担当区分：筆頭著者  

DOI： 10.1210/jc.2014-3066

PubMed

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：(一社)日本脳循環代謝学会  

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

Scopus

PubMed

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：(一社)日本動脈硬化学会  

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：(一社)日本動脈硬化学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本循環器学会  

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  

DOI： 10.5551/jat.63899

PubMed

CiNii Research

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

Scopus

PubMed

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：一般社団法人 日本動脈硬化学会  

DOI： 10.5551/jat.60921

PubMed

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

Scopus

PubMed

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

Scopus

PubMed

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：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

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1161/str.53.suppl_1.TMP78

Web of Science

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  

DOI： 10.5551/jat.63151

PubMed

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：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

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：(一社)日本脳循環代謝学会  

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

Scopus

PubMed

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  

<p>Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the <i>MTTP</i> 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. </p>

DOI： 10.5551/jat.RV17056

PubMed

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

Scopus

PubMed

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：一般社団法人 日本動脈硬化学会  

DOI： 10.5551/jat.ED184

PubMed

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

Scopus

PubMed

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

Scopus

PubMed

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  

<p><b>Aim: </b>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.<b> </b></p><p><b>Methods:</b> The individuals (male/female=486/501) with full assessments of genetic analyses for FH-genes (<i>LDLR</i> and <i>PCSK9</i>), 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.<b> </b></p><p><b>Results: </b>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.<b> </b></p><p><b>Conclusions: </b>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.</p>

DOI： 10.5551/jat.62869

PubMed

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

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

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jcmg.2021.01.033

PubMed

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

Scopus

PubMed

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  

<p>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 (<i>PCSK9</i>) 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 (<i>ABCG5</i>) 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 ¹²³I-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 <i>CD36</i> 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 <i>PCSK9</i> and <i>ABCG5</i> 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.</p>

DOI： 10.5551/jat.58909

PubMed

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

Scopus

PubMed

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

Web of Science

Scopus

PubMed

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/carcin/bgz122

PubMed

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）  

DOI： 10.1016/j.jacl.2020.05.007

PubMed

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）  

DOI： 10.1016/j.jacl.2020.03.002

PubMed

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）  

DOI： 10.1186/s12944-020-01252-4

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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Web of Science

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）  

DOI： 10.1016/j.jacl.2019.01.004

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jccase.2018.10.005

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1248/bpb.b18-00544

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/15257770.2019.1638514

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.13766

PubMed

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）  

DOI： 10.21873/invivo.11267

PubMed

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）  

DOI： 10.1016/j.jacl.2017.11.006

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.1060-18

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1253/circj.CJ-17-0041

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jacl.2017.01.005

PubMed

担当区分：筆頭著者  

DOI： 10.1007/s11604-016-0572-0

PubMed

DOI： 10.1161/ATVBAHA.115.306665

PubMed

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）  

担当区分：筆頭著者  

DOI： 10.1038/ctg.2014.5

PubMed

担当区分：筆頭著者  

DOI： 10.1097/MPA.0b013e318252ea08

PubMed

担当区分：筆頭著者  

DOI： 10.1097/MPA.0b013e318220e742

PubMed

担当区分：筆頭著者  

DOI： 10.1016/j.mrfmmm.2011.05.015

PubMed

DOI： 10.3390/cancers3010582

PubMed

担当区分：筆頭著者  

DOI： 10.1016/j.freeradbiomed.2010.02.002

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/1538-7445.AM10-2478

Web of Science

DOI： 10.1016/j.dnarep.2009.07.011

PubMed

担当区分：筆頭著者  

DOI： 10.1016/j.dnarep.2008.12.009

PubMed

DOI： 10.1093/nass/nrp112

PubMed

担当区分：筆頭著者  

DOI： 10.1016/j.dnarep.2007.06.013

PubMed

担当区分：筆頭著者  

Web of Science

担当区分：筆頭著者  

Web of Science

担当区分：筆頭著者  

DOI： 10.1016/j.dnarep.2004.07.010

PubMed

DOI： 10.1093/nass/48.1.271

PubMed

記述言語：日本語   出版者・発行元：(公財)鈴木謙三記念医科学応用研究財団  

記述言語：日本語   出版者・発行元：(公財)日本心臓財団  

記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

記述言語：日本語   出版者・発行元：(公社)日本小児科学会  

1歳3ヵ月、男児。父親の脂質異常症と狭心症に加え、父方祖父の病歴から、産業医が医療機関受診を勧めたため当院へ受診となった。患児は無症状であったが、血液検査や遺伝子検査の結果から、家族性高コレステロール血症と診断された。食事指導を行うもLDLコレステロール(LDL-C)値の改善は認められなかったため、コレスチラミン製剤の内服を開始したところ、治療開始10ヵ月で総コレステロール(TC)と中性脂肪(TG)は共に245mg/dL、LDL-C値は194mg/dLに低下し、コントロール良好となった。目下は25ヵ月でTC、TGは249mg/dL、LDL-Cは185mg/dLで経過している。

記述言語：日本語   出版者・発行元：(公社)日本薬学会  

記述言語：日本語   出版者・発行元：国立病院総合医学会  

記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：日本語   出版者・発行元：日本DDS学会  

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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Web of Science

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：日本語   出版者・発行元：日本臨床分子医学会  

記述言語：英語   出版者・発行元：(一社)日本循環器学会  

記述言語：英語   出版者・発行元：(一社)日本循環器学会  

記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER DIABETES ASSOC  

Web of Science

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

記述言語：日本語  

J-GLOBAL

記述言語：日本語   出版者・発行元：(株)協和企画  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本アフェレシス学会  

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：日本語  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：日本語  

J-GLOBAL

記述言語：英語   出版者・発行元：(公社)日本生化学会  

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

記述言語：日本語   出版者・発行元：日本分子イメージング学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(NPO)日本医工学治療学会  

記述言語：日本語  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：日本語  

J-GLOBAL

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：日本語  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本放射線影響学会  

DOI： 10.11513/jrrsabst.2010.0.113.0

J-GLOBAL

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：日本語  

J-GLOBAL

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：英語   出版者・発行元：日本癌学会  

記述言語：日本語   出版者・発行元：日本環境変異原学会  

記述言語：日本語  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本放射線影響学会  

DOI： 10.11513/jrrsabst.2008.0.108.0

J-GLOBAL

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本放射線影響学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本放射線影響学会  

記述言語：日本語  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：日本語  

J-GLOBAL

記述言語：日本語  

J-GLOBAL