., Shaghee F.K., Arca M., Averna M., Bartuli A., Bucci M., Buonuomo P.S., Calabrò P., Calandra S., Casula M., Catapano A.L., Cefalù A.B., Cicero A.F.G., D'Addato S., D'Erasmo L., Di Costanzo A., Fasano T., Gazzotti M., Giammanco A., Iannuzzo G., Ibba A., Negri E.A., Pasta A., Pavanello C., Pisciotta L., Rabacchi C., Ripoli C., Sampietro T.

The Lancet 399 巻 ( 10326 ) 頁： 719 - 728 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：The Lancet

Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. Methods: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. Findings: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5–27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6–18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6–5·8) versus non-high-income countries (9·3 mmol/L, 6·7–12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0–34·5) versus 37·0 years (29·0–49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13–2·38). Interpretation: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH. Funding: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

DOI： 10.1016/S0140-6736(21)02001-8

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Relationship Of RNF213p.R4810k Variant And Familial Hypercholesterolemia To Intracranial Major Arterial Stenosis/occlusion 査読有り

Kotaro Noda, Yorito Hattori, Mika Hori, Akito Tanaka, Mariko Harada-Shiba, Masafumi Ihara

STROKE 53 巻 2022年2月

Association between Achilles Tendon Softness and Atherosclerotic Cardiovascular Disease in Patients with Familial Hypercholesterolemia. 査読有り

Michikura M, Ogura M, Hori M, Matsuki K, Makino H, Hosoda K, Harada-Shiba M

Journal of atherosclerosis and thrombosis advpub 巻 ( 0 ) 2022年1月

Circulating Furin-Cleaved Proprotein Convertase Subtilisin/Kexin Type 9 Concentration Predicts Future Coronary Events in Japanese Subjects 査読有り

Kataoka Y., Harada-Shiba M., Hori M., Watanabe M., Kokubo Y., Noguchi T., Yasuda S., Miyamoto Y.

JACC: Asia 1 巻 ( 3 ) 頁： 360 - 368 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JACC: Asia

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, which differ in their properties to degrade low-density lipoprotein (LDL) receptors. Objectives: In this study, we sought to investigate whether PCSK9 subtypes associate with atherosclerotic cardiovascular events. Methods: We investigated 1,436 statin-naive Japanese subjects without any cardiovascular disease in the Suita Study, an epidemiologic Japanese cohort study. Total, mature, and furin-cleaved PCSK9 levels were measured by means of enzyme-linked immunosorbent assay. The occurrence of coronary and stroke events were compared in subjects stratified by PCSK9 level tertile. Results: Total, mature, and furin-cleaved PCSK9 levels were associated with non–high-density lipoprotein cholesterol (all P < 0.001) and systolic blood pressure (P = 0.001, P = 0.004, and P < 0.001, respectively). Furthermore, only furin-cleaved PCSK9 level was correlated to high-sensitivity C-reactive protein (hs-CRP) (P < 0.001). During the 13.6-year observational period, furin-cleaved PCSK9 level predicted a greater likelihood of experiencing coronary events (tertile 2: hazard ratio [HR]: 2.84 [95% confidence interval [CI]: 1.21-6.65; P = 0.01]; tertile 3: HR: 2.81 [95% CI: 1.17-6.74; P = 0.02]), but not stroke (tertile 2: HR: 1.31 [95% CI: 0.72-2.40; P = 0.36]; tertile 3: HR: 1.27 [95% CI: 0.68-2.38; P = 0.44]). Total and mature PCSK9 levels were not associated with coronary events (total PCSK9: tertile 2: HR: 1.35 [95% CI: 0.68-2.68; P = 0.39]; tertile 3: HR: 1.13 [95% CI: 0.54-2.34; P = 0.73]; mature PCSK9: tertile 2: HR: 1.02 [95% CI: 0.52-2.02; P = 0.93]; tertile 3: HR: 0.96 [95% CI: 0.47-1.95; P = 0.92]) and stroke events (total PCSK9: tertile 2: HR: 0.90 [95% CI: 0.50-1.61; P = 0.72]; tertile 3: HR: 0.99 [95% CI:0.54-1.80; P = 0.97]; mature PCSK9: tertile 2: HR: 0.86 [95% CI: 0.47-1.57; P = 0.63]; tertile 3: HR: 1.11 [95% CI: 0.61-1.99; P = 0.72]), respectively. Conclusions: Furin-cleaved but not total and mature PCSK9 was associated with both LDL cholesterol and hs-CRP and predicted future coronary events in the primary prevention settings. Our findings provide pathophysiological insights into the properties of PCSK9 subtypes in association with coronary events.

