Percorrer por autor "Chora, Joana Rita"
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- Advancements in risk stratification and management strategies in primary cardiovascular preventionPublication . Barkas, Fotios; Sener, Yusuf Ziya; Golforoush, Pelin Arabacilar; Kheirkhah, Azin; Rodriguez-Sanchez, Elena; Novak, Jan; Apellaniz-Ruiz, Maria; Akyea, Ralph Kwame; Bianconi, Vanessa; Ceasovschih, Alexandr; Chee, Ying Jie; Cherska, Mariia; Chora, Joana Rita; D'Oria, Mario; Demikhova, Nadiia; Kocyigit Burunkaya, Duygu; Rimbert, Antoine; Macchi, Chiara; Rathod, Krishnaraj; Roth, Lynn; Sukhorukov, Vasily; Stoica, Svetlana; Scicali, Roberto; Storozhenko, Tatyana; Uzokov, Jamol; Lupo, Maria Giovanna; van der Vorst, Emiel P.C.; Porsch, FlorentinaAtherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for advancements in risk ssessment and management strategies. Although significant progress has been made ecently, identifying and managing apparently healthy individuals at a higher risk of developing atherosclerosis and those with subclinical atherosclerosis still poses significant challenges. Traditional risk assessment tools have limitations in accurately predicting future events and fail to encompass the complexity of the atherosclerosis trajectory. In this review, we describe novel approaches in biomarkers, genetics, advanced imaging techniques, and artificial intelligence that have emerged to address this gap. Moreover, polygenic risk scores and imaging modalities such as coronary artery calcium scoring, and coronary computed tomography angiography offer promising avenues for enhancing primary cardiovascular risk stratification and personalised intervention strategies. On the other hand, interventions aiming against atherosclerosis development or promoting plaque regression have gained attention in primary ASCVD prevention. Therefore, the potential role of drugs like statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, omega-3 fatty acids, antihypertensive agents, as well as glucose-lowering and anti-inflammatory drugs are also discussed. Since findings regarding the efficacy of these interventions vary, further research is still required to elucidate their mechanisms of action, optimize treatment regimens, and determine their long-term effects on ASCVD outcomes. In conclusion, advancements in strategies addressing atherosclerosis prevention and plaque regression present promising avenues for enhancing primary ASCVD prevention through personalised approaches tailored to individual risk profiles. Nevertheless, ongoing research efforts are imperative to refine these strategies further and maximise their effectiveness in safeguarding cardiovascular health.
- Classificação de variantes de hipercolesterolemia familiar pelo painel de peritos do Clinical Genome ResourcePublication . Chora, Joana Rita; Bourbon, Mafalda; em nome do FH Variant Curation Expert Panelhipercolesterolemia familiar (FH) é a patologia monogénica mais comum e caracteriza-se por valores muito elevados de colesterol em circulação, levando à sua deposição nas artérias e causando aterosclerose prematura. Indivíduos com FH têm variantes patogénicas, principalmente no gene LDLR (>90%), mas também nos genes APOB e PCSK9, genes estes muito importantes no metabolismo lipídico. O diagnóstico genético é o diagnóstico definitivo, mas existem atualmente mais de 3500 variantes diferentes no LDLR listadas na ClinVar, e no início deste trabalho, 565 apresentavam classificações conflituosas de patogenicidade, não permitindo assim confirmar o diagnóstico clínico nos indivíduos portadores destas variantes. Neste trabalho apresentamos o progresso da classificação de variantes no LDLR pelo FH Variant Curation Expert Panel (VCEP) do Clinical Genome Resource (ClinGen), segundo a recomendação publicada pelo mesmo grupo para classificação de variantes no gene LDLR. No processo de classificação das variantes no gene LDLR, laboratórios associados enviam dados internos de casos índex com a variante em estudo, que são colocados no Variant Curation Interface e complementados com evidências publicadas em artigos científicos e outros dados obtidos de outras bases de dados como descrito na recomendação. Cada variante é avaliada por um biocurador sénior ou dois juniores e aprovada por três revisores antes de ser publicada oficialmente na ClinVar. Atualmente avaliámos 531 variantes no gene LDLR. O FH VCEP classificou 5% destas variantes como benignas/provavelmente benignas, 39% como patogénicas/provavelmente patogénicas, 48% como variantes de significado incerto, 1% como conflituosas e 7% estão ainda em avaliação. As classificações definitivas aumentaram de 34% para 44%, e as classificações conflituosas diminuíram de 56% para 1%. O trabalho do FH VCEP visa melhorar o diagnóstico genético da FH, para o qual a classificação correta das variantes no LDLR é de extrema importância. As recomendações do FH VCEP diminuem significativamente as classificações conflituosas, melhorando o diagnóstico da FH no mundo inteiro.
