Mutations In Low-density Lipoprotein Receptor Gene Research Articles

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.

THU149 A Novel Frameshift Mutation (p.H485fs) Of The Ldl Receptor Gene

Abstract Disclosure: S. Chang: None. E. Yang: None. C. Kim: None. Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction. It is an autosomal dominant inherited disease due to mutations in either the low-density lipoprotein receptor (LDL-R), the apolipoprotein B or the proprotein convertase subtilisin/kexin type 9 genes. In this study, we report a novel mutation in LDL receptor gene in a Korean family. A 10 year-old boy was referred to our hospital for hypercholesterolemia (530 mg/dl). On family history, His father and uncle have been treated for hypercholesterolemia and his grandfather died of coronary artery disease. Because of persisted hypercholesterolemia despite statin treatment for 18 months and his family history, we performed LDL-R gene study using polymerase chain reaction (PCR) sequencing. Direct sequencing of the 18 exons and exon-intron boundaries of LDL-R gene revealed deletions of C and A of exon 10 (c.1455_1456del). Study showed a novel heterozygous frameshift-deletion mutation (p.His485Glnfs*50) (p.H485fs). We performed PCR sequencing to detect same mutation on his family. Father and two siblings of the patient have same mutation (p.His485Glnfs*50) (p.H485fs) on study. Now we report a novel frameshift mutation (p.H485fs) located in exon 10 of LDL receptor gene that causes familial hypercholesterolemia in a Korean family. Presentation: Thursday, June 15, 2023

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.

«ОПРЕДЕЛЕННАЯ» НАСЛЕДСТВЕННАЯ СЕМЕЙНАЯ ГИПЕРХОЛЕСТЕРИНЕМИЯ В ЯКУТИИ

Cardiovascular diseases occupy a leading position in the structure of mortality in most countries of the world, including Russia. The World Health Organization predicts further increases in cardiovascular morbidity and mortality in both developed and developing countries due to population aging and lifestyle patterns. Among the causes of cardiovascular mortality, IHD ranks first, followed by cerebrovascular disease, the main cause of the occurrence and development of which is atherosclerosis of the arteries, caused by a violation of lipid metabolism. The article discusses the role of the genetic factor in the formation of familial hypercholesterolemia and presents the first clinical cases with the results of molecular genetic confirmation of the low-density lipoprotein receptor gene mutation in patients of the Lipid Cabinet, Republic’s Clinical Hospital No. 3 with a diagnosis of “Definite” familial hypercholesterolemia. Despite the unconditional need for early detection of familial hypercholesterolemia for the primary prevention of atherosclerotic cardiovascular diseases, it should be noted that patients have low adherence to lipid-lowering therapy and low interest of the index patient in conducting cascade screening. Comparison of genetic differences in FH in the Yakut population between different ethnic groups requires further research.

Analysis of Clinical and Biochemical Characteristics of Patients With Genetically Confirmed Familial Hypercholesterolemia in Russian North Western District Residents.

Aim To compare results of clinical, laboratory, and genetic examination of patients with familial hypercholesterolemia (FHC).Material and methods 112 patients aged 40.2±17.9 years (49 men) were examined. The gene of low-density lipoprotein receptor (LDLR) was analyzed and evaluated using the Dutch Lipid Clinic Network (DLCN) criterion of lipid score ≥6. The LDLR gene mutation was searched for using the conformational polymorphism analysis followed by sequencing of the DNA of isolated LDLR gene exons.Results Mean variables of the blood lipid profile were total cholesterol (C), 10.12±2.32 mmol/l, LDL-C, 7.72±2.3 mmol/l. Corneal arcus was observed in 15 % of patients, tendon xanthomas in 31.8 %, and xanthelasma palpebrarum in 5.3 %. The types of LDLR gene mutations included missense mutations (42.8 %), mutations causing a premature termination of protein synthesis (41.1 %), and frameshift mutations (16.1 %). In the presence of a mutation in exon 4, patients with IHD compared to patients with no IHD had significantly higher levels of total C (10.88±2.08 mmol/l vs. 8.74±1.57 mmol/l, respectively, р=0.001) and LDL-C (8.60±2.14 mmol/l vs. 6.62±1.79 mmol/l, respectively, р=0.005). Patients with IHD compared to patients with no IHD and a mutation in LDLR gene exon 9 had only a higher LDL-C level (8.96±1.53 mmol/l vs. 6.92±1.59 mmol/l, respectively, р=0.022). A differentiated comparison of IHD patients using a logistic regression depending on the identified type of LDLR gene mutation produced formulas for calculating the odds ratio of IHD and myocardial infarction (MI) with adjustments for the patient's age and baseline LDL.Conclusion The detection rate of the LDLR gene mutations was 42.8 % for missense mutations, 41.1 % for mutations causing a premature termination of protein synthesis, and 16.1 % for frameshift mutations. Blood lipid profiles did not differ between patients from different cities and with different types of LDLR gene mutations. Blood lipid profiles were different in IHD patients depending on the mutation type.