DOI： 10.1016/j.jacasi.2021.09.003

Scopus

Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) 査読有り国際共著

EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

The Lancet 398 巻 ( 10312 ) 頁： 1713 - 1725 2021年11月

Switching from lipoprotein apheresis to evolocumab in FH siblings on hemodialysis: case reports and discussion. 査読有り

Ishii T, Ogura M, Nakamori H, Hori M, Harada-Shiba M, Tamura K, Oyama K

CEN case reports 10 巻 ( 4 ) 頁： 592 - 597 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：CEN case reports

Familial hypercholesterolemia (FH) and chronic kidney disease, especially end-stage renal disease (ESRD), are common and put patients at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). ESRD concomitant with FH may further increase the risk of ASCVD. Achieving target levels of low-density lipoprotein cholesterol (LDL-C) is difficult owing to the limitations of statin administration due to its side effects in ESRD. Therefore, some FH patients with ESRD require lipoprotein apheresis for the prevention of secondary ASCVD events. Although proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors may offer a safe and effective option for lowering lipid levels in such patients, no guidelines are available for their use. Here, we report the case of two male siblings with FH in secondary prevention undergoing hemodialysis combined with PCSK9 inhibitor treatment. The siblings, who showed a heterozygous c.1846-1G>A mutation in the LDLR gene, underwent hemodialysis. In combination with the lipoprotein apheresis, siblings were administered evolocumab, a PCSK9 inhibitor. Both the siblings had coronary artery disease, diabetes, and ESRD, and received hemodialysis. Their LDL-C levels did not reach the target values despite administering statin, ezetimibe, and biweekly lipoprotein apheresis. On the introduction of evolocumab treatment, their LDL-C levels were significantly reduced without any adverse effects, resulting in successful withdrawal from lipoprotein apheresis therapy. Although the effects of switching from lipoprotein apheresis to PCSK9 inhibitors for cardiovascular protection remain unclear in FH patients with and without ESRD, our case report will be helpful in guiding future therapeutic decisions.

DOI： 10.1007/s13730-021-00605-x

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PubMed

Current Diagnosis and Management of Abetalipoproteinemia. 査読有り

Takahashi M, Okazaki H, Ohashi K, Ogura M, Ishibashi S, Okazaki S, Hirayama S, Hori M, Matsuki K, Yokoyama S, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 10 ) 頁： 1009 - 1019 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本動脈硬化学会

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, and failure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety of symptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular (spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to the development of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications and improve the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis are awaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, and management of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support from the Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) ＜15 mg/dL and apoB ＜15 mg/dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.

DOI： 10.5551/jat.RV17056

PubMed

Current Diagnosis and Management of Primary Chylomicronemia. 査読有り

Okazaki H, Gotoda T, Ogura M, Ishibashi S, Inagaki K, Daida H, Hayashi T, Hori M, Masuda D, Matsuki K, Yokoyama S, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 9 ) 頁： 883 - 904 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher. PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-offunction mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive. The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life. Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease. Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.

DOI： 10.5551/jat.RV17054

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PubMed

Substantially Elevated Atherosclerotic Risks in Japanese Severe Familial Hypercholesterolemia Defined by the International Atherosclerosis Society 査読有り国際誌 Open Access

Funabashi S., Kataoka Y., Hori M., Ogura M., Nakaoku Y., Nishimura K., Doi T., Nishikawa R., Tsuda K., Noguchi T., Harada-Shiba M.

