Putative Pathogenic Variants of and of Sitosterolemia in Patients With Hyper-Low-Density Lipoprotein Cholesterolemia.

Objective: Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 () or ATP-binding cassette sub-family G member 8 (). There are only few data on the pathogenicity of and . This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia.

Prevalence, self-awareness, and LDL cholesterol levels among patients highly suspected as familial hypercholesterolemia in a Japanese community.

Backgrounds: The prevalence of familial hypercholesterolemia (FH) among Japanese populations is still unclear. In addition, no prior data exist regarding the self-awareness. Accordingly, we aimed to investigate the prevalence, self-awareness, and LDL-C of patients with highly suspected as FH using data obtained in a community-based medical checkups.

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

Introduction: Familial hypercholesterolaemia (FH) is an autosomal-dominant inherited genetic disease. It carries an extremely high cardiovascular risk associated with significantly elevated low-density lipoprotein (LDL) cholesterol. The diagnostic rate of this disease in some European nations is quite high, due to the presence of multiple prospective registries.

Serum sitosterol level predicting ABCG5 or ABCG8 genetic mutations.

Background: Currently, serum concentrations of sitosterol above 10 μg/ml are considered to be one of the major diagnostic criteria of sitosterolemia.

Methods: We retrospectively investigated consecutive 206 Japanese dyslipidemic subjects (mean age = 46 yr, male n = 94) with the assessments of serum sitosterol level and the presence of ABCG5 or ABCG8 genetic mutations in our institute since 2009-2018. We divided the subjects into 3 groups based on the number of pathogenic mutations in ABCG5 or ABCG8 genes.

Remnant lipoproteins and atherosclerotic cardiovascular disease.

Lipoproteins are one of the major risk factors for atherosclerotic cardiovascular disease (ASCVD), among which, low-density lipoprotein (LDL) particles have been definitively shown to be causally associated with the development of ASCVD. Additionally, the concept of remnant lipoproteins has emerged as lipoprotein metabolism has been fully investigated. The principal concept of this lipoprotein category is triglyceride-rich lipoproteins significantly increase at the postprandial state.

Clinical whole exome sequencing in severe hypertriglyceridemia.

Background: Little data exist regarding the clinical application of whole exome sequencing (WES) for the molecular diagnosis of severe hypertriglyceridemia (HTG).

Methods: WES was performed for 28 probands exhibiting severe HTG (≥1000 mg/dl) without any transient causes. We evaluated recessive and dominant inheritance models in known monogenic HTG genes, followed by disease-network gene prioritization and copy number variation (CNV) analyses to identify causative variants and a novel genetic mechanism for severe HTG.

Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease.

Background: The genetic background of severe familial hypercholesterolemia (FH) has yet to be determined.

Objective: We tested if genetic variants associated with low-density lipoprotein (LDL)-altering autosomal recessive diseases influenced LDL cholesterol levels and the odds for coronary artery disease in patients with high LDL cholesterol.

Methods: We recruited 500 individuals with elevated LDL cholesterol levels (≥180 mg/dL or ≥140 mg/dL for subjects <15 years).

Sitosterolemia, Hypercholesterolemia, and Coronary Artery Disease.

Sitosterolemia is a rare inherited disease characterized by increased levels of plant sterols, such as sitosterol. The cause of this disease is ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively) gene mutations. Recent advances in genetics have revealed that the prevalence of subjects with deleterious mutations in ABCG5 and/or ABCG8 genes could be more than 1 in ~200,000 individuals among the general population.

Post-prandial Remnant Lipoprotein Metabolism in Sitosterolemia.

Aim: We aimed to clarify post-prandial accumulation of remnant-like particles (RLP) in patients with sitosterolemia.

Methods: Oral fat tolerance test cream (Jomo Shokuhin, Takasaki, Japan) 50 g was given per body surface area (m); blood sampling was performed at 2 h intervals up to 6 h. Plasma lipoprotein fractions and RLP fractions were determined in four sitosterolemic subjects with double mutations in ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene (mean age=18 yr, median low-density lipoprotein cholesterol [LDL-C]=154 mg/dL), six heterozygous carriers (mean age=31 yr, median LDL-C=105 mg/dL), and five subjects with heterozygous familial hypercholesterolemia (FH, mean age=32 yr, median LDL-C=221 mg/dL).