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.

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.

Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial hypercholesterolemia: A single center real-world study

Background and aimsFamilial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy. Methods and resultsWe evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54 ± 13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygous (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p = 1.00) and T36w (p = 0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p = 0.069), whereas none of compound-He/Ho-FH achieved LDL-C target. ConclusionsAfter 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations.Registration number for clinical trials: NCT04313270 extension.

SCREENING FOR GENETIC MUTATIONS IN LDLR GENE WITH FAMILIAL HYPERCHOLESTEROLEMIA IN THE MONGOLIAN POPULATION

Abstract Objective: The objective of this study was to characterize LDLR (low density lipoprotein receptor) gene mutation in patients with familial hypercholesterolemia. Design and method: Methods: This cross-sectional study was included subjects aged from 20 to 64 years, with a clinical diagnosis of familial hypercholesterolemia. Clinical diagnosis of familial hypercholesterolemia was based on Dutch Lipid Clinic Network diagnostic criteria. Possible and probable familial hypercholesterolemia were defined as a total score was 3–5 and 6–8 points. Ten ml of venous blood samples were collected from all the subjects and used for biochemical and genetic analysis. Deoxyribonucleic acid was isolated from peripheral blood samples and precise primers were designed for LDLR gene which includes 18 exons. Polymerize chain reaction test was followed by deoxyribonucleic acid sequence analysis. Results: Results: A total of 89 subjects included in the study of which, 32 (36%) were men and 57 (64%) were women. The mean age of the participants was 46.5 ± 7.8 years. In our study, we found the following 3 LDLR mutations: S265R mutation in Exon-6, C308Y mutation Exon-8 and V502 M mutation in Exon-10. Conclusions: Conclusion: This was the first study to identify genetic mutations in LDLR gene in Mongolia. We conclude that screening of family hypercholesterolemia among the Mongolian population is very important to identify individuals who are prone to develop the atherosclerotic cardiovascular disease.

Characterisation of LDL receptor gene mutations in a North Indian cohort of children with homozygous familial hypercholesterolaemia.

Homozygous familial hypercholesterolaemia (HoFH) carries agrave prognosis but is often underdiagnosed and undertreated. Confirmation of molecular diagnosis helps in planning effective management and determining prognosis accurately. Aim of the study: To determine the spectrum of mutations in the LDLR gene in acohort of children with aclinical diagnosis of HoFH. Genomic DNA was extracted from peripheral blood samples of 8 patients, who were children of either sex, aged under 16 years, and diagnosed clinically with HoFH using the Simon Broome criteria. The potential variants in the LDLR gene were analysed by Sanger sequencing. Fifty variations were found in the 8 patients; 39 (78%) were single nucleotide variations while 8 (16%) and 3 (6%) were deletions and insertions, respectively. The pathogenic variants in the LDLR gene were detected in four patients; three showed duplication in exon 17 (c.2416dupG) creating an amino acid change at position 806 (p.Val806GlyfsTer11) while one had amissense variant in the exon 9 at position c.1285G>A resulting in achange in amino acid at position 429 (p.Val429Met). The variants were found in heterozygous state in the parents or siblings of probands who showed pathogenic variants. The frequency of disease-causing variants in the LDLR gene in our patients with HoFH was 50%. Further studies to characterise mutations in genes for apolipoprotein B, proprotein convertase subtilisin/kexin type 9, or LDL adaptor protein are suggested in all children with aclinical diagnosis of HoFH.

