Healthy Brazilians Research Articles

Etoricoxib Coated Tablets: Bioequivalence Assessment between Two Formulations Administered under Fasting Conditions.

Etoricoxib is a non-steroidal anti-inflammatory drug with high selectivity for cyclooxygenase 2 (COX-2), exerting a pronounced anti-inflammatory effect with fewer adverse events when compared to COX-1 inhibitors. The present study aimed to evaluate the bioequivalence between two etoricoxib-coated tablet formulations to meet regulatory requirements for a branded generic product registration in Brazil. A crossover study with an open-label, randomized design and a single-dose regimen with two treatments and two periods was conducted on healthy Brazilians of both genders. Subjects randomly received a single dose of a 90 mg etoricoxib coated tablet of test product Xumer® 90 mg (Adium S.A.) and the reference product Arcoxia® 90 mg (Merck Sharp & Dohme Farmacêutica Ltda.) under fasting conditions separated by a 14-day period. Blood samples were collected sequentially for up to 96 h following drug administration, and the concentrations of etoricoxib in plasma were determined using a validated UPLC-MS/MS method. Pharmacokinetic parameters were computed utilizing non-compartmental analysis methods. A total of 32 healthy subjects were enrolled, and 25 subjects completed the study. Geometric mean ratios (90% confidence intervals) for Cmax, AUC0-t, and AUC0-inf were 103.98% (95.63-113.06), 96.82% (91.82-102.09), and 95.79% (90.70-101.16), respectively. In accordance with regulatory standards, the test formulation (Xumer® 90 mg) has been deemed bioequivalent to the reference product (Arcoxia® 90 mg). As a result, these formulations can be considered interchangeable in clinical practice, with both proving to be safe and well-tolerated. The need for in vivo testing for the Xumer® 60 mg strength was waived due to the proportional similarity of the formulations and the similar in vitro dissolution profiles observed across the various strengths.

Association between APOε4 allele and cognitive function in healthy Brazilians elderly from Baixada Santista

AbstractBackgroundThe faster memory decline was associated with the presence of the apolipoprotein E4 (APOε4) allele, a genetic risk factor for late‐onset Alzheimer’s disease (AD). Studies suggest that the relationship between cognitive decline and APOE ε4 allele in healthy elderly may reflect the preclinical risk to AD. This study examined the influence of apolipoprotein E4 (APOε4) genotype on the cognitive function of the older people from Baixada Santista (Brazil).MethodThis study was approved by the Ethical Committee Board from Medical School/UNIMES (Number: CAAE 20938619.4.0000.5509). Seventy‐two participants with ≥65 years old, both sexes. were eligible for the study. Cognitive function and the level of physical activity were assessed by the mini‐mental state examination (MMSE) and Baecke questionnaire for older, respectively. APOE genotyping was performed in 66 out of the 72 participants. Statistical analysis was performed by using the BioEstat version 5.0, Kolmogorov‐Smirnov test, z‐score, student t or Mann‐Whitney test was applied according to the normality. The Chi‐square test was used for comparison between the sexes. Pearson correlation was also performed. P < 0.05 was considered statistically significant.ResultsSeventy‐two older people were assessed (women = 52 and men = 20), and the mean age was 73±7 years old, Baecke score (3.74 ±3.82), MMSE (27±3), and educational status (8 ± 4 years). As expected, a positive correlation was detected between the education level and MMSE score (r = 0.359, p < 0.05). No difference was found between the sexes for age, level of physical activity, MMSE, and education status (p > 0.05). Regarding the APOE genotype, we found the following frequency ɛ2/ɛ2 (1.5%), ɛ2/ɛ3 (16.7%), ɛ2/ɛ4 (1.5%), ɛ3/ ɛ3 (59.1%), and ɛ3/ɛ4 (21.2%). No correlation was found between carriers (presence of the ɛ4 allele) and non‐carrier for the MMSE score, varying between 27 to 30.ConclusionOur preliminary data show that the less educational status influences the cognitive decline in the older Brazilian population. However, no differences between the sexes were observed for all parameters indicating a homogenous population. Additionally, the cognitive function score was not influenced by the presence of the APOɛ4 allele in this population.

Evaluation of dopamine transporter density in healthy Brazilians using Tc-99m TRODAT-1 SPECT.