JACC: Asia 1 巻 ( 2 ) 頁： 245 - 255 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JACC: Asia

Background: The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia” (FH) as a phenotype with the highest cardiovascular risk. However, whether this criteria could appropriately stratify a high-risk Japanese patient with FH remains unknown. Objectives: This study sought to characterize atherosclerotic cardiovascular diseases in IAS-defined Japanese subjects with severe FH. Methods: This study analyzed 380 clinically diagnosed subjects with heterozygous FH without any history of atherosclerotic cardiovascular diseases. Severe FH was defined as untreated low-density lipoprotein cholesterol >400 mg/dL, >310 mg/dL plus 1 high-risk feature, or >190 mg/dL plus 2 high-risk features according to IAS-proposed statement. The occurrence of first and subsequent composite outcomes (cardiac [cardiac death + coronary artery disease + coronary revascularization] and noncardiac events [stroke + peripheral artery disease] was compared between subjects with severe (n = 135) and non-severe (n = 227) FH. Results: Severe FH was identified in 40.3% of study population. They had higher low-density lipoprotein cholesterol (P < 0.001) and lipoprotein(a) (P = 0.03) levels. Moreover, they more frequently received high-intensity statin (P < 0.001), PCSK9 inhibitor (P < 0.001), and lipoprotein apheresis (P = 0.01) than nonsevere FH subjects did, which resulted in a lower on-treatment low-density lipoprotein cholesterol level of subjects with severe FH (113 ± 47.2 vs 130 ± 53.9 mg/dL; P = 0.007). However, during the 7.4-year observational period, subjects with severe FH exhibited a 9.3-, 15.4-, and 5.9-fold greater risk for first composite (P < 0.001), cardiac (P < 0.001), and noncardiac outcomes (P = 0.02), respectively. Multivariate Cox proportional hazard model consistently revealed the 7.8- and 7.9-fold elevated risks of first (P < 0.001) and of subsequent (P < 0.001) composite outcomes in subjects with severe FH. Conclusions: Japanese subjects with severe FH present profound risks of both first and subsequent atherosclerotic cardiovascular diseases in the primary prevention settings. These findings support the clinical applicability of IAS-defined severe FH in Japanese patients, which identifies those who require further stringent antiatherosclerotic management.

DOI： 10.1016/j.jacasi.2021.07.004

Open Access

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PubMed

Can We Clarify the Causative Gene/Variants Underlying Familial Hypercholesterolemia and Improve Genetic Diagnosis Rate? 招待有り査読有り

Hori M

Journal of atherosclerosis and thrombosis 2021年8月

Current Diagnosis and Management of Tangier Disease. 査読有り

Koseki M, Yamashita S, Ogura M, Ishigaki Y, Ono K, Tsukamoto K, Hori M, Matsuki K, Yokoyama S, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 8 ) 頁： 802 - 810 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a dysfunctional mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol and phospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported in Japan and 109 cases outside Japan. With dysfunctional mutations in both alleles (homozygotes or compound heterozygotes), the HDL-C level is mostly less than 5 mg/dL and there is 10 mg/dL or less of apolipoprotein A-I (apoA-I), the major protein component of HDL. In patients with Tangier disease, major physical findings are orange-colored pharyngeal tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and peripheral neuropathy. Although patients tend to have decreased low-density lipoprotein (LDL)-cholesterol (LDL-C) levels, premature coronary artery disease is frequently observed. No specific curative treatment is currently available, so early identification of patients and preventing atherosclerosis development are crucial. Management of risk factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking. Additionally, treatment for glucose intolerance might be required because impaired insulin secretion from pancreatic beta cells has occasionally been reported.

DOI： 10.5551/jat.RV17053

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PubMed

Diagnosis and Management of Sitosterolemia 2021. 査読有り

Tada H, Nomura A, Ogura M, Ikewaki K, Ishigaki Y, Inagaki K, Tsukamoto K, Dobashi K, Nakamura K, Hori M, Matsuki K, Yamashita S, Yokoyama S, Kawashiri MA, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 8 ) 頁： 791 - 801 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in selective excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plant sterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observed in patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia, and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic as well as therapeutic tips, and the latest diagnostic criteria in Japan.

DOI： 10.5551/jat.RV17052

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PubMed

Achilles Tendon Thickness Assessed by X-ray Predicting a Pathogenic Mutation in Familial Hypercholesterolemia Gene. 査読有り

Tada H, Hori M, Matsuki K, Ogura M, Nohara A, Kawashiri MA, Harada-Shiba M

Journal of atherosclerosis and thrombosis 2021年7月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本動脈硬化学会

