Apoa5genetic Variants Are Markers for Classic Hyperlipoproteinemia
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Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia Akira Matsunaga1, Mariko Nagashima1, Hideko Yamagishi1 and Keijiro Saku2
The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Original Article J Atheroscler Thromb, 2020; 27: 1264-1277. http://doi.org/10.5551/jat.51540 Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia Akira Matsunaga1, Mariko Nagashima1, Hideko Yamagishi1 and Keijiro Saku2 1Department of Laboratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan 2Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan Aim: Hypertriglyceridemia is a type of dyslipidemia that contributes to atherosclerosis and coronary heart dis- ease. Variants in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), apolipoprotein AV (APOA5), glyco- sylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation fac- tor 1 (LMF1), and glucokinase regulator (GCKR) are responsible for hypertriglyceridemia. We investigated the molecular basis of severe hypertriglyceridemia in adult patients referred to the Clinical Laboratory at Fukuoka University Hospital. Methods: Twenty-three adult patients with severe hypertriglyceridemia (>1,000 mg/dL, 11.29 mmol/L) were selected. The coding regions of candidate genes were sequenced by next-generation sequencing. Forty-nine genes reportedly associated with hypertriglyceridemia were analyzed. Results: In the 23 patients, we detected 70 variants: 28 rare and 42 common ones. Among the 28 rare variants with <1% allele frequency, p.I4533L in APOB, -
LRP2 Is Associated with Plasma Lipid Levels 311 Original Article
310 Journal of Atherosclerosis and Thrombosis Vol.14, No.6 LRP2 is Associated with Plasma Lipid Levels 311 Original Article Genetic Association of Low-Density Lipoprotein Receptor-Related Protein 2 (LRP2) with Plasma Lipid Levels Akiko Mii1, 2, Toshiaki Nakajima2, Yuko Fujita1, Yasuhiko Iino1, Kouhei Kamimura3, Hideaki Bujo4, Yasushi Saito5, Mitsuru Emi2, and Yasuo Katayama1 1Department of Internal Medicine, Divisions of Neurology, Nephrology, and Rheumatology, Nippon Medical School, Tokyo, Japan. 2Department of Molecular Biology-Institute of Gerontology, Nippon Medical School, Kawasaki, Japan. 3Awa Medical Association Hospital, Chiba, Japan. 4Department of Genome Research and Clinical Application, Graduate School of Medicine, Chiba University, Chiba, Japan. 5Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, Chiba, Japan. Aim: Not all genetic factors predisposing phenotypic features of dyslipidemia have been identified. We studied the association between the low density lipoprotein-related protein 2 gene (LRP2) and levels of plasma total cholesterol (T-Cho) and LDL-cholesterol (LDL-C) among 352 adults in Japan. Methods: Subjects were obtained from among participants in a cohort study that was carried out with health-check screening in an area of east-central Japan. We selected 352 individuals whose LDL-C levels were higher than 140 mg/dL from the initially screened 22,228 people. We assessed the relation between plasma cholesterol levels and single-nucleotide polymorphisms (SNPs) in the LRP2 gene. Results: -
Case Report: Eruptive Xanthoma in a 14-Year-Old Boy Ryan M
Case Report: Eruptive Xanthoma in a 14-year-old boy Ryan M. Proctor, DO; Warren A. Peterson, DO; Michael W. Peterson, DO: Michael R. Proctor, DO; J. Ryan Jackson, DO; Andrew C. Duncanson OMS4; Allen E. Stout, DC. Dr. R. Proctor, Dr. W. Peterson, Dr. M. Peterson are from Aspen Dermatology Residency, Spanish Fork, UT; Dr. M. Proctor is from Arizona Desert Dermatology, Kingman, AZ; Dr. Jackson is from Sampson Regional Medical Center, Clinton, NC; OMS4 Duncanson is from Des Moines University, Des Moines, IA; DC Stout is from Stout Wellness Center, Fort Mohave, AZ. INTRODUCTION CLINICAL PHOTOS DISCUSSION Xanthomas are benign collections of lipid deposits that manifest as yellow to Eruptive xanthomas (EX) are often an indicator of severe red firm papules, nodules, or plaques. This yellow/red coloration is due to the hypertriglyceridemia and can indicate undiagnosed or Figure 1 Figure 2 carotene in lipids. Xanthomas are composed of lipid filled macrophages decompensated diabetes mellitus (DM).1 The triglyceride levels in known as “foam cells”. Xanthomas can be due to genetic disorders of lipid these patients can be >3000-4000 mg/dl (normal <150 mg/dl).2 metabolism, such as autosomal dominant hypocholesteremia or familial lipoprotein lipase(LPL) deficiency.1,2 They can also be caused by severe It is important to quickly diagnose and manage these patients due hypertriglyceridemia and have been associated with undiagnosed diabetic to the possible sequela of diabetes mellitus and hyperlipidemia. dyslipidemia, hypothyroidism, cholestasis, nephrotic -
