Low-density Lipoprotein Receptor Mutations Research Articles

Heterozygous type 1 familial hypercholesterolemia patient with a rare LDL receptor mutation and the efficacy of evolocumab in the management of consequent hyperlipidemia

Heterozygous type 1 familial hypercholesterolemia patient with a rare LDL receptor mutation and the efficacy of evolocumab in the management of consequent hyperlipidemia

Novel LDLR variants affecting low density lipoprotein metabolism identified in familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant disease of lipid metabolism mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Genetic detection of patients with FH help with precise diagnosis and treatment, thus reducing the risk of coronary heart disease (CHD) and other related diseases. The study aimed to identify the causative gene mutations in a Chinese FH family and reveal the pathogenicity and the mechanism of these mutations. Whole exome sequencing was performed in a patient with severe lipid metabolism dysfunction seeking fertility guidance from a Chinese FH family. Two LDLR variants c.1875C > G (p.N625K; novel variant) and c.1448G > A (p.W483*) were identified in the family. Wildtype and mutant LDLR constructs were established by the site-direct mutagenesis technique. Functional studies were carried out by cell transfection to evaluate the impact of detected variants on LDLR activity. The two variants were proven to affect LDL uptake and binding, resulting in cholesterol clearance reduction to different degrees. According to The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, the W483* variant was classified as "Pathogenic", while the N625K variant as "VUS". Our results provide novel experimental evidence of functional alteration by LDLR variants identified in our study and expand the mutational spectrum of LDLR mutation induced FH.

IPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia.

Defects in the low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. LDLR deficiency in hepatocytes leads to elevated blood cholesterol levels, which damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully understood. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSCs) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-ECs), we detected the LDLR protein predominantly in its mature form, whereas iPSC-ECs from FH patients have reduced levels of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of mutant LDLR iPSC-ECs revealed a unique transcriptome profile with downregulated genes related to monocarboxylic acid transport, exocytosis, and cell adhesion, whereas upregulated signaling pathways were involved in cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increase the susceptibility of endothelial cells to inflammation and oxidative stress. In combination with elevated extrinsic cholesterol levels, this may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies associated with FH.

Identification of LDLR mutation in cerebral venous sinus thrombosis co-existing with dural arteriovenous fistulas: a case report

BackgroundCerebral venous sinus thrombosis (CVST) is typically associated with a prothrombotic state of the blood, with its causative factors varying widely. Prior research has not reported the simultaneous occurrence of CVST and dural arteriovenous fistulas (DAVFs) as potentially resulting from genetic mutations. In this case report, we introduce a unique occurrence wherein a patient with a heterozygous mutation of the low-density lipoprotein receptor (LDLR) gene presented with CVST in conjunction with DAVFs.CasePresentation: A male patient, aged 51, sought treatment at our facility due to a consistent decline in cognitive functions accompanied by recurrent headaches. Comprehensive evaluations were administered, including neurological examinations, laboratory tests, magnetic resonance imaging, digital subtraction angiography, and whole exome sequencing. Digital subtraction angiography identified DAVFs in the patient’s right sigmoid sinus and an occlusion within the left transverse sinus. The whole exome sequencing of blood samples pinpointed a heterozygous mutation in the LDLR gene (NM_000527:exon12:c.C1747T:p.H583Y). Following the confirmed diagnosis of CVST and DAVFs, the patient underwent anticoagulant therapy combined with endovascular procedures — these comprised embolization of the arteriovenous fistula in the right sigmoid sinus and balloon dilation with stent implantation in the left transverse sinus. A six-month follow-up indicated a significant abatement in the patient’s symptoms.ConclusionsThis report marks the first documented case of an LDLR gene mutation that could be associated with the onset of CVST and DAVFs. The mutation in the LDLR gene might foster a prothrombotic environment, facilitating the gradual emergence of CVST and the subsequent genesis of DAVFs.