Aim: The 2017 Japan Atherosclerosis Society (JAS) familial hypercholesterolemia (FH) criteria adopt a cut-off value of ≥ 9 mm of Achilles tendon thickness (ATT) detected by X-ray as one of the three key items. This threshold was determined based on an old data evaluating the ATT of 36 non-FH individuals that was published in 1977. Although the specificity of these clinical criteria is extremely high due to a strict threshold, there are a significant number of patients with FH whose ATT ＜9 mm. We aimed to determine a cut-off value of ATT detected by X-ray to differentiate FH and non-FH based on genetic diagnosis. Methods: The individuals (male/female=486/501) with full assessments of genetic analyses for FH-genes (LDLR and PCSK9), serum lipids, and ATT detected by X-ray at the Kanazawa University Hospital and National Cerebral and Cardiovascular Center Research Institute were included in this study. Receiver operating characteristic (ROC) analyses were conducted to determine a better cut-off value of ATT that predicts the pathogenic mutation of FH. Results: The ROC analyses revealed that the best cut-off values of ATT are 7.6 mm for male and 7.0 mm for female, with the sensitivities/specificities of 0.83/0.83 for male and 0.86/0.85 for female, respectively. If the thresholds of ATT of 8.0/7.5 mm and 7.5/7.0 mm were applied to the diagnosis of male/female FH, the sensitivities/specificities predicting the pathogenic mutation of FH by the 2017 JAS FH clinical criteria would be 0.82/0.90 and 0.85/0.88, respectively. Conclusions: These results suggest that the cut-off value of ATT detected by X-ray is obviously lower than 9.0 mm, which was adopted by the 2017 JAS FH clinical criteria.

DOI： 10.5551/jat.62869

PubMed

Homozygous Familial Hypercholesterolemia. 査読有り

Nohara A, Tada H, Ogura M, Okazaki S, Ono K, Shimano H, Daida H, Dobashi K, Hayashi T, Hori M, Matsuki K, Minamino T, Yokoyama S, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 7 ) 頁： 665 - 678 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis. Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases. This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.

DOI： 10.5551/jat.RV17050

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PubMed

Current Status of Familial LCAT Deficiency in Japan. 査読有り

Kuroda M, Bujo H, Yokote K, Murano T, Yamaguchi T, Ogura M, Ikewaki K, Koseki M, Takeuchi Y, Nakatsuka A, Hori M, Matsuki K, Miida T, Yokoyama S, Wada J, Harada-Shiba M

Journal of atherosclerosis and thrombosis 28 巻 ( 7 ) 頁： 679 - 691 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

DOI： 10.5551/jat.RV17051

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PubMed

Achilles Tendon Softness as a New Tool for Diagnosing Familial Hypercholesterolemia. 査読有り国際誌

Michikura M, Ogura M, Hori M, Furuta K, Hosoda K, Harada-Shiba M

JACC. Cardiovascular imaging 14 巻 ( 7 ) 頁： 1483 - 1485 2021年7月

Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy. 査読有り

Kuyama N, Kataoka Y, Takegami M, Nishimura K, Harada-Shiba M, Hori M, Ogura M, Otsuka F, Asaumi Y, Noguchi T, Tsujita K, Yasuda S

Journal of the American Heart Association 10 巻 ( 11 ) 頁： e019525 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of the American Heart Association

BACKGROUND: Statin-mediated efficacy of lowering low-density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine-protease associated with LDL metabolism, which circulates as mature and furin-cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. METHODS AND RESULTS: We analyzed 101 statin-naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10-ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01–1.24 [P=0.03]), whereas furin-cleaved level was not (per 10-ng/mL increase: OR, 1.37; 95% CI, 0.73–2.58 [P=0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). CONCLUSIONS: Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.

DOI： 10.1161/JAHA.120.019525

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PubMed

A Resuscitated Case of Acute Myocardial Infarction with both Familial Hypercholesterolemia Phenotype Caused by Possibly Oligogenic Variants of the PCSK9 and ABCG5 Genes and Type I CD36 Deficiency. 査読有り

Nishikawa R, Furuhashi M, Hori M, Ogura M, Harada-Shiba M, Okada T, Koseki M, Kujiraoka T, Hattori H, Ito R, Muranaka A, Kokubu N, Miura T

Journal of atherosclerosis and thrombosis 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本動脈硬化学会