The presynaptic dopamine transporter (DAT) modulates the uptake of dopamine by regulating its concentration in the central nervous system. We aimed to evaluate the DAT binding potential (DAT-BP) in a sample of healthy Brazilians through technetium-99 metastable TRODAT-1 single-photon emission computed tomography imaging.We selected 126 healthy individuals comprising 72 men and 54 women, aged 18 to 80 years. We conducted semi-quantitative evaluation in transaxial slices, following which we identified the regions of interest in the striatal region using the occipital lobe as a region of non-specific DAT-BP.We found a decrease in DAT-BP in healthy individuals aged over 30 years, culminating in a 42% mean reduction after 80 years. There was no difference in the decrease by age group between the right (linear regression test [R2] linear = 0.466) and left striatum (R2 linear = 0.510). Women presented a higher DAT-BP than men (women: R2 linear = 0.431; men: R2 linear = 0.457); nonetheless, their decrease by age group was equal to that in men.Our study sheds light on important DAT-BP findings in healthy Brazilian subjects. Our results will facilitate understanding of brain illnesses that involve the dopamine system, such as neuropsychiatric disorders.

Analysis of the human leukocitary antigen (HLA) system distribution in the brazilian population

This project aims to analyze the HLA alleles frequency in the Brazilian population. We used DNA samples of 36 healthy Brazilians subjects to sequence classic genes of the HLA class I (HLA-A, -B and -C) and class II (HLA-DQA1, -DQB1, -DPA1, -DPB1 and -DRB1, 3, 4 and 5) using next-generation sequencing (NGS). We used the HLA TruSight v2 Illumina kit to prepare HLA amplicons of these genes and the libraries generated were subsequently sequencied in an Illumina equipament, The FASTQ data generated by sequencing were analyzed by the TruSight Assign HLA (Illumina) software. The data generated in this study will be made publicly available in the BIPMed project (www.bipmed.org), so it can be used as a reference for further studies in the Brazilian population.

Human polyomavirus KI, WU, BK, and JC in healthy volunteers.

Despite the growing importance of infections caused by the human polyomaviruses (HPyVs), information about their transmission, pathogenesis, and epidemiology is scarce. The objective of this work was to evaluate the excretion and distribution of HPyV (HPyV1-HPyV4 [former BKPyV, JCPyV, KIPyV, and WUPyV, respectively]) among asymptomatic individuals from different geographic regions in Brazil, in order to verify the existence of distinct epidemiologic patterns among the Brazilian population. Saliva samples from 889 healthy volunteers living in nine locations in Brazil were analyzed by real-time polymerase chain reaction (PCR) to detect HPyV1-4. Among 889 participants, 346 (39%) had evidence of infection with one or more HPyV species: 127 (14.3%) had HPyV1 only; 70 (7.9%) had HPyV3 only; 60 (6.7%) had HPyV4 only, and 25 (2.8%) had HPyV2 only. Coinfections were detected in 64 participants (7.3%). Although HPyV excretion was detected in samples from all locations, the frequency and distribution of viral species varied significantly. The epidemiologic findings presented demonstrate that the four HPyV species studied are circulating in five geographic regions of Brazil. Salivary excretion of these viruses appears common among healthy Brazilians. The distribution of viral species varies considerably between regions as well as within regions.

Genetic variants in selenoprotein genes modulate biomarkers of selenium status in response to Brazil nut supplementation (the SU.BRA.NUT study)

The beneficial effects of selenium (Se) to human health are exerted by selenoproteins, which can be quantified in blood and used as biomarkers of Se status. Different responses of Se biomarkers after supplementation with selenomethionine and sodium selenite have been observed and some of them could be due to genetic polymorphisms, mainly single nucleotide polymorphisms (SNPs). Brazil nuts are known to be the richest natural source of Se. Investigate how genetic variations in selenoprotein genes modulate biomarkers of Se status in response to Brazil nut supplementation. The SU.BRA.NUT study was a four month interventional trial which involved healthy volunteers of both genders, selected in University of Sao Paulo. The supplementation was done with one Brazil nut a day for 8 weeks, followed by 8 weeks of washout. Blood samples were collected at 5 time points: baseline, 4 and 8 weeks of supplementation and 4 and 8 weeks of washout for analysis of five biomarkers of Se status - erythrocyte GPx1 (Glutathione Peroxidase 1) activity, plasma GPx3 activity, plasma Se, erythrocyte Se, and plasma selenoprotein P. The gene expression of GPX1, SELENOP, SELENOF and SELENOS was done before and after 8 weeks of supplementation. The volunteers were genotyped for SNPs in GPX1 (rs1050450, rs3811699 and rs1800699), GPX4 (rs713041), SELENOP (rs3877899 and rs7579), SELENOF (rs5845) and SELENOS (rs34713741). A total of 130 volunteers finished the protocol. The concentrations of four biomarkers of Se status increased significantly after 4 and 8 weeks of supplementation, being modulated by gender. In addition, erythrocyte GPx1 activity was associated with rs1050450, rs713041 and rs5845. Plasma Se was associated with rs7579 and selenoprotein P with plasma Se at baseline. Nut supplementation significantly increased GPX1 mRNA expression only in subjects with CC genotype at rs1050450. SELENOP mRNA expression was significantly lower in subjects with GG genotype at rs7579 before and after supplementation. Genetic variations in GPX1 and SELENOP genes are associated with different responses of molecular and biochemical biomarkers of Se status after Brazil nut supplementation in healthy Brazilians. The SU.BRA.NUT study was registred at www.clinicaltrials.gov as NCT 03111355.

