CINTHIA ELIM JANNES LEPSKI
Projetos de Pesquisa
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Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Presence and type of low density lipoprotein receptor (LDLR) mutation influences the lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia(2014) SANTOS, Paulo Caleb Junior Lima; MORGAN, Aline Cruz; JANNES, Cintia Elin; TUROLLA, Luciana; KRIEGER, Jose Eduardo; SANTOS, Raul D.; PEREIRA, Alexandre CostaObjectives: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused mainly by LDLR mutations. This study assessed the influence of the presence and type of LDLR mutation on lipid profile and the response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Methods: For 14 +/- 3 months, 156 patients with heterozygous FH receiving atorvastatin were followed. Coding sequences of the LDLR gene were bidirectionally sequenced, and the type of LDLR mutations were classified according to their probable functional class. Results: The frequencies of the types of LDLR mutations were: null-mutation (n = 40, 25.6%), defective-mutation (n = 59, 37.8%), and without an identified mutation (n = 57, 36.6%). Baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were higher in patients carrying a null mutation (9.9 +/- 1.9 mmol/L, 7.9 +/- 1.7 mmol/L), compared to those with a defective (8.9 +/- 2.2 mmol/L, 7.0 +/- 2.0 mmol/L), or no mutation (7.9 +/- 1.9 mmol/L, 5.8 +/- 1.9 mmol/L) (p < 0.001). After treatment, the proportion of patients attaining an LDL-C<3.4 mmol/L was significantly different among groups: null (22.5%), defective (27.1%), and without mutations (47.4%) (p = 0.02). The presence of LDLR mutations was independently associated with higher odds of not achieving the LDL-C cut-off (OR 9.07, 95% CI 1.41-58.16, p = 0.02). Conclusions: Our findings indicate that the presence and type of LDLR mutations influence lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Thus, more intensive care with pharmacological therapeutics should be performed in patients who have a molecular analysis indicating the presence of a LDLR mutation. (C) 2014 Published by Elsevier Ireland Ltd.
- Phenotypical, Clinical, and Molecular Aspects of Adults and Children With Homozygous Familial Hypercholesterolemia in Iberoamerica(2020) ALVES, Ana Catarina; ALONSO, Rodrigo; DIAZ-DIAZ, Jose Luis; MEDEIROS, Ana Margarida; JANNES, Cinthia E.; MERCHAN, Alonso; VASQUES-CARDENAS, Norma A.; CUEVAS, Ada; CHACRA, Ana Paula; KRIEGER, Jose E.; ARROYO, Raquel; ARRIETA, Francisco; SCHREIER, Laura; CORRAL, Pablo; BANARES, Virginia G.; ARAUJO, Maria B.; BUSTOS, Paula; ASENJO, Sylvia; STOLL, Mario; DELL'OCA, Nicolas; REYES, Maria; RESSIA, Andres; CAMPO, Rafael; MAGANA-TORRES, Maria T.; METHA, Roopa; AGUILAR-SALINAS, Carlos A.; CEBALLOS-MACIAS, Jose J.; MORALES, Alvaro J. Ruiz; MATA, Pedro; BOURBON, Mafalda; SANTOS, Raul D.Objective: Characterize homozygous familial hypercholesterolemia (HoFH) individuals from Iberoamerica. Approach and Results: In a cross-sectional retrospective evaluation 134 individuals with a HoFH phenotype, 71 adults (age 39.3 +/- 15.8 years, 38.0% males), and 63 children (age 8.8 +/- 4.0 years, 50.8% males) were studied. Genetic characterization was available in 129 (96%). The majority (91%) were true homozygotes (true HoFH, n=79, 43.0% children, 46.8% males) or compound heterozygotes (compound heterozygous familial hypercholesterolemia, n=39, 51.3% children, 46.2% males) with putative pathogenic variants in theLDLR. True HoFH due toLDLRvariants had higher total (P=0.015) and LDL (low-density lipoprotein)-cholesterol (P=0.008) compared with compound heterozygous familial hypercholesterolemia. Children with true HoFH (n=34) tended to be diagnosed earlier (P=0.051) and had a greater frequency of xanthomas (P=0.016) than those with compound heterozygous familial hypercholesterolemia (n=20). Previous major cardiovascular events were present in 25 (48%) of 52 children (missing information in 2 cases), and in 43 (67%) of 64 adults withLDLRvariants. Children who are true HoFH had higher frequency of major cardiovascular events (P=0.02), coronary heart (P=0.013), and aortic/supra-aortic valve diseases (P=0.022) than compound heterozygous familial hypercholesterolemia. In adults, no differences were observed in major cardiovascular events according to type ofLDLRvariant. From 118 subjects withLDLRvariants, 76 (64%) had 2 likely pathogenic or pathogenic variants. In 89 subjects with 2LDLRvariants, those with at least one null allele were younger (P=0.003) and had a greater frequency of major cardiovascular events (P=0.038) occurring at an earlier age (P=0.001). Conclusions: There was a high frequency of cardiovascular disease even in children. Phenotype and cardiovascular complications were heterogeneous and associated with the type of molecular defect.