A 56-year-old postmenopausal woman with out-of-hospital cardiac arrest caused by acute myocardial infraction was successfully resuscitated by intensive treatments and recovered without any neurological disability. She was diagnosed as having familial hypercholesterolemia (FH) based on a markedly elevated low-density lipoprotein cholesterol (LDL-C) level and family history of premature coronary artery disease. Genetic testing in her family members showed that a variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (c.2004C＞A, p.S668R), which had been previously reported as having uncertain significance, was associated with FH, indicating that the variant is a potential candidate for the FH phenotype. Next-generation sequencing analysis for the proband also showed that there was a heterozygous mutation of the ATP-binding cassette sub-family G member 5 (ABCG5) gene (c.1166G＞A, R389H), which has been reported to increase LDL-C level and the risk of cardiovascular disease. She was also diagnosed as having type 1 CD36 deficiency based on a lack of myocardial uptake of 123 I-labeled 15-(p-iodophenyl)-3-R,S-methyl-pentadecanoic acid in scintigraphy and the absence of CD36 antigen in both monocytes and platelets in flow cytometry. She had a homozygous mutation of the CD36 gene (c.1126-5_1127delTTTAGAT), which occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. To our knowledge, this is the first report of a heterozygous FH phenotype caused by possibly oligogenic variants of the PCSK9 and ABCG5 genes complicated with type I CD36 deficiency caused by a novel homozygous mutation. Both FH phenotype and CD36 deficiency might have caused extensive atherosclerosis, leading to acute myocardial infarction in the present case.

DOI： 10.5551/jat.58909

PubMed

Patients With LDLR and PCSK9 Gene Variants Experienced Higher Incidence of Cardiovascular Outcomes in Heterozygous Familial Hypercholesterolemia. 査読有り国際誌

Doi T, Hori M, Harada-Shiba M, Kataoka Y, Onozuka D, Nishimura K, Nishikawa R, Tsuda K, Ogura M, Son C, Miyamoto Y, Noguchi T, Shimokawa H, Yasuda S

Journal of the American Heart Association 10 巻 ( 4 ) 頁： e018263 - 11 2021年2月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of the American Heart Association

BACKGROUND: Patients with familial hypercholesterolemia who harbored both low-density lipoprotein receptor (LDLR) and PCSK9 (proprotein convertase subtilisin/kexin type 9) gene variants exhibit severe phenotype associated with substantially high levels of low-density lipoprotein cholesterol. In this study, we investigated the cardiovascular outcomes in patients with both LDLR and PCSK9 gene variants. METHODS AND RESULTS: A total of 232 unrelated patients with LDLR and/or PCSK9 gene variants were stratified as follows: patients with LDLR and PCSK9 (LDLR/PCSK9) gene variants, patients with LDLR gene variant, and patients with PCSK9 gene variant. Clinical demographics and the occurrence of primary outcome (nonfatal myocardial infarction) were compared. The observation period of primary outcome started at the time of birth and ended at the time of the first cardiac event or the last visit. Patients with LDLR/PCSK9 gene variants were identified in 6% of study patients. They had higher levels of low-density lipoprotein cholesterol (P=0.04) than those with LDLR gene variants. On multivariate Cox regression model, they experienced a higher incidence of nonfatal myocardial infarction (hazard ratio, 4.62; 95% CI, 1.66–11.0; P=0.003 versus patients with LDLR gene variant). Of note, risk for nonfatal myocardial infarction was greatest in male patients with LDLR/PCSK9 gene variants compared with those with LDLR gene variant (86% versus 24%; P<0.001). CONCLUSIONS: Patients with LDLR/PCSK9 gene variants were high-risk genotype associated with atherogenic lipid profiles and worse cardiovascular outcomes. These findings underscore the importance of genetic testing to identify patients with LDLR/ PCSK9 gene variants, who require more stringent antiatherosclerotic management.

DOI： 10.1161/JAHA.120.018263

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PubMed

Cerebrotendinous Xanthomatosis: Molecular Pathogenesis, Clinical Spectrum, Diagnosis, and Disease-Modifying Treatments 査読有り

Koyama Shingo, Sekijima Yoshiki, Ogura Masatsune, Hori Mika, Matsuki Kota, Miida Takashi, Harada-Shiba Mariko

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 28 巻 ( 9 ) 頁： 905 - 925 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Atherosclerosis and Thrombosis

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by mutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. Decreased sterol 27-hydroxylase activity results in impaired bile acid synthesis, leading to reduced production of bile acids, especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol and urine bile alcohols. The accumulation of cholestanol and cholesterol mainly in the brain, lenses, and tendons results in the characteristic clinical manifestations of CTX. Clinical presentation is characterized by systemic symptoms including neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and a broad range of neuropsychiatric manifestations. The combinations of symptoms vary from patient to patient and the presenting symptoms, especially in the early disease phase, may be nonspecific, which leads to a substantial diagnostic delay or underdiagnosis. Replacement of CDCA has been approved as a first-line treatment for CTX, and can lead to biochemical and clinical improvements. However, the effect of CDCA treatment is limited once significant neuropsychiatric manifestations are established. The age at diagnosis and initiation of CDCA treatment correlate with the prognosis of patients with CTX. Therefore, early diagnosis and subsequent treatment initiation are essential.

