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PURPOSE OF REVIEW: Not all patients with severe hypertriglyceridemia develop acute pancreatitis. We surveyed recent literature on inter-individual genetic variation in susceptibility to pancreatitis. RECENT FINDINGS: Genetic determinants of pancreatitis include: rare Mendelian disorders caused by highly penetrant pathogenic variants in genes involved in trypsinogen activation; uncommon susceptibility variants in genes involved in trypsinogen activation, protein misfolding as well as calcium metabolism and cystic fibrosis, that have variable penetrance and show a range of odds ratios for pancreatitis; and common polymorphisms in many of the same genes that have only a small effect on risk. The role of these genetic variants in modulating pancreatitis risk in hypertriglyceridemia is unclear. However, among genetic determinants of plasma triglycerides, those predisposing to more severe hypertriglyceridemia associated with chylomicronemia appear to have higher pancreatitis risk. SUMMARY: Currently, among patients with severe hypertriglyceridemia, the most consistent predictor of pancreatitis risk is the triglyceride level. Furthermore, pancreatitis risk appears to be modulated by a higher genetic burden of factors associated with greater magnitude of triglyceride elevation. The role of common and rare genetic determinants of pancreatitis itself in this metabolic context is unclear.
Assuntos
Hipertrigliceridemia , Pancreatite , Humanos , Doença Aguda , Tripsinogênio , Hipertrigliceridemia/complicações , TriglicerídeosRESUMO
PURPOSE OF REVIEW: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming more prominent as a therapeutic choice in diabetes management and their use is being expanded to other indications, such as obesity. Dyslipidemia and cardiovascular disease are common co-morbidities in these populations and understanding the impact of this class of medications on the lipid profile may be an important consideration. RECENT FINDINGS: Several GLP-1RAs trials demonstrate them to be safe and potentially beneficial for cardiovascular outcomes; improvements in surrogate markers of atherosclerosis have also been observed. Lipid data collected as secondary outcomes from large clinical trials as well as some smaller dedicated trials show that GLP-1RAs can modestly lower low-density lipoprotein (LDL) and total cholesterol (C), and most show modest fasting triglyceride (TG) lowering. Effects on high-density lipoprotein-C have been less consistent. Some have also demonstrated substantial blunting of the postprandial rise in serum TGs. Favorable effects on lipoprotein metabolism, with reduced levels of small dense LDL particles and decreased atherogenic potential of oxidized LDL, have also been seen. Mechanisms underlying these observations have been investigated. SUMMARY: This review summarizes the data available on the lipid effects of GLP-1RAs, and explores the current understanding of the mechanisms underlying these observed effects.
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Receptor do Peptídeo Semelhante ao Glucagon 1 , Metabolismo dos Lipídeos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE OF REVIEW: Amyloidosis is caused by the deposition of misfolded aggregated proteins called amyloid fibrils that in turn cause organ damage and dysfunction. In this review, we aim to summarize the genetic, clinical, and histological findings in apolipoprotein-associated hereditary amyloidosis and the growing list of mutations and apolipoproteins associated with this disorder. We also endeavor to summarize the features of apolipoproteins that have led them to be overrepresented among amyloidogenic proteins. Additionally, we aim to distinguish mutations leading to amyloidosis from those that lead to inherited dyslipidemias. RECENT FINDINGS: Apolipoproteins are becoming increasingly recognized in hereditary forms of amyloidosis. Although mutations in APOA1 and APOA2 have been well established in hereditary amyloidosis, new mutations are still being detected, providing further insight into the pathogenesis of apolipoprotein-related amyloidosis. Furthermore, amyloidogenic mutations in APOC2 and APOC3 have more recently been described. Although no hereditary mutations in APOE or APOA4 have been described to date, both protein products are amyloidogenic and frequently found within amyloid deposits. SUMMARY: Understanding the underlying apolipoprotein mutations that contribute to hereditary amyloidosis may help improve understanding of this rare but serious disorder and could open the door for targeted therapies and the potential development of new treatment options.