The Long-Term Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia

BackgroundHomozygous familial hypercholesterolemia (HoFH) is characterized by early-onset atherosclerotic cardiovascular disease due to the high low-density lipoprotein cholesterol (LDL-C) burden. Patients with null-null low-density lipoprotein receptor (LDLR) variants respond poorly, if at all, to statins and proprotein convertase subtilisin/kexin type 9 inhibitors, which act by upregulating LDLR expression. The 24-week double-blind treatment period (DBTP) of the phase 3 ELIPSE HoFH (Evinacumab Lipid Studies in Patients with Homozygous Familial hypercholesterolemia; NCT03399786) study demonstrated significant LDL-C reductions in patients with HoFH; LDL-C reductions were also observed in those with null-null LDLR mutations. ObjectivesThe purpose of this study was to evaluate longer-term efficacy and safety of evinacumab in patients with HoFH from the ELIPSE HoFH study. MethodsPatients with HoFH on stable lipid-lowering therapies (LLTs) ± lipoprotein apheresis and screening LDL-C ≥70 mg/dL who completed the DBTP entered the 24-week open-label treatment period (OLTP) and received intravenous evinacumab 15 mg/kg every 4 weeks. OLTP results were summarized descriptively. ResultsA total of 64 patients completed the DBTP and received open-label evinacumab. Despite multiple LLTs, the mean baseline LDL-C at DBTP entry was 250.5 ± 162.3 mg/dL. From baseline to week 48 (end of OLTP), evinacumab reduced mean LDL-C by 46.3% (mean reduction, 134.3 ± 117.3 mg/dL), with similar mean LDL-C reductions for patients with null-null (47.2%) and non-null variants (45.9%). Adverse events occurred in 47 (73.4%) patients; 4 (6.3%) patients experienced adverse events considered evinacumab-related (drug hypersensitivity, infusion-related reaction and asthenia, generalized pruritis, and muscle spasms). ConclusionsIn patients with HoFH, evinacumab demonstrated substantial and sustained LDL-C reduction regardless of LDLR function, and was generally well tolerated.

Age, Origin and Functional Study of the Prevalent LDLR Mutation Causing Familial Hypercholesterolaemia in Gran Canaria.

The p.(Tyr400_Phe402del) mutation in the LDL receptor (LDLR) gene is the most frequent cause of familial hypercholesterolaemia (FH) in Gran Canaria. The aim of this study was to determine the age and origin of this prevalent founder mutation and to explore its functional consequences. For this purpose, we obtained the haplotypic information of 14 microsatellite loci surrounding the mutation in one homozygous individual and 11 unrelated heterozygous family trios. Eight different mutation carrier haplotypes were identified, which were estimated to originate from a common ancestral haplotype 387 (110-1572) years ago. This estimation suggests that this mutation happened after the Spanish colonisation of the Canary Islands, which took place during the fifteenth century. Comprehensive functional studies of this mutation showed that the expressed LDL receptor was retained in the endoplasmic reticulum, preventing its migration to the cell surface, thus allowing us to classify this LDLR mutation as a class 2a, defective, pathogenic variant.

Successful treatment with lomitapide in a patient with homozygous familial hypercholesterolemia and severe fatty liver disease

Introduction and Aims: Homozygous-familial hypercholesterolemia (Ho-FH) is a rare condition due to biallelic mutations in low-density lipoprotein-receptor (LDL-R) genes characterized by high level of LDL-cholesterol (LDL-c) and huge risk of premature atherosclerotic cardiovascular disease (ASCVD), determining low quality of life and life expectancy. Lomitapide represents a therapeutic option for Ho-FH, but caution should be observed when used in fatty liver disease (FLD) and hypertransaminasemia since it is associated with onset/worsening of liver steatosis. We present a case of safe lomitapide therapy in an adult Ho-FH patient with pre-existing FLD. Case presentation: A 39-year-old man with severe hypercholesterolemia since childhood (LDL-c 405 mg/dl) and premature coronary heart disease history, was referred to our Modena Lipid Clinic. He presented an overt metabolic syndrome, FLD with hypertransaminasemia and elastosonographic significant liver fibrosis. Lipid-lowering-therapy (LLT) included rosuvastatin 20 mg, ezetimibe and evolocumab 140 mg twice a month without reaching LDL-c goal. Genetic analysis revealed homozygous pathogenic LDL-R gene mutation. Evolocumab was increased up to 420 mg twice a month and LDL-apheresis was started with quality of life worsening. Therefore, lomitapide 5 mg daily and low-fat diet were started, obtaining weight loss and lipid profile improvement. However, liver enzymes elevation higher than 5-fold was observed, leading to lomitapide discontinuation and baseline liver enzymes values restoration. After one-month wash-out, lomitapide was gradually reintroduced up to 5 mg daily without significant hypertransaminasemia recurrence, leading to LDL-c target achievement and LDL-apheresis discontinuation. Adherence to low-fat diet and weight loss resulted in FLD and fibrosis improvement. Conclusion: Ho-FH requires complex, combined treatment. Metabolic comorbidities co-existence makes Ho-FH management more difficult. Lomitapide can be safely used in Ho-FH patients with FLD and hypertransaminasemia, but strict follow-up of liver disease and a multidisciplinary approach are needed. Before lomitapide introduction, low-fat diet should be started advantageously and weight stabilization should be obtained.