DOI： 10.5551/jat.RV17055

Organoid-based ex vivo reconstitution of Kras-driven pancreatic ductal carcinogenesis. 査読有り

Matsuura T, Maru Y, Izumiya M, Hoshi D, Kato S, Ochiai M, Hori M, Yamamoto S, Tatsuno K, Imai T, Aburatani H, Nakajima A, Hippo Y

Carcinogenesis 41 巻 ( 4 ) 頁： 490-501 2020年6月

The first Japanese cases of familial hypercholesterolemia due to a known pathogenic APOB gene variant, c.10580 G>A: p.(Arg3527Gln). 査読有り

2020年5月

A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. 査読有り

Tada H, Hori M, Nomura A, Hosomichi K, Nohara A, Kawashiri MA, Harada-Shiba M

Journal of clinical lipidology 14 巻 ( 3 ) 頁： 346-351.e9 2020年5月

Morphological Characteristics of Aortic Stenosis in Familial Hypercholesterolemia and Non-Familial Hypercholesterolemia in the Elderly. 査読有り

Journal of Integrative Cardiology 3 巻 ( 2 ) 頁： 7 2020年4月

The benign c.344G > A: p.(Arg115His) variant in the LDLR gene interpreted from a pedigree-based genetic analysis of familial hypercholesterolemia. 査読有り

Hori M, Takahashi A, Son C, Ogura M, Harada-Shiba M

Lipids in health and disease 19 巻 ( 1 ) 頁： 62 2020年4月

父親の狭心症を契機に家族性高コレステロール血症と診断された1歳児査読有り

永関ひかる, 秋山政晴, 堀美香, 斯波真理子, 井田博幸, 宮田市郎

日本小児科学会雑誌 124 巻 ( 4 ) 頁： 704 - 708 2020年4月

Circulating Mature Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Level Predicts Diminished Response to Statin Therapy in Patients With Coronary Artery Disease 査読有り

Kuyama Naoto, Kataoka Yu, Mariko Harada-Shiba, Mika Hori, Masatsune Ogura, Yasuhide Asaumi, Teruo Noguchi, Satoshi Yasuda, Yu Kataoka

CIRCULATION 140 巻 2019年11月

Detection of the benign c.2579C>T (p.A860V) variant of the LDLR gene in a pedigree-based genetic analysis of familial hypercholesterolemia. 査読有り

Hori M, Miyauchi E, Son C, Harada-Shiba M

Journal of clinical lipidology 13 巻 ( 2 ) 頁： 335-339 2019年3月

Discontinuation of LDL apheresis with evolocumab in an FH patient with a duplication of exon 2-6 in the LDLR gene. 査読有り

Nose D, Hori M, Miyamoto Y, Imaizumi S, Harada-Shiba M, Saku K, Miura SI

Journal of cardiology cases 19 巻 ( 2 ) 頁： 55-58 2019年2月

No enhancing effects of plasmid-specific histone acetyltransferase recruitment system on transgene expression in vivo. 査読有り

Suzuki T, Wakao Y, Watanabe T, Hori M, Ikeda Y, Tsuchiya H, Kogure K, Harada-Shiba M, Fujimuro M, Kamiya H

Nucleosides, nucleotides & nucleic acids 38 巻 ( 12 ) 頁： 942-949 2019年

Pharmaceutical Research for Inherited Metabolic Disorders of the Liver Using Human Induced Pluripotent Stem Cell and Genome Editing Technologies. 招待有り査読有り

Yamashita T, Takayama K, Hori M, Harada-Shiba M, Mizuguchi H

Biological & pharmaceutical bulletin 42 巻 ( 3 ) 頁： 312-318 2019年

Fatty pancreas: A possible risk factor for pancreatic cancer in animals and humans. 査読有り