Remnant-like particles and coronary artery disease in familial hypercholesterolemia.

Background: Although remnant-like particle cholesterol (RLP-C) has been associated with coronary artery disease (CAD) in the general population, few data exist regarding this issue in patients with familial hypercholesterolemia (FH). The aim of our study was to investigate the association between RLP-C and the presence of CAD in patients with FH.

Methods: We examined 282 patients with FH (144 males, mean age, 41 ± 17 years) whose RLP-C levels were measured.

Assessment of arterial stiffness in patients with familial hypercholesterolemia.

Background: Recently, the concept of severe familial hypercholesterolemia (FH) has been proposed to identify individuals at an extremely high risk of developing coronary artery disease (CAD) among patients with FH. Although the adverse effects of arterial stiffness have been proven in the general population, insufficient data exist regarding its clinical impact in patients with FH.

Objectives: This study aimed to assess the association between arterial stiffness and CAD in patients with FH.

Molecular and functional characterization of familial chylomicronemia syndrome.

Background And Aims: Familial chylomicronemia syndrome is a rare autosomal recessive disorder leading to severe hypertriglyceridemia (HTG) due to mutations in lipoprotein lipase (LPL)-associated genes. Few data exist on the clinical features of the disorder or on comprehensive genetic approaches to uncover the causative genes and mutations.

Methods: Eight patients diagnosed with familial hyperchylomicronemia with recessive inheritance were included in this study (two males and six females; median age of onset 23.

Assessments of Carotid Artery Plaque Burden in Patients With Familial Hypercholesterolemia.

Although both carotid intima-media thickness (cIMT) and carotid plaque score (cPS) determined by carotid ultrasonography reflect the severity of coronary atherosclerosis, there are few reports on direct comparisons of their clinical utilities in patients with familial hypercholesterolemia (FH). We aimed (1) to compare the clinical utilities of these measurements and (2) to estimate the onset and progression of carotid atherosclerosis in patients with FH. We examined 225 patients with FH (126 males; mean age, 51 ± 18 years) who underwent carotid ultrasonography.

Impact of evolocumab treatment on low-density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemic patients withdrawing from regular apheresis.

Background And Aims: Low-density lipoprotein (LDL) apheresis has been used to treat refractory hyperlipidemia such as familial hypercholesterolemia (FH). Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor used in clinical settings, can reduce LDL cholesterol (LDL-C) levels by >70%. Therefore, this study aimed to assess the impact of evolocumab on withdrawal from regular LDL apheresis in patients with heterozygous FH (HeFH).

Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease.

Rationale: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the gene may provide insight into the efficacy of CETP inhibition.

Objective: To test whether protein-truncating variants (PTVs) at the gene were associated with plasma lipid levels and CHD.

Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia.

Aims: The impact of positive clinical signs (xanthoma and/or family history) and positive familial hypercholesterolaemia (FH) mutation status on risk of coronary artery disease (CAD) over and above that predicted by low-density lipoprotein (LDL) cholesterol level alone has not been fully determined. We assessed whether positive clinical signs and genetic FH diagnosis affected CAD risk among subjects with significantly elevated LDL cholesterol levels (≥180 mg/dL, or ≥140 mg/dL in subjects <15 years of age).

Methods And Results: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 636 patients with severe hypercholesterolaemia (mean age, 45 years; 300 males [47%], CAD diagnosis, 185 [29%]), and the presence of clinical FH signs (xanthoma and/or family history) were assessed.

Prevalence, clinical features, and prognosis of patients with extremely low high-density lipoprotein cholesterol.

Background: Little data exist on the clinical features of patients with an extremely low level of high-density lipoprotein (HDL) cholesterol (<20 mg/dL).

Objective: To assess the clinical characteristics of Japanese patients with extremely low HDL cholesterol levels.