- Screening of ABCG5 and ABCG8 Genes for Sitosterolemia in a Familial Hypercholesterolemia Cascade Screening Program(2022) TADA, Mauricio Teruo; ROCHA, Viviane Zorzanelli; LIMA, Isabella Ramos; OLIVEIRA, Theo Gremen Mimary; CHACRA, Ana Paula; MINAME, Marcio Hiroshi; NUNES, Valeria Sutti; NAKANDAKARE, Edna Regina; CASTELO, Maria Helane Costa Gurgel; JANNES, Cinthia Elim; SANTOS, Raul D.; KRIEGER, Jose Eduardo; PEREIRA, Alexandre CostaBackground: Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in ABCG5/ABCG8. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program. Methods: From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the ABCG5/8 genes. Clinical and laboratory characteristics of affected individuals were determined. Results: Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for ABCG5/ABCG8 genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2 +/- 19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean beta-Sitosterol and campesterol, respectively, 160.3 +/- 107.1 and 32.0 +/- 19.6 mu g/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0 +/- 120.0 mg/dL (range: 122-521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities. Conclusions: Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.
- Vascular age derived from coronary artery calcium score on the risk stratification of individuals with heterozygous familial hypercholesterolaemia(2020) MINAME, Marcio H.; BITTENCOURT, Marcio Sommers; PEREIRA, Alexandre C.; JANNES, Cinthia E.; KRIEGER, Jose E.; NASIR, Khurram; SANTOS, Raul D.Aims The objective of this study was to evaluate if vascular age derived from coronary artery calcium (CAC) score improves atherosclerosis cardiovascular disease (ASCVD) risk discrimination in primary prevention asymptomatic heterozygous familial hypercholesterolaemia (FH) patients undergoing standard lipid-lowering therapy. Methods and results Two hundred and six molecularly confirmed FH individuals (age 45 +/- 14 years, 36% males, baseline LDL-cholesterol 6.2 +/- 2.2 mmol/L; 239 +/- 85mg/dL) were followed by 4.4 +/- 2.9 years (median: 3.7 years, interquartile ranges 2.7-6.8). CAC measurement was performed, and lipid-lowering therapy was optimized according to FH guidelines. Vascular age was derived from CAC and calculated according to the Multi Ethnic Study of Atherosclerosis algorithm. Risk estimation based on the Framingham equations was calculated for both biological (bFRS) and vascular (vaFRS) age. During follow-up, 15 ASCVD events (7.2%) were documented. The annualized rate of events for bFRS <10%, 10-20%, and >20% was respectively: 8.45 [95% confidence interval (CI) 3.17-22.52], 23.28 (95% CI 9.69-55.94), and 28.13 (95% CI 12.63-62.61) per 1000 patients. The annualized rate of events for vaFRS <10%, 10-20%, and >20% was respectively: 0, 0, and 50.37 (95% CI 30.37-83.56) per 1000 patients. vaFRS presented a better discrimination for ASCVD events compared to bFRS 0.7058 (95% CI 0.5866-0.8250) vs. vaFRS 0.8820 (95% CI 0.8286-0.9355), P= 0.0005. Conclusion CAC derived vascular age can improve ASCVD risk discrimination in primary prevention FH subjects. This tool may help further stratify risk in FH patients already receiving lipid-lowering medication who might be candidates for further treatment with newer therapies.