Abstract 207: A Catalogue of the Pathogenic Mutations of LDL Receptor Gene in Japanese Familial Hypercholesterolemia

Background: Familial hypercholesterolemia (FH), mainly caused by LDL receptor gene mutation is attracting a lot of attention associated with the development of novel therapies. However, rare mutations tend to be ethnicity-specific, hence, it is always difficult to determine pathogenicity of LDL receptor gene mutation in a single individual in a certain ethnicity. Currently, little data exist on the pathogenic mutations of LDL receptor in Japanese familial hypercholesterolemia (FH). Objective: We aimed to catalogue the pathogenic mutations of LDL receptor gene in the 2 major Japanese FH-care centers (Kanazawa University and National Cerebral and Cardiovascular Center Research Institute), where genetic testing of FH has been performed centrally upon requests from institutes all over Japan during more than past two decades. Methods: 796 FH subjects from 472 families who had nonsynonymous mutations in LDL receptor gene were included in this study. Genetic mutations were analyzed for mutations by Sanger sequencing as well as by multiplex ligation probe dependent amplification (MLPA) technique for large rearrangements. Pathogenic mutations were defined either as 1) protein truncated variants, 2) registered as pathogenic in Clinvar, or Human Gene Mutation Database (HGMD), or meet the criteria of American College of Medical Genetics and Genomics (ACMG) guideline, or 3) CADD-score > 10. Results: We found 138 different mutations. Among them, 132 mutations were considered as pathogenic, including 19 large rearrangement mutations. Whereas, 6 missense mutations were classified as variants of unknown significance (VUS). A single mutation accounted for as much as 41 % of the FH subjects recruited from Kanazawa University mainly due to founder gene effect, whereas, many singleton mutations were found from National Cerebral and Cardiovascular Center Research Institute located in Osaka. Conclusions: We provided the largest catalogue of pathogenic mutations of LDL receptor gene in Japanese FH. This could aid to determine the pathogenicity of the LDL receptor genetic mutations not only in Japanese but also in other ethnicities.

A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia

Little data exist on the pathogenic mutations of LDL receptor in Japanese familial hypercholesterolemia (FH). We aimed to catalog the pathogenic mutations of LDL receptor gene in the 2 major Japanese FH-care centers (Kanazawa University and National Cerebral and Cardiovascular Center Research Institute), where genetic testing of FH has been performed centrally on requests from institutes all over Japan during more than past 2 decades. 796 FH subjects from 472 families who had nonsynonymous mutations in LDL receptor gene were included in this study. Genetic mutations were analyzed for mutations by Sanger sequencing as well as by multiplex ligation probe dependent amplification technique for large rearrangements. Pathogenic mutations were defined either as 1) protein truncated variants, 2) registered as pathogenic in ClinVar, or Human Gene Mutation Database (HGMD), or meet the criteria of American College of Medical Genetics and Genomics guideline, or 3) CADD score >10. We found 138 different mutations. Among them, 132 mutations were considered as pathogenic, including 19 large rearrangement mutations. However, 6 missense mutations were classified as variants of unknown significance. A single mutation accounted for as much as 41% of the FH subjects recruited from Kanazawa University mainly due to founder gene effect, whereas many singleton mutations were found from National Cerebral and Cardiovascular Center Research Institute located in Osaka. We provided the largest catalog of pathogenic mutations of LDL receptor gene in Japanese FH. This could aid to determine the pathogenicity of the LDL receptor genetic mutations not only in Japanese but also in other ethnicities.

Clinical and serum lipid profiles and LDLR genetic analysis of xanthelasma palpebrarum with nonfamilial hypercholesterolemia.

