研究者詳細 - 堀　美香

論文 - 堀　美香

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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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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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Acute Cholesterol-Lowering Effect of Exendin-4 in Ldlr<sup>-/-</sup> 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

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論文 - 堀 美香

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論文 - 堀　美香