A familial hypercholesterolemia registry as the main tool for adequate management of the disease.

To evaluate the experience of FH registry conducted in Karelia Republic. FH registry in Karelia is existing from 2004, it includes 350 patients with heterozygous FH (110 with definite FH), the mean age is 48 ± 2.3 years. The genetic study was performed in 102 patients (29.1%). The creation of the registry has contributed to the active identification of FH, and now the estimated frequency of FH occurrence in Karelia may be 1:300, in patients with cardiovascular disease 1:10. We also analyzed genetic features of FH in our republic and found that the LDL-C level, above which the probability of LDL receptor mutation increases in Karelia, is 6.5 mmol/L. We analyzed risk factors of ischemic heart disease and the prognosis in FH. The creation and maintenance of a registry is an effective way of organizing timely diagnosis and adequate treatment of FH patients.

Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia

Homozygous familial hypercholesterolemia (HoFH) is an extremely rare metabolism disorder usually caused by low-density lipoprotein receptor (LDLR) mutations. LDLR genotype is commonly known to determine blood concentrations of LDL cholesterol. However, effects of LDLR genotype on holistic metabolome remain unclear. Herein, we present metabolomic, genetic, and clinical datasets from a large multi-center panel of 142 patients with LDLR-mutated HoFH. Wefound that true homozygotes and compound heterozygotes showed few differences in clinical and metabolomic phenotypes. Compared with defective/defective mutation carriers, patients carrying one or two null mutation showed profound alterations in clinical laboratory lipids and serum cholesterol esters, lysophosphocholines, bile acids, and amino acids. Importantly, these altered metabolites are implicated in multiple biochemical reactions and associated with LDL cholesterol. This study extends the first map of different LDLR genotypes influencing the metabolome and suggests that the small-molecule metabolites serve as potential targets to mitigate the deleterious impact of LDLR mutations on HoFH.

Effect of the LDL receptor mutation type on incident major adverse cardiovascular events in familial hypercholesterolaemia.

Patients with familial hypercholesterolaemia (FH) are at increased risk of cardiovascular disease (CVD) due to extremely high circulating LDL cholesterol (LDL-C) concentrations. Our objective was to study the effect of the type of LDL receptor (LDLR) mutation on the incidence of major adverse cardiovascular events (MACEs). This was a multinational prospective cohort study, which included patients with heterozygous FH aged 18-65 years, without a prior history of CVD, and carrying a pathogenic or likely pathogenic variant in the LDLR gene. A total of 2131 patients (20 535person-years of follow-up) were included in the study, including 1234 subjects carrying a defective mutation in the LDLR and 897 subjects carrying a null mutation. During the follow-up, a first MACE occurred in 79 cases (6%) in the defective group and in 111 cases (12%) in the null group. The mean baseline LDL-C concentration was 17% higher in the null group than in the defective group (7.90 vs. 6.73 mmoL/L, P < 0.0001). In a Cox regression model corrected for traditional cardiovascular risk factors, the presence of a null mutation was associated with a hazard ratio of 2.09 (1.44-3.05), P = 0.0001. Carriers of a null mutation have an independent ∼2-fold increased risk of incident MACE compared with patients carrying a defective mutation. This study highlights the importance of genetic screening in FH in order to improve patient care.

