Putative Pathogenic Variants of ABCG5 and ABCG8 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 (ABCG5) or ATP-binding cassette sub-family G member 8 (ABCG8). There are only few data on the pathogenicity of ABCG5 and ABCG8. This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia. Methods: This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targeted-sequenced data on ABCG5 or ABCG8 (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. ABCG5 or ABCG8 variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL. Results: Twenty-three ABCG5 or ABCG8 variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5-17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5-4.1] µg/mL) in 14 individuals. Conclusion: The scheme proposed for assessing the pathogenicity of genetic variations (ABCG5 and ABCG8) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in ABCG5 or ABCG were classified.

A teenager boy with a novel variant of Sitosterolemia presented with pancytopenia.

BACKGROUND: Sitosterolemia, also known as phytosterolemia, results from increased intestinal absorption of plant sterols and decreased intestinal and biliary excretion of sterols, resulting in increased levels of plant sterols in the plasma. The most common symptoms include xanthomas, premature atherosclerosis, hemolytic anemia and macrothrombocytopenia, however delayed diagnosis or misdiagnosis also occur. PATIENT AND METHODS: Clinical exome sequencing was performed on a 10-year-old boy whom we followed up with signs of pancytopenia accompanied by macrothrombocytopenia and stomatocytosis. In addition, the blood sterol levels of the patient and his family were studied. RESULTS: A novel homozygous c.904 + 5G > C intronic variant was detected in ABCG5 gene in index case. The mother and father were identified as carriers. The blood plant sterol levels of the patient and his family were studied, and the levels in the patient confirmed Sitosterolemia. Sitosterol levels decreased dramatically with restricted diet and ezetimibe treatment. CONCLUSION: In children, signs of Sitosterolemia may be subtle and the only symptom may be hematological. Therefore, Sitosterolemia should be kept in mind in children with stomatocytosis and macrothrombocytopenia.

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. METHODS: This study included 52,276 subjects (18,588 men, 35.6%) aged ≥40 years who underwent the Japanese specific health checkup in Kanazawa City during 2018. We assessed the self-awareness of dyslipidemia (and the age) as well as the prevalence of patients with highly suspected as FH whose naïve LDL-C levels were ≥250 â€‹mg/dl. Naïve LDL-C levels were estimated by the adjustment (LDL-C/0.7) for those on lipid-lowering medication. We divided subjects into 3 groups based on their naïve LDL cholesterol level (≥250 â€‹mg/dl, 140-249, and ≤139 â€‹mg/dl). RESULTS: We identified 262 (0.5%) individuals highly suspected as FH whose naïve LDL-C levels were ≥250 â€‹mg/dl. Most of them (234 among 262, 89%) were under lipid-lowering medication; however, the self-awareness as dyslipidemia was not quite high (200 among 262, 76%), and their mean LDL-C level under lipid-lowering medication was 203 â€‹± â€‹35 â€‹mg/dl. Interestingly, the age of acknowledgement of dyslipidemia among the patients with highly suspected as FH was significantly younger than those in other categories (58 vs. 60/62 â€‹yrs, respectively, p â€‹< â€‹0.05 for both). CONCLUSIONS: The prevalence of patients highly suspected as FH was around 1 in 200, and their self-awareness as well as control were not still good enough among Japanese general populations.

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. On the other hand, few data-and in particular multicentre data-exist regarding this issue among Japanese subjects. Therefore, this study intends to assemble a multicentre registry that aims to comprehensively assess cardiovascular risk among Japanese FH patients while taking into account their genetic backgrounds. METHODS AND ANALYSIS: The Hokuriku-plus FH registry is a prospective, observational, multicentre cohort study, enrolling consecutive FH patients who fulfil the clinical criteria of FH in Japan from 37 participating hospitals mostly in Hokuriku region of Japan from April 2020 to March 2024. A total of 1000 patients will be enrolled into the study, and we plan to follow-up participants over 5 years. We will collect clinical parameters, including lipids, physical findings, genetic backgrounds and clinical events covering atherosclerotic and other important events, such as malignancies. The primary endpoint of this study is new atherosclerotic cardiovascular disease (ASCVD) events. The secondary endpoints are as follows: LDL cholesterol, secondary ASCVD events and the occurrence of other diseases including hypertension, diabetes and malignancies. ETHICS AND DISSEMINATION: This study is being conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. This study protocol has been approved by the Institutional Review Board at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000038210.

