Genetic basis of hypercholesterolemia in adults.
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ABSTRACT:
SUBMITTER: Saadatagah S
PROVIDER: S-EPMC8046820 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by high plasma concentrations of low-density lipoprotein cholesterol (LDLc), tendon xanthomas, and increased risk of premature coronary heart disease. FH is one of the most common inherited disorders; there are 10,000,000 people with FH worldwide, mainly heterozygotes. The most common FH cause is mutations along the entire gene that encode for LDL receptor (LDLR) protein, but it has been also described that mutations in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 genes produce this phenotype. About 17%-33% of patients with a clinical diagnosis of monogenic hypercholesterolemia do not harbor any genetic cause in the known loci. Because FH has been considered as a public health problem, it is very important for an early diagnosis and treatment. Recent studies have demonstrated the influence of the LDLR mutation type in the FH phenotype, associating a more severe clinical phenotype and worse advanced carotid artherosclerosis in patients with null than those with receptor-defective mutations. Since 2004, a molecular FH diagnosis based on a genetic diagnostic platform (Lipochip(®); Progenika-Biopharma, Derio, Spain) has been developed. This analysis completes the adequate clinical diagnosis made by physicians. Our group has recently proposed new FH guidelines with the intention to facilitate the FH diagnosis. The treatment for this disease is based on the benefit of lowering LDLc and a healthy lifestyle. Actually, drug therapy is focused on using statins and combined therapy with ezetimibe and statins. This review highlights the recent progress made in genetics, diagnosis, and treatment for FH.
| S-EPMC3681164 | biostudies-literature
Project description:Background Heterozygous familial hypercholesterolemia (FH) is a common genetic disorder causing premature cardiovascular disease. Despite this, there is no national screening program in the United States to identify individuals with FH or likely pathogenic FH genetic variants. Methods and Results The clinical characteristics and FH variant status of 49 738 UK Biobank participants were used to develop a regression model to predict the probability of having any FH variants. The regression model and modified Dutch Lipid Clinic Network criteria were applied to 39 790 adult participants (aged ≥20 years) in the National Health and Nutrition Examination Survey to estimate the yield of FH screening programs using Dutch Lipid Clinic Network clinical criteria alone (excluding genetic variant status), genetic testing alone, or combining clinical criteria with genetic testing. The regression model accurately predicted FH variant status in UK Biobank participants (observed prevalence, 0.27%; predicted, 0.26%; area under the receiver-operator characteristic curve, 0.88). In the National Health and Nutrition Examination Survey, the estimated yield per 1000 individuals screened (95% CI) was 3.7 (3.0-4.6) FH cases with the Dutch Lipid Clinic Network clinical criteria alone, 3.8 (2.7-5.1) cases with genetic testing alone, and 6.6 (5.3-8.0) cases by combining clinical criteria with genetic testing. In young adults aged 20 to 39 years, using clinical criteria alone was estimated to yield 1.3 (95% CI, 0.6-2.5) FH cases per 1000 individuals screened, which was estimated to increase to 4.2 (95% CI, 2.6-6.4) FH cases when combining clinical criteria with genetic testing. Conclusions Screening for FH using a combination of clinical criteria with genetic testing may increase identification and the opportunity for early treatment of individuals with FH.
| S-EPMC9238728 | biostudies-literature
Project description:Atherosclerotic cardiovascular disease is the leading cause of death globally. Despite its important risk of premature atherosclerosis and cardiovascular disease, familial hypercholesterolemia (FH) is still largely underdiagnosed worldwide. It is one of the most frequently inherited diseases due to mutations, for autosomal dominant forms, in either of the LDLR, APOB, and PCSK9 genes or possibly a few mutations in the APOE gene and, for the rare autosomal forms, in the LDLRAP1 gene. The discovery of the genes implicated in the disease has largely helped to improve the diagnosis and treatment of FH from the LDLR by Brown and Goldstein, as well as the introduction of statins, to PCSK9 discovery in FH by Abifadel et al., and the very rapid availability of PCSK9 inhibitors. In the last two decades, major progress has been made in clinical and genetic diagnostic tools and the therapeutic arsenal against FH. Improving prevention, diagnosis, and treatment and making them more accessible to all patients will help reduce the lifelong burden of the disease.