Takahashi M, Hori M, Ishigamori R, Mutoh M, Imai T, Nakagama H

Cancer science 109 巻 ( 10 ) 頁： 3013-3023 2018年10月

Activated Ductal Proliferation Induced by N-Nitrosobis (2-oxopropyl)amine in Fat-infiltrated Pancreas of KK-Ay Mice. 査読有り

Hori M, Mutoh M, Ishigamori R, Imai T, Takahashi M

In vivo (Athens, Greece) 32 巻 ( 3 ) 頁： 499-505 2018年5月

Glucagon-like peptide-1 receptor agonists reduced the low-density lipoprotein cholesterol in Japanese patients with type 2 diabetes mellitus treated with statins. 査読有り

Hasegawa Y, Hori M, Nakagami T, Harada-Shiba M, Uchigata Y

Journal of clinical lipidology 12 巻 ( 1 ) 頁： 62-69.e1 2018年1月

Coronary Artery Plaque Regression by a PCSK9 Antibody and Rosuvastatin in Double-heterozygous Familial Hypercholesterolemia with an LDL Receptor Mutation and a PCSK9 V4I Mutation. 査読有り

Shirahama R, Ono T, Nagamatsu S, Sueta D, Takashio S, Chitose T, Fujisue K, Sakamoto K, Yamamoto E, Izumiya Y, Kaikita K, Hokimoto S, Hori M, Harada-Shiba M, Kajiwara I, Ogawa H, Tsujita K

Internal medicine (Tokyo, Japan) 57 巻 ( 24 ) 頁： 3551-3557 2018年

Achilles Tendon Ultrasonography for Diagnosis of Familial Hypercholesterolemia Among Japanese Subjects. 査読有り

Michikura M, Ogura M, Yamamoto M, Sekimoto M, Fuke C, Hori M, Arai K, Kihara S, Hosoda K, Yanagi K, Harada-Shiba M

Circulation journal : official journal of the Japanese Circulation Society 81 巻 ( 12 ) 頁： 1879-1885 2017年11月

Mature proprotein convertase subtilisin/kexin type 9, coronary atheroma burden, and vessel remodeling in heterozygous familial hypercholesterolemia. 査読有り

Kataoka Y, Harada-Shiba M, Nakao K, Nakashima T, Kawakami S, Fujino M, Kanaya T, Nagai T, Tahara Y, Asaumi Y, Hori M, Ogura M, Goto Y, Noguchi T, Yasuda S

Journal of clinical lipidology 11 巻 ( 2 ) 頁： 413-421.e3 2017年3月

Evaluation of the degree of pancreatic fatty infiltration by area-based assessment of CT images: comparison with histopathology-based and CT attenuation index-based assessments. 査読有り

Hori M, Onaya H, Hiraoka N, Yamaji T, Kobayashi H, Takahashi M, Mutoh M, Shimada K, Nakagama H

Japanese journal of radiology 34 巻 ( 10 ) 頁： 667 - 676 2016年10月

Association Between Cholesterol Efflux Capacity and Atherosclerotic Cardiovascular Disease in Patients With Familial Hypercholesterolemia. 査読有り

Ogura M, Hori M, Harada-Shiba M

Arteriosclerosis, thrombosis, and vascular biology 36 巻 ( 1 ) 頁： 181 - 8 2016年1月

Possible involvement of pancreatic fatty infiltration in pancreatic carcinogenesis 査読有り

Journal of the Pancreas 17 巻頁： 166 - 175 2016年

Association of pancreatic Fatty infiltration with pancreatic ductal adenocarcinoma. 査読有り

Hori M, Takahashi M, Hiraoka N, Yamaji T, Mutoh M, Ishigamori R, Furuta K, Okusaka T, Shimada K, Kosuge T, Kanai Y, Nakagama H

Clinical and translational gastroenterology 5 巻頁： e53 2014年3月

Invasive ductal carcinoma developing in pancreas with severe Fatty infiltration. 査読有り

Hori M, Onaya H, Takahashi M, Hiraoka N, Mutoh M, Kosuge T, Nakagama H

Pancreas 41 巻 ( 7 ) 頁： 1137 - 9 2012年10月

Enhancement of carcinogenesis and fatty infiltration in the pancreas in N-nitrosobis(2-oxopropyl)amine-treated hamsters by high-fat diet. 査読有り