XP is a flat xanthoma that usually presents as bilateral, symmetrical, soft, yellowish papules over the eyelids. The etiology of XP is unknown, but it may be related to complex heterozygous mutations. To investigate the lipid profiles, important clinical characteristics, and low-density lipoprotein receptor (LDLR) gene mutation in the patients suffering from xanthelasma palpebrarum (XP) with nonfamilial hypercholesterolemia. The prospective study included 25 individuals of XP with nonfamilial hypercholesterolemia, and 30 controls neither with XP nor familial hypercholesterolemia (FH). Each one underwent detailed clinical examination, serum lipid profile, and LDLR gene detection at the 400th exon and the 1246th exon. In our study, patients with XP were often not present with FH and family history. The mean serum cholesterol (CHOL) (5.20±1.82) and the prevalence of carotid atherosclerosis (4.34±0.78) were significantly higher in study group, while there was no statistically significant difference between two groups in terms of triglyceride (TG) (P=.38) and low-density lipoprotein (LDL) (P=.23). Unusually, the mean levels of high-density lipoprotein (HDL) (1.59±0.31) in the study group were much higher than the controls (1.31±0.30), and the LDLR gene mutation was not found. Clinical and serum lipid profiles indicated that XP was sporadic and underlying lipid abnormalities especially higher HDL. XP did not occur with mutations in the LDLR gene at the two exons. We suggested too high HDL level may be contributed to pathogenesis of XP and XP is often not associated with FH.

Functional analysis of six uncharacterised mutations in LDLR gene

Background and aimsFamilial hypercholesterolemia (FH) is a primary hyperlipemia. It is an autosomal dominant genetic disorder of lipoproteins metabolism mainly caused by mutations in the low density lipoprotein receptor gene (LDLR). We aimed to investigate the functional impact on the low density lipoprotein receptor (LDLR) activity of six uncharacterised variants located in the coding region of the LDLR gene, namely c.428G > T, c.640T > C, c.1708C > T, c.1736A > T, c.1981C > G and c.2114C > G (NM_000527.4) and to attempt to define their clinical status. MethodsFunctional studies were carried out using site-directed mutagenesis techniques and expression of LDLR protein in vitro. Results were correlated with clinical data and in silico analyses in order to assess the physiopathological role of these variants. ResultsThis work provides functional information about 6 uncharacterised mutations in LDLR. ConclusionsThe six variants studied here appeared to affect the LDLR function in vitro to different degrees, ranging from receptors with normal to slightly reduced activity to receptors exhibiting less than 10% of the wild-type activity. According to these studies and The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, two variants could be classified as “Likely Benign” (p.(Ala705Gly) and p.(Leu570Phe)), three variants as “Pathogenic” (p.(Asp579Val), p.(Cys143Phe) and p.(Trp214Arg)) and one variant as “Likely Pathogenic” (p.(Pro661Ala)).

P5334A 15-year follow-up of 315 patients with familial hypercholesterolemia from the North-West region of Russia

Abstract Familial hypercholesterolemia (FH) is one of the most common inherited diseases that lead to premature atherosclerosis and coronary heart disease (CHD). Aim of the study to ascertain genetic and environmental factors influencing the time course of FH during a 15-year follow-up in a large FH cohort from the North-West region of Russia. We screened more than 1ehz746.0302 high risk patients in order to reveal FH in Saint-Petersburg and Petrozavodsk using DLCN criteria. In most patients DNA analysis was also performed. Definite FH (≥8 according to DLCN) was found in 315 patients (221 - in Saint-Petersburg, 94 - in Petrozavodsk). These patients were followed-up for 15 years and more. CHD was more frequent in male patients, patients older than 60 years of age and was associated with higher levels of total cholesterol, LDL cholesterol, lower levels of HDL cholesterol, arterial hypertension, smoking and higher DLCN scoring. Patients without CHD had lowest LDL/HDL ratio (5.2±0.45) whereas patients with stable and progressive CHD had LDL/HDL ratio - 7.7±0.89 and 10.4±0.78, respectively (p≤0.05). Genetic study revealed only 1 homozygous patient and 1 patient with apoB-100 (FDP) gene mutation. Only 1 case of FH-North Karelia mutation that is typical for Finland was found in Petrozavodsk. Most of revealed mutations in LDL-receptor gene were unique i.e. found only in 1 family. This suggest the absence of a strong founder effect associated with FH in the North-West Region of Russia. Due to high heterogeneity of FH-causing mutations we failed to establish interrelations between type of LDL-receptor gene mutations and severity of atherosclerosis and CHD time course. 14% of FH patients didn't take any hypolipidemic medications at the onset of the follow-up, whereas 61% took statins and 25% statin + ezetimibe. Homozygous patient was treated both with statin, ezetimibe, evolocumab and LDL-apheresis. Nevertheless, 26% of the treated group didn't achieve the target LDL-C levels. It is interesting that 40% of patients who didn't reach LDL-goals were current smokers (compared with 5% of patients who reached LDL-goals). 33 patients (10.5%) died during the follow-up mostly due to cardiovascular complications. Death rates in FH patients were strongly associated with age, male sex, LDL/HDL ratio, smoking and effectiveness of hypolipidemic treatment. FH is strongly associated with high CHD risk; the time course of FH is much more favourable in females, in patients with low LDL/HDL ratio and free of other modifiable risk factors. Type of LDL-receptor gene mutation doesn't influence lipid levels or clinical manifestations of FH.