Lrp1 Modulators
Last updated on February 14, 2021 Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer’s Drug Discovery Foundation (ADDF). These scientific reports include analysis of drugs, drugs-in- development, drug targets, supplements, nutraceuticals, food/drink, non-pharmacologic interventions, and risk factors. Neuroscientists evaluate the potential benefit (or harm) for brain health, as well as for age-related health concerns that can affect brain health (e.g., cardiovascular diseases, cancers, diabetes/metabolic syndrome). In addition, these reports include evaluation of safety data, from clinical trials if available, and from preclinical models. Lrp1 Modulators Evidence Summary Lrp1 has a variety of essential functions, mediated by a diverse array of ligands. Therapeutics will need to target specific interactions. Neuroprotective Benefit: Lrp1-mediated interactions promote Aβ clearance, Aβ generation, tau propagation, brain glucose utilization, and brain lipid homeostasis. The therapeutic effect will depend on the interaction targeted. Aging and related health concerns: Lrp1 plays mixed roles in cardiovascular diseases and cancer, dependent on context. Lrp1 is dysregulated in metabolic disease, which may contribute to insulin resistance. Safety: Broad-spectrum Lrp1 modulators are untenable therapeutics due to the high potential for extensive side effects. Therapies that target a specific Lrp1-ligand interaction are expected to have a better therapeutic profile. 1 Last updated on February 14, 2021 Availability: Research use Dose: N/A Chemical formula: N/A S16 is in clinical trials MW: N/A Half life: N/A BBB: Angiopep is a peptide that facilitates BBB penetrance by interacting with Lrp1 Clinical trials: S16, an Lrp1 Observational studies: sLrp1 levels are agonist was tested in healthy altered in Alzheimer’s disease, volunteers (n=10) in a Phase 1 cardiovascular disease, and metabolic study. -
Clusterin and LRP2 Are Critical Components of the Hypothalamic Feeding Regulatory Pathway
ARTICLE Received 21 Sep 2012 | Accepted 16 Apr 2013 | Published 14 May 2013 DOI: 10.1038/ncomms2896 Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway So Young Gil1, Byung-Soo Youn2, Kyunghee Byun3,4, Hu Huang5, Churl Namkoong1, Pil-Geum Jang1, Joo-Yong Lee1, Young-Hwan Jo6, Gil Myoung Kang1, Hyun-Kyong Kim1, Mi-Seon Shin7, Claus U. Pietrzik8, Bonghee Lee3,4, Young-Bum Kim3,5 & Min-Seon Kim1,7 Hypothalamic feeding circuits are essential for the maintenance of energy balance. There have been intensive efforts to discover new biological molecules involved in these pathways. Here we report that central administration of clusterin, also called apolipoprotein J, causes anorexia, weight loss and activation of hypothalamic signal transduction-activated transcript-3 in mice. In contrast, inhibition of hypothalamic clusterin action results in increased food intake and body weight, leading to adiposity. These effects are likely mediated through the mutual actions of the low-density lipoprotein receptor-related protein-2, a potential receptor for clusterin, and the long-form leptin receptor. In response to clusterin, the low-density lipoprotein receptor-related protein-2 binding to long-form leptin receptor is greatly enhanced in cultured neuronal cells. Furthermore, long-form leptin receptor deficiency or hypothalamic low-density lipoprotein receptor-related protein-2 suppression in mice leads to impaired hypothalamic clusterin signalling and actions. Our study identifies the hypotha- lamic clusterin–low-density lipoprotein receptor-related protein-2 axis as a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling. 1 Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 138-736, Korea. -
The Effect of Omega-3 Fatty Acids on Hypertriglyceridemia: a Review