Hori M, Kitahashi T, Imai T, Ishigamori R, Takasu S, Mutoh M, Sugimura T, Wakabayashi K, Takahashi M

Pancreas 40 巻 ( 8 ) 頁： 1234 - 40 2011年11月

Mutagenicity of secondary oxidation products of 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-hydroxy-2'- deoxyguanosine 5'-triphosphate). 査読有り

Hori M, Suzuki T, Minakawa N, Matsuda A, Harashima H, Kamiya H

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 714 巻 ( 1-2 ) 頁： 11 - 6 2011年9月

Experimental animal models of pancreatic carcinogenesis for prevention studies and their relevance to human disease. 査読有り

Takahashi M, Hori M, Mutoh M, Wakabayashi K, Nakagama H

Cancers 3 巻 ( 1 ) 頁： 582 - 602 2011年2月

Suppression of mutagenesis by 8-hydroxy-2 '-deoxyguanosine 5 '-triphosphate (7,8-dihydro-8-oxo-2 '-deoxyguanosine 5 '-triphosphate) by human MTH1, MTH2, and NUDT5 査読有り

Hori Mika, Satou Kazuya, Harashima Hideyoshi, Kamiya Hiroyuki

FREE RADICAL BIOLOGY AND MEDICINE 48 巻 ( 9 ) 頁： 1197 - 1201 2010年5月

Early and enhanced development of N-nitrosobis(2-oxopropyl)amine-induced hamster pancreatic adenocarcinomas by high-fat diet 査読有り

Takahashi Mami, Hori Mika, Kitahashi Tsukasa, Imai Toshio, Ishigamori Rikako, Takasu Shinji, Mutoh Michihiro, Sugimura Takashi, Wakabayashi Keiji

CANCER RESEARCH 70 巻 2010年4月

NUDT5 hydrolyzes oxidized deoxyribonucleoside diphosphates with broad substrate specificity. 査読有り

Kamiya H, Hori M, Arimori T, Sekiguchi M, Yamagata Y, Harashima H

DNA repair 8 巻 ( 10 ) 頁： 1250 - 4 2009年10月

Involvement of specialized DNA polymerases in mutagenesis by 8-hydroxy-dGTP in human cells. 査読有り

Satou K, Hori M, Kawai K, Kasai H, Harashima H, Kamiya H

DNA repair 8 巻 ( 5 ) 頁： 637 - 42 2009年5月

Roles of specialized DNA polymerases in mutagenesis by oxidized guanine.

Kamiya H, Satou K, Hori M, Yamaguchi A, Harashima H

Nucleic acids symposium series (2004) ( 53 ) 頁： 223 - 4 2009年

UvrA and UvrB enhance mutations induced by oxidized deoxyribonucleotides. 査読有り

Hori M, Ishiguro C, Suzuki T, Nakagawa N, Nunoshiba T, Kuramitsu S, Yamamoto K, Kasai H, Harashima H, Kamiya H

DNA repair 6 巻 ( 12 ) 頁： 1786 - 93 2007年12月

Effects of overexpression and antisense RNA expression of Orf17, a MutT-type enzyme 査読有り

Hori Mika, Asanuma Taketoshi, Inanami Osamu, Kuwabara Mikinori, Harashima Hideyoshi, Kamiya Hiroyuki

BIOLOGICAL & PHARMACEUTICAL BULLETIN 29 巻 ( 6 ) 頁： 1087 - 1091 2006年6月

In vivo mutagenicities of damaged nucleotides produced by nitric oxide and ionizing radiation 査読有り

Hori M, Ishiguro C, Harashima H, Kamiya H

BIOLOGICAL & PHARMACEUTICAL BULLETIN 28 巻 ( 3 ) 頁： 520 - 522 2005年3月

Dual hydrolysis of diphosphate and triphosphate derivatives of oxidized deoxyadenosine by Orf17 (NtpA), a MutT-type enzyme. 査読有り

Hori M, Fujikawa K, Kasai H, Harashima H, Kamiya H

DNA repair 4 巻 ( 1 ) 頁： 33 - 9 2005年1月

Mutagenesis by damaged deoxyribonucleotides and its prevention by MutT-type hydrolyzing enzymes.

Kamiya H, Satou K, Hori M, Iida E, Ishiguro C, Harashima H

Nucleic acids symposium series (2004) ( 48 ) 頁： 271 - 2 2004年

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