A suitable sequence of bioinformatics tools for NGS diagnosis of familial hypercholesterolemia

Background and Aims : Familial hypercholesterolemia (FH) is the most common monogenic congenital metabolic disease with an estimated frequency of 1: 200 - 500 in the population. Aberrations of the LDL receptor gene (LDLR) or mutation in his ligand apolipoprotein B100 (FDB) are the most common cause of FH. To date, over 2000 different mutations have been described in the LDLR. More rarely the pathology could be detected in other genes (APOB, LDLRAP , PCSK9, etc.). Early diagnosis using molecular genetic methods enables appropriate treatment and belongs to the basic pillars of routine practise. Considering various types of possible mutations, next - generation sequencing (NGS) method using hybridization-based enriched libraries can provide a potent solution for required multilevel genetic analysis. Each level of data analysis requires specific bioinformatic tool although the sensitivity to detect certain types of variants may partially overlap.Methods: We present three bioinformatic tools (FreeBayes, Manta and CNVkit) as an example of suitable unique combination of optimal NGS data analysis pipeline - specifically for the custom Hyperlipoproteinemia 1 (HLP) SureSelect library panel (Agilent Technologies) covering 53 HLP genes and 55 SNPs.Results: The spectrum of causal mutations detected in our FH and HLP patients cohort were as follows: 81% of single-nucleotide variants, 5% of minor and 14% of gross (two and more exons) intragenic rearrangements. Mutations in LDLR covered 74,4% of causal variants, 11,6% of mutations were in APOB and 14% in another genes from the HLP panel.Conclusions: The presented combination of bioinformatic tools represents effective diagnostic algorithm with increase diagnostic yield.*This work was supported by the Cooperatio Program, research area "Metabolic Diseases 207037" Background and Aims : Familial hypercholesterolemia (FH) is the most common monogenic congenital metabolic disease with an estimated frequency of 1: 200 - 500 in the population. Aberrations of the LDL receptor gene (LDLR) or mutation in his ligand apolipoprotein B100 (FDB) are the most common cause of FH. To date, over 2000 different mutations have been described in the LDLR. More rarely the pathology could be detected in other genes (APOB, LDLRAP , PCSK9, etc.). Early diagnosis using molecular genetic methods enables appropriate treatment and belongs to the basic pillars of routine practise. Considering various types of possible mutations, next - generation sequencing (NGS) method using hybridization-based enriched libraries can provide a potent solution for required multilevel genetic analysis. Each level of data analysis requires specific bioinformatic tool although the sensitivity to detect certain types of variants may partially overlap. Methods: We present three bioinformatic tools (FreeBayes, Manta and CNVkit) as an example of suitable unique combination of optimal NGS data analysis pipeline - specifically for the custom Hyperlipoproteinemia 1 (HLP) SureSelect library panel (Agilent Technologies) covering 53 HLP genes and 55 SNPs. Results: The spectrum of causal mutations detected in our FH and HLP patients cohort were as follows: 81% of single-nucleotide variants, 5% of minor and 14% of gross (two and more exons) intragenic rearrangements. Mutations in LDLR covered 74,4% of causal variants, 11,6% of mutations were in APOB and 14% in another genes from the HLP panel. Conclusions: The presented combination of bioinformatic tools represents effective diagnostic algorithm with increase diagnostic yield. *This work was supported by the Cooperatio Program, research area "Metabolic Diseases 207037"

Familial hypercholesterolemia care in adolescents-single centre experience from Singapore

Background and Aims : Familial Hypercholesterolemia (FH) is an autosomal dominantly inherited disease commonly due to LDL Receptor Mutations. Heterozygous individuals are at risk of developing premature vascular disease due to accumulation of LDL. Early diagnosis and treatment are likely to reduce morbidity and mortality. To study the demographics, diagnostic features and response to therapy in adolescents with suspected FH .