| S-EPMC10092380 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is a common inherited disorder that results in premature atherosclerosis. Diagnosis of FH is suspected on the basis of clinical criteria, but confirmation requires genetic testing. In the era of statins, early diagnosis and initiation of treatment can modify disease progression and outcomes. Therefore, cascade screening with a combination of lipid concentration measurements and DNA testing should be used to identify relatives of index cases with a clinical diagnosis of FH. Autosomal dominant FH is related to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Genetic screening of the LDLR gene is challenging to achieve at a feasible cost, especially in people who do not have a founder effect. Nucleotide sequencing of all exons and flanking splicing regions in combination with multiplex ligation probe amplification to detect large insertions or deletions is considered the gold-standard approach to screen for LDLR mutations. Alternatively, the cDNA can be sequenced; however, this procedure is not suitable for use in large populations, because of the need of RNA extraction. Multiplex analysis can be appropriate for population with founder effects or a low number of different mutations. Finally, there are many techniques for a mutation scanning approach, which have some benefits over sequencing, and also with the potential for detecting known and novel mutations. Familial defective Apo B is amenable to genetic diagnosis by screening for a few mutations. Recently, gain-of-function mutations in PCSK9 gene have been demonstrated to cause FH phenotype. Strategies for population screening, cost-effectiveness of genetic screening, ethical aspects, and insurance policies are discussed and need implementation worldwide.
| S-EPMC3681171 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes coding for the low density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type-9 (PCSK9) or apo-lipoprotein B-100 (APOB). The aim of the present work was to determine the genetic basis of dyslipidemia in 11 unrelated Pakistani families.High resolution melting (HRM), sequencing and restriction fragment length polymorphism (RFLP).Probands were screened for the promoter and all coding regions, including intron/exon boundaries, of LDLR and PCSK9 and part of exon 26 of APOB including p.(R3527Q). Two families were identified with previously unreported LDLR mutations (c.1019_1020delinsTG, p.(C340L) and c.1634G>A, p.(G545E)). Both probands had tendon xanthomas or xanthelasma and/or a history of cardiovascular disease. Co-segregation with hypercholesterolemia was demonstrated in both families. In silico studies predicted these variations to be damaging. In two families, novel PCSK9 variations were identified (exon2; c.314G>A, p.(R105Q) and exon3; c.464C>T, p.(P155L)). In silico studies suggested both were likely to be damaging, and family members carrying the p.(105Q) allele had lower total cholesterol levels, suggesting this is a loss-of-function mutation. For c.464C>T p.(P155L) the small number of relatives available precluded any strong inference.This report brings to seven the number of different LDLR mutations reported in FH patients from Pakistan and, as expected in this heterogeneous population, no common LDLR mutation has been identified.
| S-EPMC3701840 | biostudies-literature
Project description:Background:Familial hypercholesterolemia (FH) is a frequent autosomal dominant disorder of lipoprotein metabolism. This disorder is generally caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B 100 (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. In the present study, we aimed at identifying the common LDLR and APOB gene mutations in an Iranian population. Methods:Eighty unrelated Iranian patients with FH entered the study, based on Simon Broome diagnostic criteria. All samples were screened for two common APOB gene mutations, including R3500Q and R3500W, by the means of ARMS-PCR and PCR- RFLP assays, respectively. In addition, exons 3, 4, 9, and 10 of LDLR gene were sequenced in all patients. Results:A novel mutation in exon 3 (C95W) and a previously described mutation in exon 4 (D139H) of LDLR gene were found. Three previously reported polymorphisms in LDLR gene as well as three novel polymorphisms were detected in the patients. However, in the studied population, no common mutations were observed in APOB gene. Conclusion:The results of our study imply that the genetic basis of FH in Iranian patients is different from other populations.
| S-EPMC5786657 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with premature cardiovascular disease (CVD). Mutations in the LDLR, APOB, and PCSK9 genes are known to cause FH. In this study, we analysed the genetic spectrum of the disease in subjects from the Iranian population with a clinical diagnosis of FH. Samples were collected from 16 children and family members from five different cities of Iran. Probands were screened for mutations in the LDLR, APOB, and PCSK9 genes using next generation sequencing, with results confirmed by Sanger sequencing. The likely pathology of identified variants was examined using in silico tools. Of the probands, 14 had a clinical diagnosis of homozygous FH and two of heterozygous FH. No mutations were found in either APOB or PCSK9, but nine probands were homozygous for seven different LDLR mutations, with p.(Trp577Arg) occurring in three and p.Val806Glyfs*11 occurring in two patients. Two mutations were novel: p.(Leu479Gln) and p.(Glu668*). Seven probands with a clinical diagnosis of FH were mutation negative. This pilot study, integrating clinical and molecular-based techniques, begins to elucidate the FH heterogeneity and the mutation spectrum in the Iranian population. Such information is important for future disease management and cost savings.