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Amiloidose Familiar , Amiloidose , Apolipoproteínas/genética , Amiloidose/genética , Amiloidose Familiar/genética , HumanosRESUMO
BACKGROUND: The incidence of severe (S-HTG) and very severe hypertriglyceridemia (VS-HTG) among Canadians is unknown. This study aimed to determine the incidence, characteristics, predictors and care patterns for individuals with VS-HTG. METHODS: Using linked administrative healthcare databases, a population-based cohort study of Ontario adults was conducted to determine incidence of new onset S-HTG (serum triglycerides (TG) > 10-20 mmol/L) and VS-HTG (TG > 20 mmol/L) between 2010 and 2015. Socio-demographic and clinical characteristics of those with VS-HTG were compared to those who had no measured TG value > 3 mmol/L. Univariable and multivariable logistic regression were used to determine predictors for VS-HTG. Healthcare patterns were evaluated for 2 years following first incidence of TG > 20 mmol/L. RESULTS: Incidence of S-HTG and VS-HTG in Ontario was 0.16 and 0.027% among 10,766,770 adults ≥18 years and 0.25 and 0.041% among 7,040,865 adults with at least one measured TG, respectively. Predictors of VS-HTG included younger age [odds ratios (OR) 0.64/decade, 95% confidence intervals (CI) 0.62-0.66], male sex (OR 3.83; 95% CI 3.5-4.1), diabetes (OR 5.38; 95% CI 4.93-5.88), hypertension (OR 1.69; 95% CI 1.54-1.86), chronic liver disease (OR 1.71; 95% CI 1.48-1.97), alcohol abuse (OR 2.47; 95% CI 1.90-3.19), obesity (OR 1.49; 95% CI 1.13-1.98), and chronic kidney disease (OR 1.39; 95% CI 1.19-1.63). CONCLUSION: The 5-year incidence of S-HTG and VS-HTG in Canadian adults was 1 in 400 and 1 in 2500, respectively. Males, those with diabetes, obese individuals and those with alcohol abuse are at highest risk for VS-HTG and may benefit from increased surveillance.
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Alcoolismo/epidemiologia , Diabetes Mellitus/epidemiologia , Hipertensão/epidemiologia , Hipertrigliceridemia/epidemiologia , Hepatopatias/epidemiologia , Obesidade/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Triglicerídeos/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alcoolismo/sangue , Alcoolismo/diagnóstico , Alcoolismo/fisiopatologia , Estudos de Coortes , Bases de Dados Factuais , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/fisiopatologia , Feminino , Humanos , Hipertensão/sangue , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Hipertrigliceridemia/sangue , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/fisiopatologia , Incidência , Hepatopatias/sangue , Hepatopatias/diagnóstico , Hepatopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/diagnóstico , Obesidade/fisiopatologia , Razão de Chances , Ontário/epidemiologia , Prognóstico , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e., hypoalphalipoproteinemia) with the VarSeq-CNV® caller algorithm to screen for CNVs that disrupted the ABCA1, LCAT, or APOA1 genes. In four individuals, we found three unique deletions in ABCA1: a heterozygous deletion of exon 4, a heterozygous deletion that spanned exons 8 to 31, and a heterozygous deletion of the entire ABCA1 gene. Breakpoints were identified with Sanger sequencing, and the full-gene deletion was confirmed by using exome sequencing and the Affymetrix CytoScan HD array. Previously, large-scale deletions in candidate HDL genes had not been associated with hypoalphalipoproteinemia; our findings indicate that CNVs in ABCA1 may be a previously unappreciated genetic determinant of low levels of HDL cholesterol. By coupling bioinformatic analyses with next-generation sequencing data, we can successfully assess the spectrum of genetic determinants of many dyslipidemias, including hypoalphalipoproteinemia.
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Transportador 1 de Cassete de Ligação de ATP/deficiência , Transportador 1 de Cassete de Ligação de ATP/genética , Deleção de Genes , Hipoalfalipoproteinemias/genética , Adulto , Biologia Computacional , Variações do Número de Cópias de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Biologia Computacional , Variações do Número de Cópias de DNA , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Fator 4 Nuclear de Hepatócito/genética , Adolescente , Hibridização Genômica Comparativa , Biologia Computacional/métodos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
The increasing affordability of and access to next-generation DNA sequencing has increased the feasibility of incorporating genetic analysis into the diagnostic pathway for dyslipidaemia. But should genetic diagnosis be used routinely? DNA testing for any medical condition has potential benefits and pitfalls. For dyslipidaemias, the overall balance of advantages versus drawbacks differs according to the main lipid disturbance. For instance, some patients with severely elevated low-density lipoprotein cholesterol levels have a monogenic disorder, namely heterozygous familial hypercholesterolaemia. In these patients, DNA diagnosis can be definitive, in turn yielding several benefits for patient care that tend to outweigh any potential disadvantages. In contrast, hypertriglyceridaemia is almost always a polygenic condition without a discrete monogenic basis, except for ultrarare monogenic familial chylomicronaemia syndrome. Genetic testing in patients with hypertriglyceridaemia is therefore predominantly non-definitive and evidence for benefit is presently lacking. Here we consider advantages and limitations of genetic testing in dyslipidaemias.