Review Article ISSN: 2574 -1241 DOI: 10.26717/BJSTR.2020.26.004382 The Effect of Omega-3 Fatty Acids on Hypertriglyceridemia: A Review Alaa Abousetta, Ibrahim Abousetta, Theresa Dobler, Lia Ebrahimi, Vassillis Frangoullis, Stephanos Christodoulides and Ioannis Patrikios* School of Medicine, European University Cyprus, Cyprus *Corresponding author: Ioannis Patrikios, School of Medicine, European University Cyprus, Cyprus ARTICLE INFO Abstract Received: March 06, 2020 Hypertriglyceridemia is a common problem in adults in the developed world. It is associated with increased levels of triglycerides within the blood, which subsequently Published: March 17, 2020 promote the development of other diseases such as cardiovascular disease and pancreatitis. Triglycerides are mostly consumed through the diet and act as a source of energy in between meals. However, the levels of triglycerides increase proportionally Citation: Alaa A, Ibrahim A, Theresa D, Lia with the number of calories consumed. This only leads to a problem if the total daily E, Ioannis P, et al., The Effect of Omega-3 energy expenditure is exceeded. Additionally, the type of macronutrients taken in Fatty Acids on Hypertriglyceridemia: A Re- view. Biomed J Sci & Tech Res 26(4)-2020. for instance, high carbohydrate intake has been associated with an increased plasma BJSTR. MS.ID.004382. triglyceridethrough the level.diet has If thea direct levels influence of the triglycerideson having an inincreased the blood level rise of abovetriglycerides, 150 mg/ as Abbreviations: FHTG: Familial hypertri- dL, it is considered as hypertriglyceridemia. Increasing numbers of triglycerides can glyceridemia; FCH: Familial Combined Hy- have multiple underlying causes, which can be divided into primary and secondary perlipidemia, systemic lupus erythemato- causes. -
Other Types of Primary Hyperlipoproteinemia
82 Journal of Atherosclerosis and Thrombosis Vol.21, No.2 Committee Report 10 Other Types of Primary Hyperlipoproteinemia (Hyperlipidemia) Executive Summary of the Japan Atherosclerosis Society (JAS) Guidelines for the Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases in Japan ― 2012 Version Tamio Teramoto, Jun Sasaki, Shun Ishibashi, Sadatoshi Birou, Hiroyuki Daida, Seitaro Dohi, Genshi Egusa, Takafumi Hiro, Kazuhiko Hirobe, Mami Iida, Shinji Kihara, Makoto Kinoshita, Chizuko Maruyama, Takao Ohta, Tomonori Okamura, Shizuya Yamashita, Masayuki Yokode and Koutaro Yokote Committee for Epidemiology and Clinical Management of Atherosclerosis 1. Primary Hyperlipoproteinemias (Hyperlipidemias) enhanced hepatic apolipoprotein (apo) B-100 synthe- Other Than Familial Hypercholesterolemia sis, decreased LPL activity, increased very-low-density There are various types of primary hyperlipopro- lipoprotein (VLDL) secretion from the liver and the teinemias (hyperlipidemias) other than familial hyper- accumulation of visceral fat as factors for the develop- cholesterolemia (FH). These types are clinically ment of symptoms and has been reported to be related important and classified according to their associated to abnormalities of the LPL and APOC-Ⅱ genes or pathophysiology and genetic abnormalities (Table 1)1). APOA-Ⅰ/C-Ⅲ/A-Ⅳ gene cluster. However, none of Familial lipoprotein lipase (LPL) deficiency manifests these findings have been proven to be definitive. It has as severe hyperchylomicronemia and may present with also been suggested that FCHL is caused by a poly- eruptive cutaneous xanthomas or acute pancreatitis, genic background that tends to induce hyperlipopro- although it does not necessarily accompany atheroscle- teinemia due to environmental factors, such as over- rotic cardiovascular disease (CVD). On the other nutrition and a low level of physical activity. -
Severe Hypertriglyceridemia in a Patient Heterozygous for a Lipoprotein Lipase Gene Allele with Two Novel Missense Variants
European Journal of Human Genetics (2015) 23, 1259–1261 & 2015 Macmillan Publishers Limited All rights reserved 1018-4813/15 www.nature.com/ejhg SHORT REPORT Severe hypertriglyceridemia in a patient heterozygous for a lipoprotein lipase gene allele with two novel missense variants Ursula Kassner*,1, Bastian Salewsky2,3, Marion Wühle-Demuth1, Istvan Andras Szijarto1, Thomas Grenkowitz1, Priska Binner4, Winfried März4,5,6, Elisabeth Steinhagen-Thiessen1,2 and Ilja Demuth*,2,3 Rare monogenic hyperchylomicronemia is caused by loss-of-function mutations in genes involved in the catabolism of triglyceride-rich lipoproteins, including the lipoprotein lipase gene, LPL. Clinical hallmarks of this condition are eruptive