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. We compared serum lipids and serum sitosterol among those groups, and tried to validate the cutoff value discriminating patients of sitosterolemia with double mutations from others. RESULTS: We identified 8 individuals with sitosterolemia with double mutations (affected), 26 individuals with a single mutation (carrier), and 172 individuals without any mutations (wildtype control). Serum sitosterol level of patients with sitosterolemia with double mutations (affected) exhibited significantly higher than those of any other groups (45.2. vs. 7.9 µg/ml, p = 2.5 × 10-2, 45.2 vs. 3.1 µg/ml, p = 1.8 × 10-2). Under these conditions, a cutoff value of sitosterol 10 µg/ml could discriminate the patients with sitosterolemia with double mutations in ABCG5 or ABCG8 gene from no mutation carrier (wildtype control) perfectly, although 6 heterozygous mutation carries exhibited sitosterol level greater than 10 µg/ml. Receiver-operating characteristic (ROC) analysis predicting double mutation status showed that the best cut-off value was 14.81 µg/ml. CONCLUSION: We suggest a cutoff value of sitosterol 15 µg/ml that shows higher positive predictive value than 10 µg/ml.

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. Although there is no clear definition of remnant lipoproteins, they typically include chylomicron remnants, which are lipolyzed particles from chylomicron, as well as very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) remnants that are lipolyzed particles from VLDL and IDL particles. However, the most important factor of these lipoproteins is such remnant lipoproteins seem to be causally associated with ASCVD, independent of LDL particles or LDL cholesterol. It has been challenging to assert a causal association of remnant lipoproteins and ASCVD; however, accumulated evidence from epidemiological studies, as well as recent Mendelian randomization studies from common and rare genetic variations strongly support this association. In this article, a basic explanation of lipoprotein metabolism is presented, including remnant lipoproteins and the important causal associations with ASCVD from a clinical point of view.

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. RESULTS: We identified possible causative variants for severe HTG, including three novel variants, in nine probands (32%). In the recessive inheritance model, we identified two homozygous subjects with lipoprotein lipase (LPL) deficiency and one subject harboring compound heterozygous variants in both LPL and APOA5 genes (hyperchylomicronemia). In the dominant inheritance model, we identified probands harboring deleterious heterozygous variants in LPL, glucokinase regulatory protein, and solute carrier family 25 member 40 genes, possibly associated with this extreme HTG phenotype. However, gene prioritization and CNV analyses did not validate the novel genes associated with severe HTG. CONCLUSIONS: In 28 probands with severe HTG, we identified potential causative variants within nine genes associated with rare Mendelian dyslipidemias. Clinical WES may be feasible for such extreme cases, potentially leading to appropriate therapies.

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). We sequenced the exons of 3 FH genes (LDLR, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9) and 4 LDL-altering accessory genes (ABCG5, ABCG8, APOE, and LDL receptor adaptor protein 1). In addition, 4 single nucleotide polymorphisms associated with polygenic FH in East Asian subjects were genotyped. Oligogenic FH patients were defined as those who harbored damaging variants of both conventional FH genes and LDL-altering accessory genes. RESULTS: We identified damaging variants of conventional FH genes in 248 participants (50%). We also detected damaging variants in accessory genes in 57 patients (11%) and identified oligogenic FH in 27 of these patients (5%). Polygenic score in the subjects without any FH mutations was significantly higher than those in any other groups. Compared with monogenic FH, oligogenic FH exhibited significantly higher LDL cholesterol (265 mg/dL, 95% confidence interval [CI] 216-312, and 210 mg/dL, 95% CI 189-243; P = .04). Oligogenic FH exhibited higher odds for coronary artery disease when compared with monogenic FH, although it did not reach statistical significance (odds ratio 1.41, 95% CI 0.68-2.21, P = .24). CONCLUSIONS: Among patients with elevated LDL cholesterol, those with oligogenic FH had higher LDL cholesterol than monogenic FH.

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 (m2); 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). The incremental area under curve (iAUC) of lipids, including LDL-C, apolipoprotein B-48 (apoB48), RLP cholesterol (RLP-C), and RLP triglyceride (RLP-TG) were evaluated. RESULTS: After oral fat load, there was no significant difference of the iAUC of LDL-C between sitosterolemia and heterozygous FH, whereas the iAUC of apoB48 was significantly larger in the sitosterolemic subjects compared with that of heterozygous FH (2.9 µg/mL×h vs. 1.3 µg/mL×h, p＜0.05). Under these conditions, the iAUCs of RLP-C and RLP-TG levels were significantly larger in the sitosterolemic subject compared with those of heterozygous FH (9.5 mg/dL×h vs. 5.7 mg/dL×h, p＜0.05; 149 mg/dL×h vs. 40 mg/dL×h, p＜0.05, respectively), whereas those of heterozygous carriers were comparable with those with heterozygous FH. CONCLUSIONS: Post-prandial lipoprotein metabolism in sitosterolemia appeared to be impaired, leading to their elevation in serum sterol levels. (UMIN Clinical Trials Registry number, UMIN000020330).