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Dislipidemias , Hiperlipoproteinemia Tipo I , Hipertrigliceridemia , Humanos , Testes Genéticos , Hiperlipoproteinemia Tipo I/genética , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/genética , Hipertrigliceridemia/terapia , Dislipidemias/diagnóstico , Dislipidemias/genética , Dislipidemias/terapia , LipídeosRESUMO
We have used DNA sequencing in our lipid clinic for >20 years. Dyslipidaemia is typically ascertained biochemically. For moderate deviations in the lipid profile, the etiology is often a combination of a polygenic susceptibility component plus secondary non-genetic factors. For severe dyslipidaemia, a monogenic etiology is more likely, although a discrete single-gene cause is frequently not found. A severe phenotype can also result from strong polygenic predisposition that is aggravated by secondary factors. A young age of onset plus a family history of dyslipidaemia or atherosclerotic cardiovascular disease can suggest a monogenic etiology. With severe dyslipidaemia, clinical examination focuses on detecting manifestations of monogenic syndromic conditions. For all patients with dyslipidaemia, secondary causes must be ruled out. Here we describe an experience-based practical approach to genetic testing of patients with severe deviations of low-density lipoprotein, triglycerides, high-density lipoprotein and also combined hyperlipidaemia and dysbetalipoproteinemia.
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Dislipidemias , Testes Genéticos , Humanos , Fenótipo , Dislipidemias/diagnóstico , Dislipidemias/genética , Triglicerídeos , Fatores de RiscoRESUMO
Lipid disorders involving derangements in serum cholesterol, triglycerides, or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and overall health. Recent advances in knowledge, recommendations, and treatment options have necessitated an updated approach to these disorders. Older classification schemes have outlived their usefulness, yielding to an approach based on the primary lipid disturbance identified on a routine lipid panel as a practical starting point. Although monogenic dyslipidemias exist and are important to identify, most individuals with lipid disorders have polygenic predisposition, often in the context of secondary factors such as obesity and type 2 diabetes. With regard to cardiovascular disease, elevated low-density lipoprotein cholesterol is essentially causal, and clinical practice guidelines worldwide have recommended treatment thresholds and targets for this variable. Furthermore, recent studies have established elevated triglycerides as a cardiovascular risk factor, whereas depressed high-density lipoprotein cholesterol now appears less contributory than was previously believed. An updated approach to diagnosis and risk assessment may include measurement of secondary lipid variables such as apolipoprotein B and lipoprotein(a), together with selective use of genetic testing to diagnose rare monogenic dyslipidemias such as familial hypercholesterolemia or familial chylomicronemia syndrome. The ongoing development of new agents-especially antisense RNA and monoclonal antibodies-targeting dyslipidemias will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Dislipidemias , Doenças Cardiovasculares/genética , Colesterol , Dislipidemias/diagnóstico , Dislipidemias/terapia , Humanos , Fatores de Risco , TriglicerídeosRESUMO
BACKGROUND: Combined hyperlipidemia (CHL) is a common disorder defined by concurrently elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Despite decades of study, the genetic basis of CHL remains unclear. OBJECTIVE: To characterize the genetic profiles of patients with CHL and compare them to those in patients with isolated hypercholesterolemia and isolated hypertriglyceridemia (HTG). METHODS: DNA from 259, 379 and 124 patients with CHL, isolated hypercholesterolemia and isolated HTG, respectively, underwent targeted sequencing. We assessed: 1) rare variants disrupting canonical LDL-C or TG metabolism genes; and 2) two polygenic scores-for elevated LDL-C and TG-calculated using common trait-associated single-nucleotide polymorphisms (SNPs). Genetic profiles were compared against 1000 Genomes Project controls. RESULTS: Both CHL and isolated HTG patients had significantly increased odds of a high polygenic score for TG: 2.50 (95% confidence interval [CI] 1.61-3.88; P < 0.001) and 3.72 (95% CI 2.24-6.19; P < 0.001), respectively. CHL patients had neither a significant accumulation of rare variants for LDL-C or TG, nor a high polygenic score for LDL-C. In contrast, patients with isolated hypercholesterolemia had a 3.03-fold increased odds (95% CI 2.22-4.13; P < 0.001) of carrying rare variants associated with familial hypercholesterolemia, while patients with isolated HTG had a 2.78-fold increased odds (95% CI 1.27-6.10; P = 0.0136) of carrying rare variants associated with severe HTG. CONCLUSION: CHL is genetically similar to isolated HTG, a known polygenic trait. Both cohorts had a significant accumulation of common TG-raising variants. Elevated LDL-C levels in CHL are not associated with common or rare LDL-C-related genetic variants.