Dietary Cholesterol Is Highly Associated with Severity of Hyperlipidemia and Atherosclerotic Lesions in Heterozygous LDLR-Deficient Hamsters.

Objective: Familial hypercholesterolemia (FH) is a dominant inherited disease caused mainly by low-density lipoprotein receptor (LDLR) gene mutations. To different extents, both heterozygous and homozygous FH patients develop premature coronary heart disease (CHD). However, most of the experimental animal models with LDLR deficiency could not fully recapitulate FH because they develop hyperlipidemia and atherosclerosis only in homozygous, but not in heterozygous, form. In the current study, we investigated the responsiveness of the LDLR+/− hamster to dietary cholesterol and whether plasma cholesterol levels were positively associated with the severity of atherosclerosis. Approach and Methods: wild type WT and LDLR+/− hamsters were fed a high fat diet with different cholesterol contents (HCHF) for 12 or 16 weeks. Plasma lipids, (apo)lipoproteins, and atherosclerosis in both the aorta and coronary arteries were analyzed. After a HCHF diet challenge, the levels of total cholesterol (TC) in WT and LDLR+/− hamsters were significantly elevated, but the latter showed a more pronounced lipoprotein profile, with higher cholesterol levels that were positively correlated with dietary cholesterol contents. The LDLR+/− hamsters also showed accelerated atherosclerotic lesions in the aorta and coronary arteries, whereas only mild aortic lesions were observed in WT hamsters. Conclusions: Our findings demonstrate that, unlike other rodent animals, the levels of plasma cholesterol in hamsters can be significantly modulated by the intervention of dietary cholesterol, which were closely associated with severity of atherosclerosis in LDLR+/− hamsters, suggesting that the LDLR+/− hamster is an ideal animal model for FH and has great potential in the study of FH and atherosclerosis-related CHD.

A rare low-density lipoprotein receptor (LDLR) gene mutation associated with heterozygous familial hypercholesterolemia

A rare low-density lipoprotein receptor (LDLR) gene mutation associated with heterozygous familial hypercholesterolemia

Low-density lipoprotein receptor gene mutation at Exon 2 and 4 in premature coronary artery disease in our population.

Objective:To determine the frequency of mutations in Low density lipoprotein receptor gene at exon 2 and 4 and its association with premature coronary artery disease (PCAD).Methods:A case-control study was conducted at Armed Forces Institute of Cardiology and Chemical Pathology department of Army Medical College Rawalpindi for a period of six months from June 2017 to December 2017. A sample size of 50 (40 patients, 10 controls) with 5% significance and 95% confidence interval was calculated with 4:1 case to control ratio. Consecutive sampling was used for distribution of participants into both groups. .Diagnosed patients of premature coronary artery disease that is any cardiac event before the age of 45 in males and 50 in females were taken as cases. Controls were healthy males less than 45 years of age and females less than 50 years. Patients with diabetes mellitus, thyroid illnesses, any acute infection, low white blood cells count and kidney disorders were excluded. A total of fasting 10ml blood was withdrawn from each patient. 5ml was utilized for the routine blood tests and the rest 5ml was used for further genetic analysis.Results:Total 50 participants were included in study. Mean age of participants in years was 42.48 ± 4.02 SD. Mean total cholesterol (TC) (mmol/l) were higher among cases (4.91±0.64 SD) than controls (4.22±0.66 SD). Serum triglyceride(Tg) (mmol/l) and low-density lipoprotein(LDL) (mmol/l) was also high among cases (2.07±0.58; 2.84±0.46) than controls (1.99±0.24; 1.98±0.32). One synonymous mutation in exon 2 of low-density lipoprotein receptor gene (LDLR) and one non-synonymous mutation in exon 4 (LDLR gene) were identified in our population in four patients among the forty cases. Data was analyzed by Statistical Package for the Social Science (SPSS) 21 version and a p-value of less than 0.05 was taken as significant.Conclusion:Glutamic acid (E) is replaced by Lysine (K) at position number 207 (E207K) mutation at exon 4 of low-density lipoprotein receptor (LDLR) gene may be the causative genetic basis of premature coronary artery disease among Pakistani population. The identified synonymous mutation at exon 2 was not causative as there is no change in the amino acid.

