JOSE EDUARDO KRIEGER
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Cardio-Pneumologia, Faculdade de Medicina - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
19 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 19
- Health related quality of life in individuals at high risk for familial hypercholesterolemia undergoing genetic cascade screening in Brazil(2018) SOUTO, Ana Cristina; MINAME, Marcio H.; FUKUSHIMA, Julia; JANNES, Cinthia E.; KRIEGER, Jose E.; HAGGER, Martin; PEREIRA, Alexandre C.; SANTOS, Raul D.Background and aims: Familial hypercholesterolemia (FH) is a genetic disorder associated with high risk of early major cardiovascular events (MACE) that can impact the health related quality of life (HRQoL), however, this association is unclear. This study evaluated HRQoL in index cases (IC) and first-degree relatives (FDR) of individuals at high risk of FH undergoing genetic cascade screening. Methods: Data collection was performed before awareness of molecular diagnosis results. Individuals were divided into four groups according to the molecular diagnosis: IC with (ICthorn) and without (IC-) identified mutations (n = 93 and n = 175, respectively), and affected (FDRthorn, n = 231) and non-affected (FDR-, n = 159) FDR of ICthorn. HRQoL measurements, mental (MCS) and physical component (PCS) scores were carried out with SF-12 questionnaire. Associations were tested by generalized linear models. Results: The mean age was 49 +/- 15 years, 42.2% were men, MACE had occurred in 30.7%. Overall, both PCS and MCS did not differ between FH and non-FH individuals, however, IC trended to have lower PCS independent of FH presence (p = 0.003). Lower PCS were associated with female sex (p = 0.018), lower education (p < 0.001), professional inactivity (p = 0.028), previous MACE occurrence (p < 0.001), hypertension (p = 0.016), depression (p < 0.001) and obesity (p < 0.001). Lower MCS were associated with female sex (p = 0.009), previous MACE occurrence (p = 0.034), depression (p < 0.001) and smoking (p = 0.009). Neither the presence of FH causing mutations nor pharmacological lipid lowering treatment was associated with HRQoL. Conclusions: HRQoL is not reduced in both IC and FDR FH individuals in comparison with their nonaffected counterparts. Previous MACE and co-morbidities are associated with reduced HRQoL.
- 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.
- Thioredoxin interacting protein genetic variation is associated with diabetes and hypertension in the Brazilian general population(2012) FERREIRA, Noely E.; OMAE, Samantha; PEREIRA, Abel; RODRIGUES, Mariliza V.; MIYAKAWA, Ayumi A.; CAMPOS, Luciene C. G.; SANTOS, Paulo C. J. L.; DALLAN, Luiz A.; MARTINEZ, Tania L.; SANTOS, Raul D.; MILL, Jose G.; KRIEGER, Jose E.; PEREIRA, Alexandre C.Objective: To investigate the relationship between TXNIP polymorphisms, diabetes and hypertension phenotypes in the Brazilian general population. Methods: Five hundred seventy-six individuals randomly selected from the general urban population according to the MONICA-WHO project guidelines were phenotyped for cardiovascular risk factors. A second, independent, sample composed of 487 family-trios from a different site was also selected. Nine TXNIP polymorphisms were studied. The potential association between TXNIP variability and glucose-phenotypes in children was also explored. TXNIP expression was quantified by real-time PCR in 53 samples from human smooth muscle cells primary culture. Results: TXNIP rs7211 and rs7212 polymorphisms were significantly associated with glucose and blood pressure related phenotypes. In multivariate logistic regression models the studied markers remained associated with diabetes even after adjustment for covariates. TXNIP rs7211 T/rs7212 G haplotype (present in approximately 17% of individuals) was significantly associated to diabetes in both samples. In children, the TXNIP rs7211 T/rs7212 G haplotype was associated with fasting insulin concentrations. Finally, cells harboring TXNIP rs7212 G allele presented higher TXNIP expression levels compared with carriers of TXNIP rs7212 CC genotype (p = 0.02). Conclusion: Carriers of TXNIP genetic variants presented higher TXNIP expression, early signs of glucose homeostasis derangement and increased susceptibility to chronic metabolic conditions such as diabetes and hypertension. Our data suggest that genetic variation in the TXNIP gene may act as a ""common ground"" modulator of both traits: diabetes and hypertension.
