Atualização da Diretriz Brasileira de Hipercolesterolemia Familiar – 2021

Izar, Maria Cristina; Giraldez, Viviane Zorzanelli Rocha; Bertolami, Adriana; Filho, Raul Dias dos Santos; Lottenberg, Ana Maria; Assad, Marcelo Heitor Vieira; Saraiva, José Francisco Kerr; Chacra, Ana Paula Marte; Martinez, T.L.R.; Bahia, Luciana; Fonseca, Francisco Antônio Helfenstein; Faludi, André Árpád; Spósito, Andrei C.; Chagas, Antônio Carlos Palandri; Jannes, Cinthia E.; Amaral, Cristiane Kovacs; Araújo, Daniel Branco de; Cintra, Dennys Esper; Coutinho, Elaine dos Reis; Cesena, Fernando H; Xavier, Hermes Tóros; Mota, Isabela Cardoso Pimentel; Giuliano, Isabela de Carlos Back; Neto, José Rocha Faria; Kato, Juliana Tieko; Bertolami, Marcelo Chiara; Miname, Márcio H.; Castelo, Maria Helane Costa Gurgel; Lavrador, Maria Sílvia Ferrari; Machado, Roberta Marcondes; Souza, Patrícia Guedes de; Alves, Renato Jorge; Machado, Valéria A.; Filho, Wilson Albino Pimentel

doi:10.36660/abc.20210788

Cited by 19 publications

(22 citation statements)

References 401 publications

(512 reference statements)

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“…This is related to the FHBGEP project that investigates genomic, epigenomic, and pharmacogenomic factors associated with FH in the Brazilian population [20]. FH was clinically diagnosed according to Dutch Lipid Clinic Network (DLCN) modified criteria [21]. Subjects aged less than 18 years old, liver failure, severe chronic kidney and/or nephrotic syndrome, thyroid or adrenal diseases, neoplasms or positive HIV were not included.…”

Section: Subjects and Study Protocolmentioning

confidence: 99%

“…Treatment intensity was established according to the following criteria: (1) moderate intensity: simvastatin 20-40 mg, atorvastatin 10-20 mg or rosuvastatin 5-10 mg; (2) high intensity: simvastatin 80 mg + ezetimibe 10 mg, atorvastatin 40-80 mg or rosuvastatin 20-40 mg [21]. Patients were grouped as responders (RE) if they reached the therapy target (≥50% LDLc reduction) [21] or non-responders (NRE) if they did not reach the therapy target. Drug-drug interactions were annotated when a concomitant medication could inhibit or induce enzymatic activity and affect statin response [22].…”

Section: Subjects and Study Protocolmentioning

confidence: 99%

“…Statins used in treatment included either simvastatin, atorvastatin, or rosuvastatin. Treatment intensity was established according to the following criteria: (1) moderate intensity: simvastatin 20-40 mg, atorvastatin 10-20 mg or rosuvastatin 5-10 mg; (2) high intensity: simvastatin 80 mg + ezetimibe 10 mg, atorvastatin 40-80 mg or rosuvastatin 20-40 mg [21]. Patients were grouped as responders (RE) if they reached the therapy target (≥50% LDLc reduction) [21] or non-responders (NRE) if they did not reach the therapy target.…”

Section: Subjects and Study Protocolmentioning

confidence: 99%

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Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability

Dagli-Hernandez,

Ferreira,

Freitas

et al. 2024

Pharmacogenetics and Genomics

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Objectives This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability. Methods Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies. Results A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability. Conclusion Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability.

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Section: Subjects and Study Protocolmentioning

confidence: 99%

Section: Subjects and Study Protocolmentioning

confidence: 99%

Section: Subjects and Study Protocolmentioning

confidence: 99%

See 1 more Smart Citation

Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability

Dagli-Hernandez,

Ferreira,

Freitas

et al. 2024

Pharmacogenetics and Genomics

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“…Its origin is related, in 60–80% of cases, to structural alterations in three canonical genes (CanGen), LDLR , APOB , and PCSK9 , which encode proteins with direct functions in LDL catabolism. However, FH may also be caused by pathogenic mutations in unidentified genes or in several genes, a situation known as Polygenic FH 1 , 2 .…”

Section: Introductionmentioning

confidence: 99%

LDLR gene’s promoter region hypermethylation in patients with familial hypercholesterolemia