- Classification of genetic variants for clinical use – the case of Familial Hypercholesterolemia (Part 2) - How to classify LDLR variantsPublication . Chora, Joana RitaLecture on the Classification of Genetic Variants for Clinical Use – The Case of Familial Hypercholesterolemia (Part 2): How to Classify LDLR Variants, presented within the framework of Genetics and Genomics in Clinical Practice: Advanced Training. This advanced course is aimed at healthcare professionals seeking to understand, interpret, and apply genomic information in clinical practice in a critical, ethical, and effective manner, particularly physicians and professionals with a background in life sciences.
- Development of Gene-Specific ACMG/AMP Guidelines for the Interpretation of APOB and PCSK9 Variants in Familial HypercholesterolemiaPublication . Chora, Joana Rita; Hooper, Amanda; Gutierrez-Ford, Christina; Kullo, Iftikhar; Bourbon, Mafalda; on behalf of the ClinGen Familial Hypercholesterolemia Variant Curation Expert PanelBackground and Aims: The general ACMG/AMP guidelines for standardized variant interpretation provide a critical framework for determining pathogenicity but require adaptation to specific genes and diseases. While LDLR-specific guidelines for familial hypercholesterolemia (FH) have been in use since 2020, similar adaptations for APOB and PCSK9 are needed to address the unique characteristics of these genes in FH diagnosis. Methods: The Clinical Genome Resource (ClinGen) consortium’s FH variant curation expert panel (FH VCEP) expanded its efforts to develop tailored guidelines for APOB and PCSK9. A panel of international FH experts proposed and voted on specifications for these genes, based on current evidence. These adaptations were compared to LDLR-specific criteria for consistency and refined based on gene-specific attributes. Results: The proposed guidelines address the unique features of APOB and PCSK9 variants. For both genes, adaptations included adjustment of thresholds for population frequency criteria (PM2/BA1/BS1), specification of appropriate functional studies (PS3/BS3) to reflect each gene’s role in the LDLR cycle, and documented critical protein regions (PM1). Several criteria were considered to be applicable in the same manner as for LDLR: phenotype specificity (PP4), frequency of cases (PS4), co-segregation data (PP1), and cases with more than onevariant (PM3/BP2). As null variants in APOB and loss-of-function variants in PCSK9 are not mechanisms for FH, the evidence code for truncating variants (PVS1) was deemed not applicable for both genes. Lack of segregation (BS4) in APOB was also deemed not applicable due to documented incomplete penetrance of APOB variants. Conclusions: With the increasing detection of variants through advances in sequencing and genotyping technologies, these guidelines represent a significant step toward standardizing APOB and PCSK9 variant interpretation in FH diagnosis. Following ClinGen approval, these gene-specific recommendations will enable high-confidence classification of APOB and PCSK9 variants in ClinVar, enhancing the accuracy of FH diagnosis and supporting personalized management strategies for patients worldwide.
- e_LIPID–Characterization of hypercholesterolemia and association with cardiovascular disease in the Portuguese populationPublication . Chora, Joana Rita; Alves, Ana Catarina; Mariano, Cibelle; Antunes, Marília; Rato, Quitéria; Bourbon, MafaldaThe e_LIPID study aimed to characterise the lipid profile of the Portuguese population and study its association with cardiovascular disease (CV D) events. Demographic, clinical, and biochemical data derived from the e_COR Study, a cross-sectional epidemiological study with 1688 adults (18-79 years old) from five Portuguese continental regions. Population specific percentiles for lipid and lipoprotein biomarkers were esmated stratified by sex and age. All calculations were weighted by sex, age, and geographic region to be representative of the mainland Portuguese population. Odds ratio was calculated to study association of biochemical profile with CV D. Associations of total cholesterol (TC), LDL, ApoB and non-HDL were performed only on individuals under no lipid-lowering therapy. Individuals with LDL above the 9th5 percentile and fulfilling Simon-Broome criteria of Familial Hypercholesterolemia (FH) were sequenced for LDLR, APOB and PCSK9. National prevalence of individuals with TC≥190mg/dl were 52.4%, with LDL≥116mg/dl were 53.9%, with ApoB≥90mg/dl were 53.8%, with non- HDL≥146mg/dl were 38.9%, and with Lp(a)≥125nmol/L were 21.1%. The 90th percentile for lipid and lipoprotein biomarkers for the Portuguese population are TC of 244mg/dl, LDL of 169mg/dl, ApoB of 128mg/dl, non-HDL of 193mg/dl, and Lp(a) of 223nmol/L. The 10th percentile for HDL is 38mg/dl. Individuals with LDL≥116mg/dl presented 2.50 [1.13-6.07] higher odds of having had CV D events (p=0.018), with non-HDL≥146mg/dl had 2.06 [1.01-4.31] higher odds (p=0.041), and with high Lp(a)≥125nmol/L had 1.77 [1.13-2.72] higher odds (p=0.008) than their respective counterparts. From the 33 individuals sequenced 3 individuals were found to have heterozygous FH. Population age and sex specific values are important for dyslipidaemia assessment. Having LDL≥116mg/dl, non-HDL≥146mg/dl or Lp(a) ≥125nmol/L can double the odds of CV D. Our results highlight that hypercholesterolemia is a neglected cardiovascular risk factor with more than 50% of the population with TC≥190mg/dl, LDL≥116mg/dl, or ApoB≥90mg/dl. Since hypercholesterolemia is a modifiable risk factor in the majority of cases, strategies to increase adherence to changes in lifestyle habits need to be urgently discussed.