Acute coronary syndrome in an 8-year-old child with familial hypercholesterolemia: a case report

BackgroundFamilial hypercholesterolemia (FH) is the most commonly inherited metabolic disease and has an autosomal dominant mode of inheritance. Patients with FH usually present with high levels of low-density lipoprotein-cholesterol, xanthomas and early coronary artery disease. Children with FH are subject to developing early and enhanced atherosclerosis, leading to an increased risk of coronary events. We report here an 8-year-old patient with acute coronary syndrome (ACS) who was diagnosed with homozygous FH (HoFH) due to mutations in the low-density lipoprotein receptor (LDLR) gene and subsequently treated with percutaneous transluminal coronary angioplasty (PTCA) after filtration plasma. To the best of our knowledge, this patient is the youngest case of HoFH treated with filtration plasma followed by PTCA reported to date.Case presentationAn 8-year-old Asian patient was admitted to Gansu Provincial Hospital presenting symptoms of ACS. Laboratory tests showed that the patient’s cholesterol and low-density lipid levels were extremely high. An electrocardiogram (ECG) revealed sinus arrhythmia and electric axis deviation to the right, but the ECG was roughly normal. Multiple cardiac function abnormalities were diagnosed on the ECG. Multiple sites of coronary artery stenosis were determined by computed tomography angiography. DNA sequencing of exons showed a C-to-A substitution at nucleotide 126 in exon 2, resulting in a LDLR mutation in the patient and seven other family members. Following combination treatment with lipid-lowering drugs, anti-thrombosis drugs, filtration plasma and PTCA, the patient’s symptoms were significantly improved and the patient discharged.ConclusionWe report the rare case of a patient with ACS attributable to HoFH who was treated with PTCA following filtration plasma. The patient was shown to have clinically diagnosed and molecularly confirmed HoFH that resulted from a mutation in the LDLR gene. Children with HoFH have higher risk of early coronary events and death from myocardial infarction due to premature atherosclerosis than adults. Earlier intervention and treatment will bring great benefits to the long-term survival of pediatric patients.

Long-term cancer risk in heterozygous familial hypercholesterolemia relatives: a 25-year cohort study

BackgroundHeterozygous familial hypercholesterolemia (HeFH) due to low-density lipoprotein receptor (LDLR) mutations predisposes patients to highly elevated levels of cholesterol, and patients are at increased risk of adverse cardiovascular events and other morbidities. Whether the LDLR mutation and high cholesterol levels affect the risk of cancer remains unknown. The purpose of the present study was to assess the long-term cancer risk in HeFH relatives.MethodsStudy participants were identified by cascade screening during 1992–1994. A comparison cohort was matched 10:1 to the relatives from the Danish general population based on birth year, gender and address. All participants were followed until a cancer diagnosis, migration, death, or end of follow-up as of December 31, 2019. The primary endpoint was any incident cancer diagnosis.ResultsIn total, we included 221 relatives with a median age of 37 years (interquartile range: 27–53 years). A total of 117 (53%) of the relatives carried a LDLR gene mutation. The crude hazard ratio of our primary endpoint did not reveal any differences in cancer incidence in mutation-carrying relatives compared with the general population cohort (1.18; 95% CI, 0.81–1.71). Nonmutation-carrying relatives however had a lower cancer incidence than the general population (0.45: 95% CI, 0.26–0.80). Thus, the risk among mutation-carrying HeFH relatives compared with nonmutation-carrying HeFH relatives was increased (HR: 2.39; 95% CI, 1.24–4.61).ConclusionIn Denmark, LDLR mutation-carrying HeFH relatives did not have a different cancer risk than the general population. In contrast, nonmutation-carrying relatives had a lower risk of cancer.