Zorzo,

Suen,

Santos

et al. 2023

Sci Rep

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Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein cholesterol (LDL-C) levels and a high risk of early coronary heart disease. Structural alterations in the LDLR, APOB, and PCSK9 genes were not found in 20–40% of patients diagnosed using the Dutch Lipid Clinic Network (DCLN) criteria. We hypothesized that methylation in canonical genes could explain the origin of the phenotype in these patients. This study included 62 DNA samples from patients with a clinical diagnosis of FH according to the DCLN criteria, who previously tested negative for structural alterations in the canonical genes, and 47 DNA samples from patients with normal blood lipids (control group). All DNA samples were tested for methylation in the CpG islands of the three genes. The prevalence of FH relative to each gene was determined in both groups and the respective prevalence ratios (PRs) were calculated. The methylation analysis of APOB and PCSK9 was negative in both groups, showing no relationship between methylation in these genes and the FH phenotype. As the LDLR gene has two CpG islands, we analyzed each island separately. The analysis of LDLR-island1 showed PR = 0.982 (CI 0.33–2.95; χ2 = 0.001; p = 0.973), also suggesting no relationship between methylation and the FH phenotype. Analysis of LDLR-island2 showed a PR of 4.12 (CI 1.43–11.88; χ2 = 13,921; p = 0.00019), indicating a possible association between methylation on this island and the FH phenotype.

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“…As Estatinas de alta potência diminuem a síntese de colesterol no fígado e são a primeira escolha, sendo a maioria delas liberada para uso em crianças a partir de 10 anos de idade. A Pravastatina, porém, é liberada para crianças a partir dos 8 anos, enquanto a Rosuvastatina já vem sendo utilizada em crianças a partir de Administrada via oral, a Lomitapida tem se mostrado uma droga promissora no tratamento de HoHF e estudos, de fase 1 e 2, mostram redução em cerca de 40-50% do LDL-c em um espaço de 8 a 12 semanas quando associada à Estatina + Ezetimiba, tanto em heterozigóticos como em homozigóticos (IZAR MCO, et al, 2021). No Brasil, a Lomitapidafoi aprovada em 2020 pela Agência Nacional de Vigilância Sanitária (ANVISA) para uso em adultos na hipercolesterolemia familiar homozigótica (IZAR MCO, et al, 2021).…”

Section: Introductionunclassified

Impacto da mutação C681X no tratamento de hipercolesterolemia familiar homozigótica: um relato de caso

Fadul¹,

Valente²,

Lima

et al. 2023

Acervo Saúde

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Objetivo: Relatar o impacto da mutação C681X no tratamento de hipercolesterolemia familiar homozigótica. Detalhamento do caso: Paciente, sexo masculino, 17 anos, com história de colesterol alto (LDL-c: 760 mg/dl), xantomas tuberosos e arcos corneanos desde os sete anos. Teste genético confirmou mutação homozigótica da C681X no receptor de LDL, sem alterações cardiovasculares. Pai, mãe, irmão apresentaram hipercolesterolemia com LDL-c >190mg/dl. Avó e tio maternos faleceram de infarto agudo do miocárdio antes dos 50 anos. Iniciou tratamento com Atorvastatina 40mg/dia e Ezetimibe 10mg/dia. Posteriormente, foi alterado Atorvastatina pela Rosuvastatina 40 mg/dia. Aos 11 anos, iniciou terapia tripla com Mipomersen 200mg, apresentou resposta adequada após 1 ano. O medicamento foi suspenso devido baixa segurança para sua idade, vindo elevar os níveis de LDL-c. Aos 13 anos utilizou Evolocumab (inibidor da PCSK9), na posologia de 140mg, associado a Rosuvastatina e a Ezetimibe. Depois de um ano, em terapia tripla, os resultados foram CT: 561 mg/dL;HDL-c: 27 mg/dL; LDL-c: 512 mg/dL; e TG: 110 mg/dL. Considerações finais: Paciente retornou após 3 anos sem ir às consultas, em uso de Atorvastatina 40mg/dia, Ezetimibe 10mg/dia e Evolocumab 140mg a cada 15 dias, sem controle adequado. Foi realizado ajuste da medicação e encaminhado paraseguimento multiprofissional.

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Atualização da Diretriz Brasileira de Hipercolesterolemia Familiar – 2021

Cited by 19 publications

References 401 publications

Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability

Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability

LDLR gene’s promoter region hypermethylation in patients with familial hypercholesterolemia

Impacto da mutação C681X no tratamento de hipercolesterolemia familiar homozigótica: um relato de caso

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