xanthomas, recurrent pancreatitis and abdominal pain. Patients with LPL deficiency and severe or recurrent pancreatitis are eligible for the first gene therapy treatment approved by the European Union. Therefore the precise molecular diagnosis of familial hyperchylomicronemia may affect treatment decisions. We present a 57-year-old male patient with excessive hypertriglyceridemia despite intensive lipid-lowering therapy. Abdominal sonography showed signs of chronic pancreatitis. Direct DNA sequencing and cloning revealed two novel missense variants, c.1302A4T and c.1306G4A, in exon 8 of the LPL gene coexisting on the same allele. The variants result in the amino-acid exchanges p.(Lys434Asn) and p.(Gly436Arg). They are located in the carboxy-terminal domain of lipoprotein lipase that interacts with the glycosylphosphatidylinositol- anchored HDL-binding protein (GPIHBP1) and are likely of functional relevance. No further relevant mutations were found by direct sequencing of the genes for APOA5, APOC2, LMF1 and GPIHBP1. We conclude that heterozygosity for damaging mutations of LPL may be sufficient to produce severe hypertriglyceridemia and that chylomicronemia may be transmitted in a dominant manner, at least in some families. -
Evaluation and Treatment of Hypertriglyceridemia: an Endocrine Society Clinical Practice Guideline
SPECIAL FEATURE Clinical Practice Guideline Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline Lars Berglund, John D. Brunzell, Anne C. Goldberg, Ira J. Goldberg, Frank Sacks, Mohammad Hassan Murad, and Anton F. H. Stalenhoef University of California, Davis (L.B.), Sacramento, California 95817; University of Washington (J.D.B.), Seattle, Washington 98195; Washington University School of Medicine (A.C.G.), St. Louis, Missouri 63110; Columbia University (I.J.G.), New York, New York 10027; Harvard School of Public Health (F.S.), Boston, Massachusetts 02115; Mayo Clinic (M.H.M.), Rochester, Minnesota 55905; and Radboud University Nijmegen Medical Centre (A.F.H.S.), 6525 GA Nijmegen, The Netherlands Objective: The aim was to develop clinical practice guidelines on hypertriglyceridemia. Participants: The Task Force included a chair selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), five additional experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Consensus Process: Consensus was guided by systematic reviews of evidence, e-mail discussion, conference calls, and one in-person meeting. The guidelines were reviewed and approved sequen- tially by The Endocrine Society’s CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. Conclusions: The Task Force recommends that the diagnosis of hypertriglyceridemia be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150–999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hyper- triglyceridemia (triglycerides of Ͼ 1000 mg/dl) be considered a risk for pancreatitis. -
Familial Partial Lipodystrophy
Familial Partial Lipodystrophy Purvisha Patel; Ralph Starkey, MD; Michele Maroon, MD The lipodystrophies are rare disorders character- ized by insulin resistance and the absence or loss of body fat. The 4 subtypes of lipodystrophy are characterized by onset and distribution. Partial lipodystrophy is rare, with loss of fat from the extremities and excess fat accumulation in the face and neck; recognizing this phenotype and subsequent referral for endocrinologic care may improve outcome and reduce mortality. ipodystrophies are rare disorders characterized by insulin resistance and the absence or L loss of body fat.1 Classification of the 4 main subtypes of lipodystrophy is based on onset (congenital/familial vs acquired/sporadic) and dis- Figure not available online tribution (total/generalized vs partial). Congenital total lipodystrophy (also known as Berardinelli syndrome, Seip syndrome) is a rare autosomal- recessive disorder marked by an almost complete lack of adipose tissue from birth. Familial partial lipodystrophy (also known as Kobberling-Dunnigan syndrome) involves loss of subcutaneous fat from the extremities and accumulation of excess fat in the face and neck and to a lesser extent in the hands and feet. Acquired total lipodystrophy (also known as lipoatrophy, Lawrence-Seip syndrome) presents with generalized loss of fat beginning in childhood. Acquired partial lipodystrophy (also known as progressive lipodystrophy, partial lipoat- Figure 1. Accentuation of fat pads in the face and neck. rophy, Barraquer-Simons syndrome) is character- ized by loss of fat only from the upper extremities, face, and trunk.2 tional uterine bleeding (gravida 2, para 1, AB 1) Case Report necessitating total hysterectomy. On physical A 39-year-old white woman presented with the examination, accentuation of fat pads in the face complaint of thickened brown skin on the neck and and neck (Figure 1), central obesity, and prominent medial thighs. -