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Hiperlipidemias , Adulto , Humanos , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: Copy-number variations (CNVs) are large-scale deletions or duplications of DNA that have required specialized detection methods, such as microarray-based genomic hybridization or multiplex ligation probe amplification. However, recent advances in bioinformatics have made it possible to detect CNVs from next-generation DNA sequencing (NGS) data. Maturity-onset diabetes of the young (MODY) 5 is a subtype of autosomal-dominant diabetes that is often caused by heterozygous deletions involving the HNF1B gene on chromosome 17q12. We evaluated the utility of bioinformatic processing of raw NGS data to detect chromosome 17q12 deletions in MODY5 patients. METHODS: NGS data from 57 patients clinically suspected to have MODY but who were negative for pathogenic mutations using a targeted panel were re-examined using a CNV calling tool (CNV Caller, VarSeq version 1.4.3). Potential CNVs for MODY5 were then confirmed using whole-exome sequencing, cytogenetic analysis and breakpoint analysis when possible. RESULTS: Whole-gene deletions in HNF1B, ranging from 1.46 to 1.85 million basepairs in size, were detected in 3 individuals with features of MODY5. These were confirmed by independent methods to be part of a more extensive 17q12 deletion syndrome. Two additional patients carrying a 17q12 deletion were subsequently diagnosed using this method. CONCLUSIONS: Large-scale deletions are the most common cause of MODY5 and can be detected directly from NGS data, without the need for additional methods.
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Biomarcadores/análise , Variações do Número de Cópias de DNA , Diabetes Mellitus Tipo 2/diagnóstico , Deleção de Genes , Testes Genéticos/métodos , Fator 1-beta Nuclear de Hepatócito/genética , Mutação , Adolescente , Criança , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , PrognósticoRESUMO
A 22-year-old woman presented with elevated low-density lipoprotein (LDL) cholesterol and clinically suspected familial hypercholesterolemia. Initial genetic analysis by Sanger sequencing found no causal variants in LDLR or other familial hypercholesterolemia genes. More than a decade later, her 9-year-old daughter was also found to have elevated LDL cholesterol. Re-analysis using current genetic methodology detected a novel whole-gene duplication of APOB in both individuals, which was tentatively assumed to explain their elevated LDL cholesterol based mainly on biological plausibility. However, on further assessment with cascade screening and cosegregation analysis involving multiple family members, the APOB duplication was eventually discounted as being causative. This case illustrates the risk of assuming pathogenicity of a novel genetic variant without undertaking corroborative diagnostic measures. It further highlights the time and skill required for accurate variant analysis and emphasizes the challenges faced by clinicians who are increasingly expected to rapidly interpret such results without sufficient time or resources to pursue supportive or corroborating evidence.
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Apolipoproteína B-100/genética , Duplicação Gênica , Hiperlipoproteinemia Tipo II/genética , Adulto , Idoso , Apolipoproteína B-100/sangue , Criança , Pré-Escolar , LDL-Colesterol/sangue , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prognóstico , Adulto JovemRESUMO
A 36-year-old woman presented at 16 weeks' gestation with severe hypertension. In comparison to the non-pregnant reference normal ranges, potassium was 3.1-3.9 mmol/L, aldosterone 2570-3000 pmol/L (N 250-2885) renin was unsuppressed (24-76.4 ng/L (N1.7-23.9)), with aldosterone to renin ratios in the reference range. An adrenal MRI scan demonstrated a 1.8 × 1.4 cm left adrenal adenoma. Primary aldosteronism was strongly suspected and surgery considered. However, she was managed conservatively with labetalol and modified-release nifedipine with no obstetric complications. Post-partum blood pressures remained elevated with normal aldosterone (539 pmol/L), unsuppressed renin (5.2 ng/L) and normal aldosterone-to-renin ratio (104 (N < 144)). Suspected primary hyperaldosteronism is challenging to investigate and manage in pregnancy. The accepted screening and confirmatory tests are either contraindicated or not validated in pregnancy. Pregnancy has significant effects on the renin-angiotensin-aldosterone pathway leading to physiologic elevations in both aldosterone and renin. While primary hyperaldosteronism has been associated with poor pregnancy outcomes, optimal management in pregnancy is not clearly established.