- Clinical and molecular aspects of familial hypercholesterolemia in Ibero-American countries(2017) SANTOS, Raul D.; BOURBON, Mafalda; ALONSO, Rodrigo; CUEVAS, Ada; VASQUES-CARDENAS, Norma Alexandra; PEREIRA, Alexandre C.; VILLAMIZAR, Alonso M.; ALVES, Ana Catarina; MEDEIROS, Ana Margarida; JANNES, Cinthia E.; KRIEGER, Jose E.; SCHREIER, Laura; ISLA, Leopoldo Perez de; MAGANA-TORRES, Maria Teresa; STOLL, Mario; MATA, Nelva; OCA, Nicolas Dell; CORRAL, Pablo; ASENJO, Sylvia; BANARES, Virginia G.; REYES, Ximena; MATA, PedroBACKGROUND: There is little information about familial hypercholesterolemia (FH) epidemiology and care in Ibero-American countries. The Ibero-American FH network aims at reducing the gap on diagnosis and treatment of this disease in the region. OBJECTIVE: To describe clinical, molecular, and organizational characteristics of FH diagnosis in Argentina, Brazil, Chile, Colombia, Mexico, Portugal, Spain, and Uruguay. METHODS: Descriptive analysis of country data related to FH cascade screening, molecular diagnosis, clinical practice guidelines, and patient organization presence in Ibero-America. RESULTS: From a conservative estimation of an FH prevalence of 1 of 500 individuals, there should be 1.2 million heterozygous FH individuals in Ibero-America and roughly 27,400 were diagnosed so far. Only Spain, Brazil, Portugal, and Uruguay have active cascade screening programs. The prevalence of cardiovascular disease ranged from 10% to 42% in member countries, and the highest molecular identification rates are seen in Spain, 8.3%, followed by Portugal, 3.8%, and Uruguay with 2.5%. In the 3 countries with more FH patients identified (Spain, Portugal, and Brazil) between 10 and 15 mutations are responsible for 30% to 47% of all FH cases. Spain and Portugal share 5 of the 10 most common mutations (4 in low density lipoprotein receptor [LDLR] and the APOB3527). Spain and Spanishspeaking Latin American countries share 6 of the most common LDLR mutations and the APOB3527. LDL apheresis is available only in Spain and Portugal and not all countries have specific FH diagnostic and treatment guidelines as well as patient organizations. CONCLUSIONS: Ibero-American countries share similar mutations and gaps in FH care.
- Cardiovascular disease onset in old people with severe hypercholesterolemia(2023) COUTINHO, Elaine R.; MINAME, Marcio H.; ROCHA, Viviane Z.; BITTENCOURT, Marcio S.; JANNES, Cinthia E.; KRIEGER, Jose E.; PEREIRA, Alexandre C.; SANTOS, Raul D.Background and aims: Familial hypercholesterolemia (FH) variants are associated with higher atherosclerotic cardiovascular disease risk (ASCVD) even when compared with other forms of severe hypercholesterolemia, especially in young people. Lipid lowering therapies (LLT) may change hypercholesterolemia natural history. This study aimed at evaluating factors associated with occurrence of ASCVD in old severe hypercholesterolemics diagnosed or not with FH and undergoing LLT.Methods: Hypercholesterolemic individuals >= 60 years participating on a genetic cascade screening for FH were divided in 4 groups (2 x 2) according to the presence (variant+) or not (variant-) of FH genetic variants and previous ASCVD (ASCVD+ and ASCVD-). Biomarkers associated with new incident ASCVD events were tested using Cox models. Continuous data shown as medians (%25; %75).Results: From 4,111 genotyped individuals, 377 (9.1%) were elderly [age 66 (63; 71) years], 28.9% males, 42.7% variant+, 32.1% with previous ASCVD, LLT duration 9 (5; 16) years, and on treatment LDL-cholesterol 144 (109; 200) mg/dL. After 4.8 (7; 3) years of follow up there were 47 incident events (12.4%, 2.7% patient/year). The annualized event rates were 0.8% (95% CI 0.36%; 1.70%), 2.3% (95% CI 1.3%; 4.1%), 5.2% (95% CI 2.8%; 9.7%) and 6.3% (95% CI 4.0%; 10.0%) respectively for groups variant-/ASCVD-, variant+/ASCVD-, variant-/ ASCVD+ and, variant+/ASCVD+ (p log rank p < 0.001). Only presence of previous ASCVD was independently associated with incident ASCVD [hazard ratio 3.236 (95%CI 1.497-6.993, p = 0.003)]. No interaction was found for previous ASCVD and variants.Conclusions: In old severe hypercholesterolemic individuals undergoing long-term LLT previous ASCVD was associated with incident events while FH causing variants were not.