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. Furthermore, accumulated evidence, including infantile cases exhibiting progression/regression of systemic xanthomas associated with LDL cholesterol levels, have shown that the elevation of LDL cholesterol seems to be the major cause of development of atherosclerosis and not the elevation of sitosterol. Regarding therapies, LDL apheresis, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, could be useful for sitosterolemia, in addition to ezetimibe and/or colestimide. In this study, we provide the current understanding and future perspectives of sitosterolemia, which is currently considered an extremely rare disorder but is expected to be much more prevalent in clinical settings.

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 ±â€¯17 years) whose RLP-C levels were measured. We assessed the baseline characteristics, including lipid levels, other conventional risk factors for cardiovascular events, the presence of CAD, and the serum RLP-C levels. RESULTS: Serum RLP-C levels significantly correlated with serum triglyceride (TG) levels (Pearson's r = 0.631, p < 0.001). We observed that a larger proportion of individuals in the higher tertiles of serum RLP-C had a larger number of diseased coronary arteries (p < 0.001 for the trend of multi-vessel disease). Logistic regression analysis, after adjusting for age, sex, hypertension, diabetes, smoking, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoprotein (a) [Lp(a)], revealed that RLP-C was significantly associated with CAD [odds ratio (OR): 1.08, 95% confidence interval (CI): 1.00-1.16, p = 0.046]; however, adding serum TG levels into the logistic regression model nullified this association (OR: 1.07, 95% CI: 0.98-1.17, p = 0.141), whereas Lp(a) was independently associated with CAD (OR: 1.02, 95% CI: 1.00-1.03, p = 0.015). CONCLUSIONS: Serum RLP-C levels were significantly associated with the presence and severity of CAD in patients with FH. However, the clinical usefulness of measuring RLP-C levels beyond that of measuring TG levels should be further assessed.

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. METHODS: We examined 245 patients with FH (162 males; mean age, 46 ± 17 years) and brachial-ankle pulse wave velocity (baPWV) measurements. We assessed baseline characteristics including lipid profiles, other traditional risk factors, the presence of CAD, and the baPWV. RESULTS: Multivariable logistic analysis adjusted for age, sex, hypertension, diabetes, smoking, and low-density lipoprotein cholesterol revealed that the baPWV was independently associated with CAD (odds ratio [OR]: 1.25, 95% confidence interval: 1.10-1.41; P = .000372; per 100 cm/s). Moreover, considering the baPWV with other traditional risk factors improved the risk discrimination of CAD (C-statistics 0.736 vs 0.799; P = .006067). Compared with the reference group without hypertension and low baPWV, patients with hypertension and high baPWV had a significantly higher OR for CAD (OR: 18.68, 95% confidence interval: 6.62-60.62; P = 1.7 × 10-7). CONCLUSIONS: Arterial stiffness assessed by the baPWV was significantly associated with the presence of CAD in patients with FH. Such assessments are useful in the risk stratification of CAD and are independent of hypertension 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 23.0 years; mean triglyceride level 3446 mg/dl). We evaluated their clinical features, including coronary artery disease using coronary computed tomography, and performed targeted next-generation sequencing on a panel comprising 4813 genes associated with known clinical phenotypes. After standard filtering for allele frequency <1% and in silico annotation prediction, we used three types of variant filtering to identify causative mutations: homozygous mutations in known familial hyperchylomicronemia-associated genes, homozygous mutations with high damaging scores in novel genes, and deleterious mutations within 37 genes known to be associated with HTG. RESULTS: A total of 1810 variants out of the 73,389 identified with 94.3% mean coverage (×20) were rare and nonsynonymous. Among these, our schema detected four pathogenic or likely pathogenic mutations in the LPL gene (p.Ala248LeufsTer4, p.Arg270Cys, p.Ala361Thr, and p.Val227Gly), including one novel mutation and a variant of uncertain significance. Patients harboring LPL gene mutations showed no severe atherosclerotic changes in the coronary arteries, but recurrent pancreatitis with long-term exposure to HTG was observed. CONCLUSIONS: These results demonstrate that LPL gene plays a major role in extreme HTG associated with hyperchylomicronemia, although the condition may not cause severe atherosclerosis.