| S-EPMC5719081 | biostudies-other
Project description:Hypercholesterolemia was prevalent in 44.9% of The Malaysian Cohort participants, of which 51% were Malay. This study aimed to identify the variants involved in hypercholesterolemia among Malays and to determine the association between genetic and non-genetic risk factors. This nested case-control study included 25 Malay participants with the highest low-density lipoprotein cholesterol (LDL-C, >4.9 mmol/L) and total cholesterol (TC, >7.5 mmol/L) and 25 participants with the lowest LDL-C/TC. Genomic DNA was extracted, and whole-exome sequencing was performed using the Ion ProtonTM system. All variants were annotated, filtered, and cross-referenced against publicly available databases. Forty-five selected variants were genotyped in 677 TMC Malay participants using the MassARRAY® System. The association between genetic and non-genetic risk factors was determined using logistic regression analysis. Age, fasting blood glucose, tobacco use, and family history of hyperlipidemia were significantly associated with hypercholesterolemia. Participants with the novel OSBPL7 (oxysterol-binding protein-like 7) c.651_652del variant had 17 times higher odds for hypercholesterolemia. Type 2 diabetes patients on medication and those with PCSK9 (proprotein convertase subtilisin/kexin type 9) rs151193009 had low odds for hypercholesterolemia. Genetic predisposition can interact with non-genetic factors to increase hypercholesterolemia risk in Malaysian Malays.
| S-EPMC10048611 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) has been associated with early coronary artery disease (CAD) and increased risk of atherosclerotic cardiovascular disease. However, the prevalence of FH and its long-term outcomes in a CAD-high-risk cohort, defined as patients with hypercholesteremia who underwent coronary angiography, remains unknown. Besides, studies regarding the impact of genetic variations in FH on long-term cardiovascular (CV) outcomes are scarce. In total, 285 patients hospitalized for coronary angiography with blood low-density lipoprotein cholesterol (LDL-C) levels ≥ 160 mg/dL were sequenced to detect FH genetic variations in LDL receptors apolipoprotein B and proprotein convertase subtilisin/kexin type 9. Risk factors associated with long-term CV outcomes were evaluated. The prevalence of FH was high (14.4%). CAD and early CAD were significantly more prevalent among FH variation carriers than non-carriers, despite comparable blood LDL-C levels. Moreover, the FH variation carriers also underwent more revascularization after a mean follow-up of 6.1 years. Multivariate logistic regression demonstrated that FH genetic variation was associated with increased incidence of cardiovascular disease and mortality (odds ratio = 3.17, p = 0.047). Two common FH variants, LDLR c.986G>A and LDLR c.268G>A, showed the most significant impacts on high blood LDL-C levels and early-onset CAD. Our results indicate that FH genetic variants may exhibit differential effects on early-onset CAD and revascularization risks in patients undergoing coronary angiography. FH genetic information might help identify high-risk patients with typical CAD symptoms for appropriate intervention.
| S-EPMC8467756 | biostudies-literature
Project description:The first studies of familial hypercholesterolemia (FH) in Russia go back to late 1980-ies. For more than 10 years the research in this field was carried out in Saint-Petersburg, the megapolis in the North-West Russia. Studies were focused on the search for causative mutations in low-density lipoprotein receptor gene (LDLR). Gradually the research was spread to Petrozavodsk in Karelia and in the XXI century two more centers contributed in investigations of genetics of FH, i.e., in Moscow and Novosibirsk. The best studied is the spectrum of mutations in LDLR, though genetic abnormalities in APOB and PCSK9 genes were also considered. Despite that some 40% mutations in LDLR found in Saint-Petersburg and Moscow are referred to as specific for Russian population, and this proportion is even higher in Karelia (ca. 70%), rapid introduction of NGS and intensifying genetic research all over the world result in continuous decrease of these numbers as “Slavic” mutations become documented in other countries. The samplings of genetically characterized patients in Russia were relatively small, which makes difficult to specify major mutations reflecting the national specificity of FH. Moreover, the majority of studies accomplished so far did not explore possible associations of certain mutations with ethnic origin of patients. By now the only exception is the study of Karelian population showing the absence of typical Finnish mutations in the region that borders on Finland. It can be concluded that the important primary research partly characterizing the mutation spectrum in FH patients both in the European and Siberian parts of Russia has been done. However, it seems likely that the most interesting and comprehensive genetic studies of FH in Russia, concerning various mutations in different genes and the variety of ethnic groups in this multi-national country, are still to be undertaken.
| S-EPMC7773754 | biostudies-literature