PAULO CALEB JUNIOR DE LIMA SANTOS
Projetos de Pesquisa
Unidades Organizacionais
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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- CYP2C9 and VKORC1 Polymorphisms Are Differently Distributed in the Brazilian Population According to Self-Declared Ethnicity or Genetic Ancestry(2012) SOARES, Renata Alonso Gadi; SANTOS, Paulo Caleb Junior Lima; MACHADO-COELHO, George Luiz Lins; NASCIMENTO, Raimundo Marques do; MILL, Jose Geraldo; KRIEGER, Jose Eduardo; PEREIRA, Alexandre CostaBackground: Warfarin-dosing pharmacogenetic algorithms have presented different performances across ethnicities, and the impact in admixed populations is not fully known. Aims: To evaluate the CYP2C9 and VKORC1 polymorphisms and warfarin-predicted metabolic phenotypes according to both self-declared ethnicity and genetic ancestry in a Brazilian general population plus Amerindian groups. Methods: Two hundred twenty-two Amerindians (Tupinikin and Guarani) were enrolled and 1038 individuals from the Brazilian general population who were self-declared as White, Intermediate (Brown, Pardo in Portuguese), or Black. Samples of 274 Brazilian subjects from Sao Paulo were analyzed for genetic ancestry using an Affymetrix 6.0 (R) genotyping platform. The CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), and VKORC1 g.-1639G>A (rs9923231) polymorphisms were genotyped in all studied individuals. Results: The allelic frequency for the VKORC1 polymorphism was differently distributed according to self-declared ethnicity: White (50.5%), Intermediate (46.0%), Black (39.3%), Tupinikin (40.1%), and Guarani (37.3%) (p < 0.001), respectively. The frequency of intermediate plus poor metabolizers (IM + PM) was higher in White (28.3%) than in Intermediate (22.7%), Black (20.5%), Tupinikin (12.9%), and Guarani (5.3%), (p < 0.001). For the samples with determined ancestry, subjects carrying the GG genotype for the VKORC1 had higher African ancestry and lower European ancestry (0.14 +/- 0.02 and 0.62 +/- 0.02) than in subjects carrying AA (0.05 +/- 0.01 and 0.73 +/- 0.03) (p = 0.009 and 0.03, respectively). Subjects classified as IM + PM had lower African ancestry (0.08 +/- 0.01) than extensive metabolizers (0.12 +/- 0.01) (p = 0.02). Conclusions: The CYP2C9 and VKORC1 polymorphisms are differently distributed according to self-declared ethnicity or genetic ancestry in the Brazilian general population plus Amerindians. This information is an initial step toward clinical pharmacogenetic implementation, and it could be very useful in strategic planning aiming at an individual therapeutic approach and an adverse drug effect profile prediction in an admixed population.
- BDKRB2+9/-9 Polymorphism Is Associated with Higher Risk for Diabetes Mellitus in the Brazilian General Population(2012) ALVIM, Rafael de Oliveira; SANTOS, Paulo C. J. L.; NASCIMENTO, Raimundo M.; COELHO, George L. L. M.; MILL, Jose G.; KRIEGER, Jose E.; PEREIRA, Alexandre C.Some mechanisms have been proposed to explain the role of bradykinin on glucose homeostasis and some studies reported that the BDKRB2 +9/-9 polymorphism was associated to the transcriptional activity of the receptor. In this scenario, the main aim of this study was to evaluate the association of the BDKRB2 +9/-9 polymorphism with diabetes mellitus risk in the Brazilian general population. This study included 1,032 subjects of the general urban population. Anthropometrical, blood pressure, biochemical, and genotype analyses for the BDKRB2 +9/-9 bp insertion/deletion polymorphism were performed. Individuals carrying +9/+9 or +9/-9 genotypes had higher glucose values (84.5 mg/dL versus 80.6 mg/dL, resp.) and higher frequency of diabetes mellitus (7.6% versus 3.6%, resp.) compared to individuals carrying -9/-9, adjusting for age and gender. In addition, higher diabetes mellitus risk was associated to presence of the +9/+9 or +9/-9 genotypes (OR = 1.91; 95% CI = 1.09-4.19; P = 0.03). Our data suggest that the BDKRB2 +9/-9 polymorphism may act as a genetic modulator of glucose homeostasis. It was previously associated to insulin sensitivity, glucose uptake, and insulin secretion, and, in this study, data suggest that the polymorphism may increase susceptibility to chronic metabolic conditions such as diabetes in the Brazilian population.