*Ketogenic Diets Exacerbating Hypercholesterolemia in APOE Variants and APOB Mutations-Potential Role for Measuring Intestinal Absorption of Lipids

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis Familial Hypercholesterolemia (FH) is caused primarily by mutations in either LDL receptor, APOB, or PCSK9 genes. There are other genetic causes of LDL elevation including APOE4 variants. Objective/Purpose We present two patients with markedly elevated LDL suspicious for FH who were subsequently diagnosed with APOE3/4 variants while on ketogenic diets. We also present a patient with a known APOB mutation who had a marked elevation of LDL on a ketogenic diet. Methods Case 1: 58-year-old male with no prior medical history was found to have elevated cholesterol of 600mg/dL and LDL>455mg/dL while on a ketogenic diet. Prior to initiating the diet, his cholesterol was 206mg/dL and LDL was 132mg/dL. Genetic testing revealed a ApoE3/4 variant. His most recent cholesterol increased to 706mg/dL and LDL to >500mg/dL. Case 2: 53-year-old male with hypertension cholesterol of 282mg/dL and LDL of 212mg/dL went on a ketogenic diet and lost 100lbs. Follow up lipid panel demonstrated a cholesterol of 400mg/dL and LDL of 317mg/dL. Genetic testing revealed a APOE3/4 variant. Case 3: 45-year-old female with FH and known APOB missense mutation went on a ketogenic diet for weight loss. Prior to initiating the diet, her total cholesterol was 311 mg/dL and LDL was 211 mg/dL. While on the ketogenic diet, her total cholesterol was 550 mg/dL and LDL was 454 mg/dL. Her LDL decreased to 276mg/dl on a less strict ketogenic diet. Results All three patients had a normal exercise stress test, normal carotid duplex ultrasound, and coronary calcium score of zero. They refused the initiation of a statin. All 3 patients had the Boston Heart Cholesterol Balance Test performed that directly measures the absorption markers (beta-sitosterol, campesterol and cholestanol) for circulating plasma cholesterol. Only the patient with the APOB mutation had increased intestinal absorption of cholesterol, suggesting a response to ezetimibe. She agreed to initiate ezetimibe, her LDL subsequently decreased by 52% to 132mg/dl. Conclusions We hypothesize patients with APOE variants and APOB mutations could have an exaggerated elevation of their LDL levels while on ketogenic diets. Although these 3 patients did not demonstrate progressive atherosclerosis, the long-term effect of this diet is unknown. We recommend that all patients on a ketogenic diet have their LDL monitored and if there is a significant increase, undergo genetic testing for FH, APOE and other genetic variants. Since this patient group is often reluctant to start statins, the Cholesterol Balance Test may be useful to identify patients who may respond well to ezetimibe. Nothing to disclose.

Analysis of the low density lipoprotein receptor gene (LDLR) mutation spectrum in Russian familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a very common human hereditary disease in Russia and in the whole world with most of mutations localized in the gene coding for the low density lipoprotein receptor (LDLR). The object of this review is to systematize the knowledge about LDLR mutations in Russia. With this aim we analyzed all available literature on the subject and tabulated the data. More than 1/3 (80 out of 203, i. e. 39.4 %) of all mutations reported from Russia were not described in other populations. To date, most LDLR gene mutations have been characterized in large cities: Moscow (130 entries), Saint Petersburg (50 entries), Novosibirsk (34 mutations) and Petrozavodsk (19 mutations). Other regions are poorly studied. The majority of pathogenic mutations (142 out of 203 reported here or 70 %) were revealed in single pedigrees; 61 variants of mutations were described in two or more genealogies; only 5 mutations were found in 10 or more families. As everywhere, missense mutations prevail among all types of nucleotide substitutions in LDLR, but the highest national specificity is imparted by frameshift mutations: out of 27 variants reported, 19 (or 70 %) are specific for Russia. The most abundant in mutations are exons 4 and 9 of the gene due to their largest size and higher occurrence of mutations in them. Poland,the Czech Republic, Italy and the Netherlands share the highest number of mutations with the Russian population. Target sequencing significantly accelerates the characterization of mutation spectra in FH, but due to the absence of systematic investigations in the regions, one may suggest that most of LDLR mutations in the Russian population have not been described yet.