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. We assessed baseline characteristics including lipid levels, other traditional risk factors, and the presence of coronary artery disease (CAD) as well as mean cIMT and cPS. Multivariate logistic analysis revealed that cPS was significantly associated with CAD (odds ratio [OR] 1.22, 95% confidence interval (CI) 1.10-1.37, p = 0.00036), whereas cIMT was not (OR 1.26, 95% CI 0.15 to 11.76, p = 0.84). Adding cPS information to other traditional risk factors improved the risk discrimination of CAD (C-index 0.887 vs 0.909, p = 0.030), whereas adding cIMT information did not (C-index 0.887 vs 0.893, p = 0.33). Regression equations were Y = 0.219X - 3.74 (r = 0.65, p < 0.001) in male and Y = 0.215X - 5.47 (r = 0.72, p < 0.001) in female patients with FH. In conclusion, cPS may provide superior risk stratification in patients with FH compared with cIMT. On average, carotid atherosclerosis may develop at 17 and 26 years of age in male and female patients with heterozygous FH, respectively.

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). METHODS: Eleven patients with HeFH undergoing biweekly LDL apheresis were enrolled and were subsequently switched to a biweekly subcutaneous injection of 140 mg of evolocumab. The primary endpoints were percent changes in mean LDL-C and apolipoprotein B (apoB) serum levels, which were averages of two different time point measurements, due to the switch in the treatment method. RESULTS: The mean LDL-C and apoB serum levels significantly reduced from 2.55 ± 0.62 mmol/L to 0.96 ± 0.40 mmol/L (-62.5%, p < 0.0001) and from 82.8 ± 12.3 mg/dL to 45.4 ± 10.9 mg/dL (-45.2%, p < 0.0001), respectively. Serum lipoprotein (a) levels also significantly reduced from 148 (116-351) mg/L to 91 (53-289) mg/L (-38.5%, p < 0.01). The reduction in LDL-C and apoB levels was not associated with the basal serum levels of PCSK9 or cholesterol production/absorption markers. Although evolocumab significantly reduced serum vitamin E levels, they were still within the normal range, and no subjective or objective side effects were observed. CONCLUSIONS: Compared to biweekly LDL apheresis, biweekly evolocumab injection therapy is less expensive, less invasive, less time-consuming, and more effective in reducing atherogenic lipoprotein levels without severe adverse side effects.

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 CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for 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. CAD prevalence was compared between four subject groups categorized based on these parameters. Compared with the reference group without FH mutations or clinical signs of FH, subjects with clinical signs of FH or FH mutations had three- to four-fold higher odds of developing CAD (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.5-14.5; P = 0.0011 and OR, 3.4; 95% CI, 1.0-10.9; P = 0.0047, respectively), whereas those with clinical signs of FH and FH mutation(s) had >11-fold higher odds of developing CAD (OR, 11.6; 95% CI, 4.4-30.2; P = 1.1 × 10-5) after adjusting for known risk factors including LDL cholesterol. CONCLUSION: Our findings revealed an additive effect of positive clinical signs of FH and positive FH mutation status to CAD risk among patients with significantly elevated LDL cholesterol.

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, 34.2%) aged 40-74 years who underwent specific health checkups from 2012 to 2014 in Kanazawa city, Japan, were included in this study. We evaluated the attainment rates of the lipid management targets according to the JAS2012 guideline and investigated the clinical characteristics of the subjects without achieving the targets. RESULTS: The target for LDL cholesterol (LDL-C) was the least attained in all risk categories, 89, 72, 50, and 34% for category I, II, III, and secondary prevention, respectively, in 2014. In addition, these rates inversely correlated with the grade of risk categories (p-value for trends ＜0.001). Attainment rate of the LDL-C target in the suspected chronic kidney disease (CKD) group was significantly lower than in the groups with diabetes, stroke, or absolute risk in category III (49.2, 60.3, 63.5, 54.4%, respectively, p-value ＜0.001 for each). Moreover, the attainment rate of the LDL-C target was significantly lower in subjects that did not receive lipid-lowering therapy than in those who received it in the secondary prevention (27.7 and 40.6%, respectively, p-value ＜0.001). CONCLUSIONS: Lipid management is inadequate in community-based settings, particularly, in subjects with CKD and secondary prevention.

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. RESULTS: Most patients (n = 425, 99%) exhibited secondary causes, including malignancies (n = 157, 37%), inflammatory diseases (n = 219, 51%), or other critical situations, such as major bleeding (n = 58, 14%). During the median 175-day follow-up period, 106 patients died. The causes of death in 80 (75%) patients were malignancies, inflammatory diseases, or major bleeding, in contrast to a relatively low incidence of death from atherosclerotic cardiovascular disease (n = 10, 10%). Multiple regression analysis showed that the presence of malignancy and HDL cholesterol was independently associated with death, in addition to age. The cumulative survival curve revealed that patients with an HDL cholesterol of <15 mg/dl, determined using the receiver-operating characteristic curve, had significantly higher mortality than those whose HDL cholesterol level was ≥15 mg/dL. CONCLUSIONS: Extremely low HDL cholesterol levels could be a useful marker for poor prognosis, not necessarily related to cardiovascular diseases.