- 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.
conferenceObject Cardiovascular Disease in Elderly Familial Hypercholesterolemia Individuals Attending a Cascade Screening Program(2020) COUTINHO, Elaine; MINAME, Marcio H.; ROCHA, Viviane Z.; BITTENCOURT, Marcio S.; JANNES, Cinthia; PEREIRA, Alexandre; KRIEGER, Jose E.; SANTOS, Raul D.- The removal from plasma of chylomicrons and remnants is reduced in heterozygous familial hypercholesterolemia subjects with identified LDL receptor mutations: Study with artificial emulsions(2012) CARNEIRO, Marcia M.; MINAME, Marcio H.; GAGLIARDI, Ana C.; PEREIRA, Carolina; PEREIRA, Alexandre C.; KRIEGER, Jose E.; MARANHAO, Raul C.; SANTOS, Raul D.Chylomicron remnants bind to both their specific receptors (LRP) and to the LDL receptor (LDLR) in the liver. There is controversy whether disturbances of chylomicron metabolism occur in subjects with familial hypercholesterolemia (FH). The aim of this study was to evaluate whether there are defects on the removal from plasma of chylomicrons and their remnants in heterozygous FH patients with determined LDLR mutations. We studied 20 heterozygous FH patients (43.2 +/- 12 years old, 60% males) and 50 normolipidemic subjects matched for age and gender. FH subjects were not in use of LDL-lowering drugs for at least 6 weeks. The removal from plasma of chylomicrons and their remnants was measured by isotopic decay after venous injection of a chylomicron-like emulsion radiolabeled with C-14-cholesteryl ester (C-14-CE) and H-3-triolein (H-3-TO). These track respectively removal from plasma of chylomicrons and remnants and lipolysis. There was a significant reduction in the fractional catabolic rates (FCR in h(-1)) of C-14-CE in FH in comparison with normolipidemics: 0.048 (1.46.10-7; 0.57) vs. 0.71(0.049; 1.62), [median (25th-75th percentile)], p = 0.003. No differences were found in FCR of H-3-TO between FH and controls, respectively 1.62 (1.02; 2.331) and 1.914 (1.34; 2.878), p = 0.405. In conclusion heterozygous FH subjects had a significant decrease on the removal from plasma of chylomicrons and their remnants compared with normolipidemics.
conferenceObject Cardiovascular Disease Progression in Children With Homozygous Familial Hypercholesterolemia Despite Early Diagnosis on a Genetic Cascade Screening Program(2022) JULIANI, Fabiana C.; CHACRA, Ana Paula M.; MINAME, Marcio H.; SALGADO FILHO, Wilson; MIZUTA, Marjorie H.; JANNES, Cinthia E.; KRIEGER, Jose E.; MARANHAO, Raul C.; SANTOS, Raul D.; ROCHA, Viviane Z.- Polygenic risk score for hypercholesterolemia in a Brazilian familial hypercholesterolemia cohort(2022) LIMA, Isabella Ramos; TADA, Mauricio Teruo; OLIVEIRA, Theo G. M.; JANNES, Cinthia Elim; BENSENOR, Isabela; LOTUFO, Paulo A.; SANTOS, Raul D.; KRIEGER, Jose E.; PEREIRA, Alexandre C.Background and aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of LDL-C leading to premature cardiovascular disease (CAD). Only about 40% of individuals with a clinical diagnosis of FH have a causative genetic variant identified, and a proportion of genetically negative cases may have a polygenic cause rather than a still unidentified monogenic cause. This work aims to evaluate and validate the role of a polygenic risk score (PRS) associated with hypercholesterolemia in a Brazilian FH cohort and its clinical implications. Methods: We analyzed a previously derived PRS of 12 and 6 SNPs (Single Nucleotide Polymorphism) in 684 FH individuals (491 mutation-negative [FH/M-], 193 mutation-positive [FH/M+]) and in 1605 controls. Coronary artery calcium (CAC) score was also evaluated. Results: The PRS was independently associated with LDL-C in control individuals (p < 0.001). Within this group, in individuals in the highest quartile of the 12 SNPs PRS, the odds ratio for CAC score 100 was 1.7 (95% CI: 1.01-2.88, p = 0.04) after adjustment for age and sex. Subjects in the FH/M- group had the highest mean score in both 12 and 6 SNPs PRS (38.25 and 27.82, respectively) when compared to the other two groups (p = 2.2 x 10-16). Both scores were also higher in the FH/M+ group (36.48 and 26.26, respectively) when compared to the control group (p < 0.001 for the two scores) but inferior to the FH/M- group. Within FH individuals, the presence of a higher PRS score was not associated with LDL-C levels or with CAD risk. Conclusion: A higher PRS is associated with significantly higher levels of LDL-C and it is independently associated with higher CAC in the Brazilian general population. A polygenic cause can explain a fraction of FH/M- individuals but does not appear to be a modulator of the clinical phenotype among FH individuals, regardless of mutation status. (C) 2022 The Authors.