Aortic valve calcium score in hypercholesterolemic patients with and without low-density lipoprotein receptor gene mutation.

The aim of this study was a comparison of aortic valve calcium score (AVCS) between patients with hypercholesterolemia and genetic diagnosis of familial hypercholesterolemia with low-density lipoprotein receptor gene mutation (LDLR-M group), versus patients with hypercholesterolemia without LDLR gene mutation (LDLR-WT group). A total of 72 LDLR-M patients and 50 LDLR-WT patients were enrolled in the study and underwent CT as a part of an assessment of coronary calcium scoring. AVCS was determined and compared between the two patient groups. AVCS was significantly higher in the LDLR-M group in comparison to the LDLR-WT group (13.8 ± 37.9 vs. 0.94 ± 3.1, p = 0.03). The Yates' chi-squared test for independence revealed that LDLR mutation and AVCS were significantly dependable (Chi^2 = 6.106, p = 0.013). The LDLR mutation was a strong predictor of a high AVCS (OR 7.83, 95% CI 2.08–29.50, p = 0.002) on multivariate regression analysis. Among the traditional risk factors, age (odds ratio 1.12, 95% CI 1.05–1.18, p<0.001) and SBP (OR 1.04, 95% CI 1.00–1.07, p = 0.045) were also significant for high result of AVCS. An assessment of computed tomography calcium scores showed that LDLR-M patients have increased AVCS in comparison to those with LDLR-WT. In addition, LDLR mutation can be considered as an independent risk factor of having high AVSC even after adjustment for risk factors including cholesterol levels. This may result from the associated process connected with the regulatory role of LDLR in evolution of aortic valve calcifications.

Genetically confirmed familial hypercholesterolemia in outpatients with hypercholesterolemia.

BackgroundFamilial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism which can lead to premature coronary heart disease (pCHD). There are about 3.8 million potential FH patients in China, whereas the clinical and genetic data of FH are limited.MethodsDutch Lipid Clinic Network (DLCN) criteria was used to diagnose FH in outpatients with hypercholesterolemia. Resequencing chip analysis combined with Sanger sequencing validation were used to identify mutations in the definite FH patients according to DLCN criteria. In silico analysis was conducted in mutations with previously unknown pathogenicity. Then, the novel mutant receptors were transfected into human embryo kidney 293 (HEK-293) cells. The binding and the internalization activities of the mutant receptors were analyzed by flow cytometry.ResultsThe prevalence of definite FH in outpatients with hypercholesterolemia in this study is 3.2%. Using genetic testing, one homozygous FH (HoFH), one heterozygous FH (HeFH) and three compound heterozygous FH patients were confirmed. Eight mutations in low-density lipoprotein receptor (LDLR) gene were identified, in which c.357delG was a novel mutation and co-segregated with the FH phenotype. Bioinformatic analysis confirmed that c.357delG was a pathogenic mutation. Furthermore, when compared with the wild-type LDLRs by flow cytometry analysis, the binding and internalization activities of c.357delG mutant LDLRs were reduced by 35% and 49%, respectively.ConclusionsThis study identified eight LDLR gene mutations in five patients with definite FH, in which c.357delG is a novel pathogenic mutation. These findings increase our understanding of the genetic spectrum of FH in China.