- Estudo Português de Hipercolesterolemia FamiliarPublication . Medeiros, Ana Margarida; Alves, Ana Catarina; Chora, Joana Rita; Bourbon, MafaldaA Hipercolesterolemia Familiar (FH) é uma doença genética associada a um elevado risco cardiovascular. Doentes com FH possuem valores muito elevados de colesterol no plasma, desde o nascimento. Até à data 3 genes foram associados à FH: LDLR (85-90%), APOB (5-8%) e PCSK9 (1-2%). Em 1999 foi estabelecido, no Instituto Nacional de Saúde Doutor Ricardo Jorge, o Estudo Português de Hipercolesterolemia Familiar (EPHF). Este estudo de investigação tem como objetivo principal identificar a causa genética da dislipidemia em doentes com critérios clínicos de FH. O EPHF identificou molecularmente 718 doentes heterozigotos com uma variante patogénica ou provavelmente patogénica (segundo as diretrizes da ACMG) num dos 3 genes associados à FH. Adicionalmente, 90 indivíduos possuem uma das 35 variantes de significado incerto cuja patogenicidade necessita de ser avaliada através de estudos funcionais. Foram também identificados 10 homozigotos (3 homozigotos verdadeiros e 7 heterozigotos compostos), com variantes patogénicas nos genes LDLR e PCSK9. O EPHF conseguiu identificar 3,8% dos portugueses que se calcula terem FH, colocando Portugal entre os dez países com mais doentes identificados. O risco cardiovascular dos doentes com FH é determinado pelos valores elevados de colesterol que os doentes apresentam desde o nascimento, mas também pela patogenicidade da variante identificada. A identificação precoce dos doentes com FH, através do diagnóstico genético, permite ao clínico implementar medidas terapêuticas adequadas e mais agressivas, de modo a diminuir o risco cardiovascular inerente a estes doentes.
- Estudo Português de Hipercolesterolemia Familiar (1999-2021): relação fenótipo-genótipoPublication . Medeiros, Ana Margarida; Alves, Ana Catarina; Chora, Joana Rita; Miranda, Beatriz; Bourbon, Mafalda; em nome dos investigadores do Estudo Português de Hipercolesterolemia FamiliarA Hipercolesterolemia Familiar (FH) é uma condição genética comum do metabolismo dos lípidos, que se encontra subdiagnosticada. Existem três genes primários associados à FH (LDLR, APOB e PCSK9) e 5 genes fenocópias (LDLRAP1, LIPA, ABCG5, ABCG8 e APOE), que conferem um fenótipo semelhante à FH. Neste trabalho pretende-se apresentar a relação fenótipo-genótipo dos indivíduos com critérios clínicos de FH referenciados ao Estudo Português de Hipercolesterolemia Familiar. Até ao fim de 2021 foram estudados molecularmente 1005 indivíduos com critérios clínicos de FH. Destes, foram confirmados geneticamente com FH (FH positivos), 417 casos-índex (408 heterozigotos e 9 homozigotos). Com os estudos familiares identificaram- se adicionalmente 581 heterozigotos e 2 homozigotos. De entre os FH positivos, os casos-índex com variantes de alelo nulo apresentam um fenótipo mais severo do que os casos-índex com variantes de alelo defeituoso. Cerca de 1% dos casos-índex foram diagnosticados com outras causas monogénicas. Dos FH negativos, 34% apresenta hiper-Lp(a), 18% tem uma hipercolesterolemia de causa poligénica e 1% possui uma variante patogénica em heterozigotia nos genes fenocópias da FH. As diferentes causas genéticas contribuem para uma variedade de fenótipos que requerem diferentes formas de gestão da doença, terapias específicas e têm implicações na estratificação do risco cardiovascular e no rastreio dos familiares, sendo por esta razão essencial que seja identificada a etiologia da hipercolesterolemia o mais precocemente possível para melhorar o prognóstico dos indivíduos com FH.