Methods: In this observational study of 429 patients with extremely low HDL cholesterol levels among 43,368 subjects whose HDL cholesterol was measured for any reason at Kanazawa University Hospital from April 2004 to March 2014, we investigated the presence of coronary artery disease, chronic kidney disease, the potential causes of reduced HDL cholesterol, their prognosis, and the cause of death.

Lipid Management in a Japanese Community:Attainment Rate of Target Set by the Japan Atherosclerosis Society Guidelines for the Prevention of Atherosclerotic Cardiovascular Diseases 2012.

Aim: The Japan Atherosclerosis Society (JAS) guidelines for the prevention of atherosclerotic diseases 2012 (JAS2012) proposed lipid management targets; however, less data is available regarding the attainment rates of each target in community-based settings. Therefore, we assessed the attainment rates of lipid management targets among subjects who underwent Japanese specific health checkups.

Methods: A total of 85,716 subjects (male=29,282, 34.

A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing.

Whole exome sequencing (WES) technologies have accelerated genetic studies of Mendelian disorders, yielding approximately 30% diagnostic success. We encountered a 13-year-old Japanese female initially diagnosed with familial hypercholesterolemia on the basis of clinical manifestations of severe hypercholesterolemia (initial LDL cholesterol=609 mg/dl at the age of one) and systemic intertriginous xanthomas with histories of recurrent self-limiting episodes of fever and arthritis. Both her phenotypes seemed to co-segregate in a recessive manner.

Changes in lipoprotein lipase and endothelial lipase mass in familial hypercholesterolemia during three-drug lipid-lowering combination therapy.

Background: This study was performed to compare the effects of three different lipid-lowering therapies (statins, ezetimibe, and colestimide) on lipoprotein lipase and endothelial lipase masses in pre-heparin plasma (pre-heparin LPL and EL mass, respectively) from patients with familial hypercholesterolemia (FH). FH is usually treated by coadministration of these three drugs.

Methods: The pre-heparin LPL and EL masses were measured in fresh frozen plasma drawn and stored at various time points during coadministration of the three drugs from patients with heterozygous FH harboring a single mutation in the LDL receptor (n = 16, mean age 63 years).

A de novo mutation of the LDL receptor gene as the cause of familial hypercholesterolemia identified using whole exome sequencing.

We report a rare case of heterozygous familial hypercholesterolemia (FH) caused by a de novo mutation in LDL receptor (LDLR) gene identified using whole exome sequencing. An 11-year-old female without any family histories of hypercholesterolemia was referred to our hospital to make clinical as well as molecular diagnoses. She was first diagnosed as hypercholesterolemia at the age of 3 (initial total cholesterol=381mg/dl) without any secondary causes.

Lipoprotein(a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Gain-of-Function Mutations.

Background: It has been shown that serum lipoprotein(a) [Lp(a)] is elevated in familial hypercholesterolemia (FH) with mutation(s) of the LDL receptor (LDLR) gene. However, few data exist regarding Lp(a) levels in FH with gain-of-function mutations of the PCSK9 gene.

Methods and results: We evaluated 42 mutation-determined heterozygous FH patients with aPCSK9gain-of-function mutation (FH-PCSK9, mean age 52, mean LDL-C 235 mg/dl), 198 mutation-determined heterozygous FH patients with aLDLRmutation (FH-LDLR, mean age 44, mean LDL-C 217 mg/dl), and 4,015 controls (CONTROL, mean age 56, mean LDL-C 109 mg/dl).

Clinical characteristics of Japanese patients with severe hypertriglyceridemia.

Background: Although of interest, few data exist on the clinical characteristics of Japanese patients with an extremely high triglyceride level (≥ 1000 mg/dL).

Objective: We assessed the clinical characteristics of Japanese patients with an extremely high triglyceride level.

Methods: We investigated the presence of coronary artery disease, history of pancreatitis, the presence of fatty liver, and the potential causes of elevated triglyceride in Japanese subjects with an extremely high level of fasting triglyceride (≥ 1000 mg/dL) among 70,368 subjects whose serum triglyceride was measured for any reason at Kanazawa University Hospital from April 2004 to March 2014.