Management of Hypertriglyceridemia BMJ: First Published As 10.1136/Bmj.M3109 on 12 October 2020
STATE OF THE ART REVIEW Management of hypertriglyceridemia BMJ: first published as 10.1136/bmj.m3109 on 12 October 2020. Downloaded from Vinaya Simha ABSTRACT Hypertriglyceridemia is one of the most common lipid abnormalities encountered in clinical practice. Many monogenic disorders causing severe hypertriglyceridemia have been identified, but in most patients triglyceride elevations result from a Division of Endocrinology, Mayo combination of multiple genetic variations with small effects and environmental Clinic, Rochester, MN 55905, USA factors. Common secondary causes include obesity, uncontrolled diabetes, alcohol Correspondence to: misuse, and various commonly used drugs. Correcting these factors and optimizing [email protected] Cite this as: BMJ 2020;371:m3109 lifestyle choices, including dietary modification, is important before starting http://dx.doi.org/10.1136/bmj.m3109 drug treatment. The goal of drug treatment is to reduce the risk of pancreatitis in Series explanation: State of the Art Reviews are commissioned patients with severe hypertriglyceridemia and cardiovascular disease in those on the basis of their relevance with moderate hypertriglyceridemia. This review discusses the various genetic and to academics and specialists in the US and internationally. acquired causes of hypertriglyceridemia, as well as current management strategies. For this reason they are written predominantly by US authors. Evidence supporting the different drug and non-drug approaches to treating hypertriglyceridemia is examined, and an easy to adopt step-by-step management strategy is presented. Introduction independent risk factor for ASCVD and optimal drug Hypertriglyceridemia is a fairly common clinical treatment, including novel and emerging therapies, condition, but it continues to evoke considerable to mitigate this will be examined in greater detail. -
Common Genetic Variations Involved in the Inter-Individual Variability Of
nutrients Review Common Genetic Variations Involved in the Inter-Individual Variability of Circulating Cholesterol Concentrations in Response to Diets: A Narrative Review of Recent Evidence Mohammad M. H. Abdullah 1 , Itzel Vazquez-Vidal 2, David J. Baer 3, James D. House 4 , Peter J. H. Jones 5 and Charles Desmarchelier 6,* 1 Department of Food Science and Nutrition, Kuwait University, Kuwait City 10002, Kuwait; [email protected] 2 Richardson Centre for Functional Foods & Nutraceuticals, University of Manitoba, Winnipeg, MB R3T 6C5, Canada; [email protected] 3 United States Department of Agriculture, Agricultural Research Service, Beltsville, MD 20705, USA; [email protected] 4 Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada; [email protected] 5 Nutritional Fundamentals for Health, Vaudreuil-Dorion, QC J7V 5V5, Canada; [email protected] 6 Aix Marseille University, INRAE, INSERM, C2VN, 13005 Marseille, France * Correspondence: [email protected] Abstract: The number of nutrigenetic studies dedicated to the identification of single nucleotide Citation: Abdullah, M.M.H.; polymorphisms (SNPs) modulating blood lipid profiles in response to dietary interventions has Vazquez-Vidal, I.; Baer, D.J.; House, increased considerably over the last decade. However, the robustness of the evidence-based sci- J.D.; Jones, P.J.H.; Desmarchelier, C. ence supporting the area remains to be evaluated. The objective of this review was to present Common Genetic Variations Involved recent findings concerning the effects of interactions between SNPs in genes involved in cholesterol in the Inter-Individual Variability of metabolism and transport, and dietary intakes or interventions on circulating cholesterol concen- Circulating Cholesterol trations, which are causally involved in cardiovascular diseases and established biomarkers of Concentrations in Response to Diets: cardiovascular health.