- Genotyping of the hemochromatosis HFE p.H63D and p.C282Y mutations by high-resolution melting with the Rotor-Gene 6000 (R) instrument(2011) SANTOS, Paulo Caleb Junior Lima; SOARES, Renata Alonso Gadi; KRIEGER, Jose Eduardo; GUERRA-SHINOHARA, Elvira Maria; PEREIRA, Alexandre CostaBackground: The genotyping of HFE p.C282Y and p.H63D mutations is one of the most requested molecular analyses in the laboratorial routine. In this scenario, the main aim was to develop a genotyping assay that has advantages compared to other methods. Methods: Genotypes for the HFE p.C282Y (c.G845A; rs1800562) and p.H63D (c.C187G, rs1799945) mutations were assessed by polymerase chain reaction (PCR) followed by high resolution melting (HRM) analysis with the Rotor-Gene 6000 (R) instrument. Validation studies were conducted in samples bi-directionally sequenced. Results: The melting assay was developed in a unique procedure and to ensure the result in approximately 112 min (31 min for sample preparation and 81 min for the PCR-HRM step). Genotypes for the HFE p.C282Y mutation were easily distinguished in the region of 80-86 degrees C. For the HFE p.H63D, genotypes were also easily distinguished in the region of 76-82 degrees C, but using the addition of known wildtype genotype DNA in all unknown samples plus a reaction without addition. In validation, genotypes were 100% concordant between methods. Conclusions: Our genotyping assay with the Rotor-Gene 6000 (R) instrument applies to the laboratorial routine with several advantages, especially in large-scale demand. The main advantages were the non-dependence on gel electrophoresis and on mutagenic reagents for visualization of fragments, reduction of the chances for contamination due to sample preparation, the lack of use of probe-based methods and cost-effectiveness.
- Non-HFE hemochromatosis(2012) SANTOS, Paulo Caleb Júnior de Lima; DINARDO, Carla Luana; CANÇADO, Rodolfo Delfini; SCHETTERT, Isolmar Tadeu; KRIEGER, José Eduardo; PEREIRA, Alexandre CostaHereditary hemochromatosis (HH) is an autosomal recessive disorder classically related to HFE mutations. However, since 1996, it is known that HFE mutations explain about 80% of HH cases, with the remaining around 20% denominated non-HFE hemochromatosis. Nowadays, four main genes are implicated in the pathophysiology of clinical syndromes classified as non-HFE hemochromatosis: hemojuvelin (HJV, type 2Ajuvenile HH), hepcidin (HAMP, type 2B juvenile HH), transferrin receptor 2 (TFR2, type 3 HH) and ferroportin (SLC40A1, type 4 HH). The aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.
- Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population(2013) ALVIM, Rafael de Oliveira; SANTOS, Paulo Caleb Junior Lima; MUSSO, Mariane Manso; CUNHA, Roberto de Sa; KRIEGER, Jose Eduardo; MILL, Jose Geraldo; PEREIRA, Alexandre CostaBackground: Independent of other cardiovascular (CV) risk factors, increased arterial stiffness has been established as a predictor of morbidity and mortality. The main aim of this study was to investigate the impact of diabetes on arterial stiffness in a representative sample of an urban Brazilian population plus Amerindians. Methods: A total of 1,415 individuals from the general population were randomly selected plus 588 Amerindians from a native community in Brazil. In addition, a sub-sample of 380 individuals from the general population had 5-year follow-up data. Pulse wave velocity (PWV) was measured with a non-invasive automatic device (Complior, Colson; Garges les Gonesses, France) and increased arterial stiffness was defined as PWV >= 12 m/s. Results: In the overall group, diabetic individuals had higher frequencies of increased arterial stiffness and hypertension. They also had higher values of PWV, body mass index, total cholesterol, triglycerides, systolic and diastolic blood pressures compared to non-diabetic individuals (p < 0.01). In an analysis stratified by hypertension, PWV values and increased arterial stiffness frequency were higher in diabetic individuals in both groups (hypertensive and non-hypertensive) (p < 0.05). Furthermore, higher risk for increased arterial stiffness was observed in the diabetic individuals from the overall group (OR = 2.27; CI = 1.47-3.52, p < 0.001) and from the hypertensive group (OR = 2.70; CI = 1.58-4.75, p < 0.001), adjusted for covariates. Regarding the ethnic stratification, diabetic individuals from Amerindian, White, and Mulatto (mixed-race) groups had higher PWV values and a greater frequency of increased arterial stiffness compared to non-diabetic individuals. Both diabetic and non-diabetic individuals had higher PWV values after 5 years. There was no significant difference in the 5-year PWV progression in diabetic compared to non-diabetic individuals. Conclusions: These results confirm, in a sample of Brazilian population, that the presence of diabetes is associated with increased arterial stiffness and it may contribute in part to increased cardiovascular risk in diabetic patients.