- Familial hypercholesterolemia [CHAPTER 17]Publication . Chora, Joana Rita; Medeiros, Ana Margarida; Alves, Ana Catarina; Bourbon, MafaldaFamilial hypercholesterolemia (FH) is a common autosomal dominant disorder of lipid metabolism, with a heterozygous frequency of 1/250e1/500 in most of the European countries. Clinically FH is characterized by elevated concentrations of plasma cholesterol that accumulates in arteries and tendons from birth leading to premature coronary heart disease (pCHD). (...)
- Farmacogenética de fármacos antidislipidémicosPublication . Chora, Joana Rita; Bourbon, MafaldaDoentes com dislipidemia grave necessitam de tomar medicação antidislipidémica para diminuir as concentrações elevadas de colesterol de forma a reduzirem o seu elevado risco cardiovascular. Distintos tipos e/ou doses de estatinas levam a diferentes níveis de redução dos níveis de LDL-C, mas existe uma grande variação interpessoal na resposta, que se pensa estar associada a variantes nos genes envolvidos na farmacodinâmica e farmacocinética desta classe de fármacos. Este trabalho tem como objetivo determinar a prevalência de genótipos associados a uma menor eficácia ou a um maior risco de efeitos secundários adversos no tratamento com estatinas na população portuguesa. Foram genotipados vários SNPs envolvidos no metabolismo, absorção, transporte e/ou excreção dos vários tipos de estatinas numa amostra de adultos da população portuguesa proveniente das diferentes regiões do país. A variante SLCO1B1*5, associada com um maior risco de desenvolver miopatia com o tratamento com sinvastatina, tem uma frequência 2 vezes superior na nossa amostra do que o descrito nas bases de dados populacionais. Este fato, aliado ao grande aumento de consumo nacional de estatinas, principalmente de sinvastatina, é um fator importante que deve ser considerado na tomada de decisão da prescrição de antidislipidémicos.
- From Uncertainty To Diagnosis: Functional Reclassification Of LDLR Variants In Familial HypercholesterolemiaPublication . Chora, Joana Rita; Islam, Mohammad Majharul; Alves, Ana Catarina; Pfisterer, Simon; Bourbon, MafaldaObjectives: Familial hypercholesterolaemia (FH) is a common disorder of lipid metabolism marked by an increased risk of premature atherosclerotic cardiovascular disease. While genetic testing confirms diagnosis, many LDLR variants are classified as variants of uncertain significance (VUS) due to lack of evidence, limiting clinical actionability. Functional assays can support reclassification, but conventional approaches are time-consuming. This study aims to use a high-throughput functional pipeline to evaluate LDLR VUS and improve diagnostic precision in FH. Methods: We analysed 133 LDLR VUS lacking functional evidence using an automated analysis platform based on multiplexed high-content imaging to quantify LDL uptake. Variants were classified based on uptake relative to wild-type: <70% for PS3_Supporting (pathogenic) and >90% for BS3_Supporting (benign), according to LDLR-specific ACMG/AMP guidelines. A subset of 46 “hot VUS” required only one supporting criterion to reach a likely benign or likely pathogenic classification. Results: Of the 133 variants, 53 showed <70% uptake and were assigned PS3_Supporting, while 41 showed >90% uptake and received BS3_Supporting. The remaining 39 variants exhibited intermediate activity (70–90%). Among the 46 hot VUS, 12 were reclassified as likely benign and 11 as likely pathogenic. An additional 43 variants are now one supporting criterion away from potential reclassification. Conclusions: High-throughput functional testing provides robust and rapid evidence for LDLR variant interpretation. By adding evidence about LDLR activity these assays contribute to resolve diagnostic uncertainty and enables earlier and more accurate diagnosis, optimizes cascade screening, and enables better risk stratification to inform treatment options. These findings support a shift toward personalised genomic medicine in lipid disorders, with direct implications for patient care and cardiovascular risk reduction.
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