A Matter of Timing: Rudy Tanzi on Alzheimer's Disease

A Matter of Timing: Rudy Tanzi on Alzheimer's Disease

Low-density lipoprotein receptor and apolipoprotein A 5, myocardial infarction biomarkers in plasma-derived exosomes

ObjectivesMyocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. Previously, rare mutations in low-density lipoprotein receptor (LDLR) genes and apolipoprotein A V (APOA5) have been shown to contribute to MI risk in individual families. Exosomes provide a potential source of biomarkers for MI. This study is to determine the role of LDLR and APOA5 as biomarkers for early diagnosis of MI. MethodsIn this study, we detected the levels of LDLR, APOA5, and cardiac troponin T in plasma-derived exosomes in MI patients and age-matched healthy people by enzyme linked immunosorbent assay and observed the morphology and number of exosomes using transmission electron microscope and nanoparticle tracking analysis. Oxygen-glucose deprivation (OGD) method was used to induce MI in H9C2 cardiomyocytes to explore the effect of exosomes. ResultsWe found that the levels of LDLR and APOA5 in plasma-derived exosomes in MI patients were significantly decreased. Furthermore, exosomes of MI patients were significantly larger in size and the concentration of exosomes was higher than that of age-matched non-MI people. In vitro experiments showed that OGD treatment induced apoptosis of myocardial cells and decreased the expression of LDLR and APOA5, while addition of exosomes isolated from healthy people rescued these phenotypes. ConclusionExosomal APOA5 and LDLR are intimately associated with MI, and thereby have the potential to function as diagnostic markers of MI.

Generation of a non-integrated induced pluripotent stem cell line (SMBCi009-A) from urine-derived cells of a Chinese Familial hypercholesterolemia patient

Familial hypercholesterolemia (FH; OMIM: # 143890) is a common inherited autosomal dominant disease, characterized by high-level low-density lipoprotein cholesterol (LDL-C) in plasma. Elevated LDL-C levels is closely related with atherosclerotic plaques and premature cardiovascular disease if not treated in time. Here we generated an induced pluripotent stem cell (iPSC) line using urine cells (UCs) derived from an 8-year-old male FH patient who carrying two coding and pathogenic mutations of low-density lipoprotein receptor (LDLR) gene (exon12:c.C1747T and exon13: c. 1948 del G). This induced pluripotent stem cell line named SMBCi009-A can be used to understand more cellular details about FH.

An Untargeted Lipidomic Analysis Reveals Depletion of Several Phospholipid Classes in Patients with Familial Hypercholesterolemia on Treatment with Evolocumab

Rationale: Familial hypercholesterolemia (FH) is caused by mutations in genes involved in low-density lipoprotein cholesterol (LDL-C) metabolism, including those for pro-protein convertase subtilisin/kexin type 9 (PCSK-9). The effect of PCSK-9 inhibition on the plasma lipidome has been poorly explored. Objective: Using an ultra-high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry method, the plasma lipidome of FH subjects before and at different time intervals during treatment with the PCSK-9 inhibitor Evolocumab was explored. Methods and Results: In 25 FH subjects, heterozygotes or compound heterozygotes for different LDL receptor mutations, untargeted lipidomic revealed significant reductions in 26 lipid classes belonging to phosphatidylcholine (PC), sphingomyelin (SM), ceramide (CER), cholesteryl ester (CE), triacylglycerol (TG) and phosphatidylinositol (PI). Lipid changes were graded between baseline and 4- and 12-week treatment. At 12-week treatment, five polyunsaturated diacyl PC, accounting for 38.6 to 49.2% of total PC at baseline; two ether/vinyl ether forms; seven SM; five CER and glucosyl/galactosyl-ceramide (HEX-CER) were reduced, as was the unsaturation index of HEX-CER and lactosyl—CER (LAC-CER). Although non quantitative modifications were observed in phosphatidylethanolamine (PE) during treatment with Evolocumab, shorter and more saturated fatty acyl chains were documented. Conclusions: Depletion of several phospholipid classes occurs in plasma of FH patients during treatment with the PCSK-9 inhibitor Evolocumab. The mechanism underlying these changes likely involves the de novo synthesis of SM and CER through the activation of the key enzyme sphingomyelin synthase by oxidized LDL and argues for a multifaceted system leading to vascular improvement in users of PCSK-9 inhibitors.