- MTRR rs326119 polymorphism is associated with plasma concentrations of homocysteine and cobalamin, but not with congenital heart disease or coronary atherosclerosis in Brazilian patients(2017) HORITA, Melanie; BUENO, Carolina Tosin; HORIMOTO, Andrea R.; LEMOS, Pedro A.; MORANDINI-FILHO, Antonio A.; KRIEGER, Jose E.; SANTOS, Paulo C. J. L.; PEREIRA, Alexandre C.Background: Differences in the distribution of the MTRR rs326119 polymorphism (c.56+ 781 A>C) between patients with congenital heart disease (CHD) and controls have been described in Chinese individuals. The association is thought to be due to deregulation of homocysteine-cobalamin pathways. This has not been replicated in other populations. The primary objective of this study was to assess the influence of the MTRR rs326119 polymorphism on biochemical parameters of vitamin B12 metabolism, coronary lesions, and congenital heart disease in Brazilian subjects. Methods: We selected 722 patients with CHD, 1432 patients who underwent coronary angiography, and 156 blood donors. Genotyping for the MTRR polymorphism was evaluated by high-resolution melting analysis, and biochemical tests of vitamin B12 metabolism were measured. Results: Subjects carrying the AC or CC genotypes had higher homocysteine concentrations (9.7 +/- 0.4 mu mol/L and 10.1 +/- 0.6 mu mol/L) and lower cobalamin concentrations (260.5 +/- 13.3 pmol/L and 275.6 +/- 19.9 pmol/L) compared with the subjects carrying the AA genotype (8.7 +/- 0.5 mu mol/L and 304.8 +/- 14.7 pmol/L), respectively. A multiple linear regression model also identified a significant association between the number of C variant alleles with the concentrations of homocysteine and cobalamin. Nonetheless, the allelic and genotypic distributions for MTRR rs326119 were not associated with CHD or coronary atherosclerosis in the studied samples. Conclusion: Our findings indicate that the MTRR rs326119 variant might be a genetic marker associated with homocysteine and cobalamin concentrations, but not a strong risk factor for CHD or coronary atherosclerosis in the Brazilian population. (C) 2016 The Authors.
- Age is associated with time in therapeutic range for warfarin therapy in patients with atrial fibrillation(2016) MARCATTO, Leiliane Rodrigues; SACILOTTO, Luciana; DARRIEUX, Francisco Carlos da Costa; HACHUL, Denise Tessariol; SCANAVACCA, Mauricio Ibrahim; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa; SANTOS, Paulo Caleb Junior LimaBackground: Warfarin is the most prescribed oral anticoagulant used for preventing stroke in patients with atrial fibrillation. Time in the therapeutic range (TTR) has been accepted as the best method to evaluate the quality of warfarin therapy. The main aim of the present study was to evaluate the impact of variables on the time in the therapeutic range for warfarin therapy in patients with atrial fibrillation from a referral cardiovascular hospital. Methods: This retrospective study included 443 patients were included (190 patients with age < 65 years and 253 patients with age >= 65 years) from 2011 to 2014 and TTR was computed according to Rosendaal's method. Results: Patients with age >= 65 years had higher TTR value (67+/-22%) compared with patients with < 65 years (60+/-24%) (p = 0.004). In a linear regression model, only age >= 65 years emerged as a significant predictor of greater TTR values. In multivariate logistic regression model, the variable age = 65 years was associated with higher OR for having a TTR higher than the median value (OR = 2.17, p < 0.001). Conclusion: We suggest that the age influenced TTR through greater drug adherence. Strategies for increasing drug adherence might improve quality of warfarin anticoagulation.
- 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.
- CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population(2011) SANTOS, Paulo C. J. L.; SOARES, Renata A. G.; SANTOS, Diogo B. G.; NASCIMENTO, Raimundo M.; COELHO, George L. L. M.; NICOLAU, Jose C.; MILL, Jose G.; KRIEGER, Jose E.; PEREIRA, Alexandre C.Background: Recent studies have reported the clinical importance of CYP2C19 and ABCB1 polymorphisms in an individualized approach to clopidogrel treatment. The aims of this study were to evaluate the frequencies of CYP2C19 and ABCB1 polymorphisms and to identify the clopidogrel-predicted metabolic phenotypes according to ethnic groups in a sample of individuals representative of a highly admixtured population. Methods: One hundred and eighty-three Amerindians and 1,029 subjects of the general population of 4 regions of the country were included. Genotypes for the ABCB1c.C3435T (rs1045642), CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*4 (rs28399504), CYP2C19*5 (rs56337013), and CYP2C19*17 (rs12248560) polymorphisms were detected by polymerase chain reaction followed by high resolution melting analysis. The CYP2C19*3, CYP2C19*4 and CYP2C19*5 variants were genotyped in a subsample of subjects (300 samples randomly selected). Results: The CYP2C19*3 and CYP2C19*5 variant alleles were not detected and the CYP2C19*4 variant allele presented a frequency of 0.3%. The allelic frequencies for the ABCB1c.C3435T, CYP2C19*2 and CYP2C19*17 polymorphisms were differently distributed according to ethnicity: Amerindian (51.4%, 10.4%, 15.8%); Caucasian descent (43.2%, 16.9%, 18.0%); Mulatto (35.9%, 16.5%, 21.3%); and African descent (32.8%, 20.2%, 26.3%) individuals, respectively. As a result, self-referred ethnicity was able to predict significantly different clopidogrel-predicted metabolic phenotypes prevalence even for a highly admixtured population. Conclusion: Our findings indicate the existence of inter-ethnic differences in the ABCB1 and CYP2C19 variant allele frequencies in the Brazilian general population plus Amerindians. This information could help in stratifying individuals from this population regarding clopidogrel-predicted metabolic phenotypes and design more cost-effective programs towards individualization of clopidogrel therapy.
- 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.