- The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification(2022) CHORA, Joana R.; IACOCCA, Michael A.; TICHY, Lukas; WAND, Hannah; KURTZ, C. Lisa; ZIMMERMANN, Heather; LEON, Annette; WILLIAMS, Maggie; HUMPHRIES, Steve E.; HOOPER, Amanda J.; TRINDER, Mark; BRUNHAM, Liam R.; PEREIRA, Alexandre Costa; JANNES, Cinthia E.; CHEN, Margaret; CHONIS, Jessica; WANG, Jian; KIM, Serra; JOHNSTON, Tami; SOUCEK, Premysl; KRAMAREK, Michal; LEIGH, Sarah E.; CARRIE, Alain; SIJBRANDS, Eric J.; HEGELE, Robert A.; FREIBERGER, Tomas; KNOWLES, Joshua W.; BOURBON, MafaldaPurpose: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified. Methods: The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached. Results: The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others. Conclusion: Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.
- Cascade screening and genetic diagnosis of familial hypercholesterolemia in clusters of the Southeastern region from Brazil(2020) SILVINO, Junea Paolucci de Paiva; JANNES, Cinthia Elim; TADA, Mauricio Teruo; LIMA, Isabella Ramos; SILVA, Ieda de Fatima Oliveira; PEREIRA, Alexandre Costa; GOMES, Karina BragaFamilial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by high levels of low-density lipoprotein-cholesterol (LDLc), associated to premature cardiovascular disease. The detection of the variants related to FH is important to improve the early diagnosis in probands / index-cases (ICs) and their relatives. We included ICs with FH and their relatives, living in a small region of Minas Gerais state-Brazil, which were classified according to Dutch Lipid Clinic Network Criteria (DLCNC) and submitted to sequencing of genes related to FH (LDLR, APOB, PCSK9, LDLRAP1, LIPA, STAP1, APOE, ABCG5 e ABCG8). In a total of 143 subjects (32 ICs and 111 relatives), eight variants were identified in 91 individuals. From these variants, five were in LDLR [p.(Asp224Asn), p.(Ser854Gly), p.(Cys34Arg), p.(Asp601His), deletion of exon15 in LDLR)], one in APOB [p.(Met499Val)], one in PCSK9 [p.(Arg237Trp)] and one in APOE [p.(Pro28Leu)] genes. The variants were detected in 100% of those subjects classified as definitive, 87% as probable and 69% as possible FH cases based on DLCNC. The LDLc level was higher in individuals with corneal arch and xanthomas or xanthelasmas, as well as in pathogenic or probably pathogenic variants carriers. This study showed higher frequency of LDLR gene variants compared to other genes related to LDL metabolism in individuals with FH in Minas Gerais - Brazil and the presence of FH in relatives without previous diagnosis. Our data reinforce the importance of molecular and clinical evaluation of FH relatives in order to early diagnosis the FH, as well as cardiovascular diseases prevention.
- Phenotypic characterization and predictive analysis of p.Asp47Asn LDL receptor mutation associated with Familial Hypercholesterolemia in a Chilean population(2021) SANCHEZ, Andrea; BUSTOS, Paulina; HONORATO, Paula; BURGOS, Carlos F.; BARRIGA, Natalia; JANNES, Cinthia E.; SAEZ, Katia; ALONSO, Rodrigo; ASENJO, Sylvia; RADOJKOVIC, ClaudiaBACKGROUND: Familial hypercholesterolemia (FH) is an inherited disorder mainly caused by mutations in the LDL receptor (LDL-R) and characterized by elevation of low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. OBJECTIVE: In this study, we evaluated the clinical phenotype of the p.Asp47Asn, described as an uncertain pathogenic variant, and its effect on the structure of LDL-R and ligand interactions with apolipoproteins. METHODS: 27 children and adolescents with suspected FH diagnosis were recruited from a pediatric endocrinology outpatient clinic. Blood samples were collected after 12 h fasting for lipid profile analysis. DNA sequencing was performed for six FH-related genes by Ion Torrent PGM platform and copy number variation by MLPA. For index cases, a familial cascade screening was done restricted to the same mutation found in the index case. In silico analysis were developed to evaluate the binding capacity of LDL-R to apolipoproteins B100 and E. RESULTS: Lipid profile in children and adolescents demonstrated higher LDL-C levels in p.Asp47Asn carriers compared to the wild type genotype. In silico analysis predicted a reduction in the binding capacity of the ligand-binding modules LA1-2 of p.Asp47Asn LDL-R for ApoB100 and ApoE, which was not produced by local structural changes or folding defects but as a consequence of a decreased apparent affinity for both apolipoproteins. CONCLUSION: The clinical phenotype and the structural effects of p.Asp47Asn LDL-R mutation suggest that this variant associates to FH. (C) 2021 Published by Elsevier Inc. on behalf of National Lipid Association.