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OBJECTIVE: Non-parathyroid hormone (PTH) mediated hypercalcemia in young patients is rare. It encompasses a broad differential including malignancy, granulomatous diseases, Addison disease, and toxicity of vitamin A and D. We present an unusual case of non-PTH mediated hyper-calcemia in a previously healthy bodybuilder, secondary to multifocal granulomatous disease from paraffin oil injections. METHODS: The patient was evaluated with laboratory tests including serum calcium, 25-hydroxyvitamin D, 1,25-hydroxyvitamin D, parathyroid hormone, and parathyroid hormone-related peptide. Imaging studies such as thorax computed tomography and bone scans were also performed. RESULTS: A 31-year-old male bodybuilder presented with severe hypercalcemia (corrected calcium 3.1 mmol/L) and renal failure (creatinine 840 µmol/L), with suppressed PTH 1.0 pmol/L (normal, 1.6 to 6.9 pmol/L), and 1,25-vitamin D 205 pmol/L (normal, 60 to 208 pmol/L). He had used anabolic steroids for bodybuilding purposes for 8 years, with the possibility that he may also have used paraffin oil injections. Computed tomography imaging along with patient history suggested multiple paraffinomas in the pectoralis muscles causing granulomatous foreign body reaction as a potential cause for his hypercalcemia. He was prescribed a trial of prednisone, but he discontinued it due to symptoms of acne. Unfortunately, due to poor adherence with medical direction, management of his hypercalcemia remains challenging with inconsistent use of steroids and pamidronate infusions. CONCLUSION: Granulomatous foreign-body reactions are a rare side effect of paraffin oil injections used for muscle augmentation. These can lead to serious long-term side effects of severe hypercalcemia and renal failure, as seen in our patient. Prognosis is generally poor, with long term steroids as the preferred treatment.
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Dyslipidaemias encompass about two dozen relatively rare monogenic disorders and syndromes for which the genetic basis has largely been defined. In addition, the complex polygenic basis of disturbed lipids and lipoproteins has been characterised in many patients, and has been shown to result from accumulation of many common polymorphisms with small effects on lipids. Genetic technologies, including dedicated genotyping and sequencing methods can detect both rare and common DNA variants underlying dyslipidaemias. Some dyslipidaemias may be clinically silent for years, but early diagnosis, including genetic diagnosis, may permit early intervention to prevent or delay deleterious downstream clinical consequences, such as premature vascular disease or acute pancreatitis. The potential clinical utility of genetic testing for familial hypercholesterolaemia, familial chylomicronaemia syndrome, lysosomal acid lipase deficiency and some others will increase demand for reliable genetic diagnostic methods. We review some current technologies, such as targeted next-generation sequencing that seem to be helpful with DNA diagnosis of dyslipidaemias. We also address technical, biological and clinical limitations of genetic testing in dyslipidaemias. Finally, genetic counselling issues, the potential impact of results on patients and health care providers, current gaps and future directions will be discussed.
Assuntos
Dislipidemias/diagnóstico , Testes Genéticos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo I/diagnóstico , Polimorfismo Genético/genética , Variações do Número de Cópias de DNA , Dislipidemias/genética , Aconselhamento Genético , Técnicas de Genotipagem , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo II/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNARESUMO
Familial hypercholesterolaemia is the most commonly encountered genetic condition that predisposes individuals to premature cardiovascular disease. Nevertheless, most patients are undiagnosed, and treatment is often suboptimal even when the diagnosis seems certain. Advances in molecular technologies are reshaping our understanding of this condition, including revision upwards of the population prevalence. Furthermore, the underlying pathophysiological complexity has been exposed by the range of causative genetic loci, breadth of types and classes of rare disease-causing variants, and polygenic basis of the phenotype in many patients. Genetic testing is not always helpful or definitive. Familial hypercholesterolaemia can be envisioned as a group of related disorders, of which the classic 'textbook' phenotype is a subset. Features such as clinical stigmata, family history of dyslipidaemia or cardiovascular disease, and presence of a rare pathogenic variant all increase diagnostic certainty. However, even in the absence of these elements, the essential feature remains an elevated level of plasma LDL cholesterol, which alone should prompt a dialogue between the care provider and the patient on lifestyle modification and lipid-lowering therapy as the foundation of a long-term strategy to prevent or delay the onset of cardiovascular disease.