Normative data for the Montreal Cognitive Assessment (MoCA) and the Memory Index Score (MoCA-MIS) in Brazil: Adjusting the nonlinear effects of education with fractional polynomials.

To provide age-corrected and education-corrected norms for the Montreal Cognitive Assessment (MoCA) and the Memory Index Score (MoCA-MIS) in Brazil. Community-dwelling outpatients were enrolled if they had no history of neurologic or psychiatric diseases and were not taking any drugs with effects on the central nervous system. Dementia has been excluded with the Functional Activities Questionnaire. The final sample consisted of 597 cognitively healthy Brazilians aged 50 to 90years. To account for nonlinear relationships, we have used fractional polynomials that provide a flexible parameterization for continuous variables. According to the original proposed cutoff (≤25 points), 87% of our sample would be considered impaired. Even using a more conservative suggestion (≤22 points), 67% of our normative sample would be regarded as impaired. These data reinforce the need of adjusting cutoffs for schooling in populations with heterogeneous educational backgrounds. MoCA scores presented a nonlinear positive association with education tending to a plateau at higher levels (P<0.001). On the other hand, MoCA-MIS scores presented a nonlinear negative relationship with age, with an accelerated pattern at higher age levels (P<0.001). We presented normative data for the MoCA and the MoCA-MIS that will facilitate the use of the test in Brazil and, potentially, in other populations with substantial proportions of low-educated individuals. Moreover, we described a systematic approach for adjusting the effects of age and education using fractional polynomials and provided suggestions on how to account for the nonlinear relationship that is frequently encountered between demographic factors and measures of cognitive performance.

Influence of Gender and SNPs in GPX1 Gene on Biomarkers of Selenium Status in Healthy Brazilians.

Selenium (Se) status varies worldwide as a result of natural variation of Se content in soils, dietary pattern, and the presence of SNPs. Further, Se status in Brazilians and its relationship between genetic variation and Se biomarkers is unknown. This work investigated the association between SNPs in glutathione peroxidase genes and biomarkers of Se status in healthy Brazilians. The study was conducted in 116 healthy adults in São Paulo, Brazil. Plasma and erythrocyte Se were measured by HGFAAS. Erythrocyte GPx (eGPx) activity was measured spectrometrically in a biochemical analyzer. Genotypes were determined by real-time PCR using Taqman® Assays. eGPx activity was higher in females compared with males. Lower erythrocyte Se concentrations were found in heterozygous GC carriers for GPX1 rs8179169. eGPx activity was higher in females with the common genotypes, except for rs8179169. GC carriers for rs8179169 had lower erythrocyte Se in both genders, and only male carriers of the variant alleles of both rs1050450 and rs1800668 had higher eGPx activity. In conclusion, the genotype for SNPs in GPX1 and gender affected biomarkers of Se status in this pilot study with healthy Brazilians.

Corneal confocal microscopy in a healthy Brazilian sample.

This study aims to evaluate the characteristics of the corneal sub-basal plexus by performing in vivo confocal microscopy of healthy Brazilians to provide reference values for the Brazilian population. This study is an observational, cross-sectional, descriptive study comparing corneas from 55 healthy Brazilian individuals across the age span of 20-70 years. The average number of fibers was 5.35 ± 1.36, fiber density was 33.4 ± 8.5 fibers per field, and the mean number of Langerhans cells was 5.13 ± 8.10. A correlation between the average number of fibers and age showed an inverse relationship between the number and density of fibers and age for women (p < 0.05). In the multivariate analysis, each annual increase of age showed an average increase of 1.017 (95%CI: 1.008 to 1.026) in the number of Langerhans cells, adjusting for sex and thickness. Compared to other samples, this Brazilian population showed a higher average number of fibers, though further studies with a larger sample should be performed.

Six-minute walk test and respiratory muscle strength in patients with uncontrolled severe asthma: a pilot study.

OBJECTIVE: To evaluate respiratory muscle strength and six-minute walk test (6MWT) variables in patients with uncontrolled severe asthma (UCSA). METHODS: This was a cross-sectional study involving UCSA patients followed at a university hospital. The patients underwent 6MWT, spirometry, and measurements of respiratory muscle strength, as well as completing the Asthma Control Test (ACT). The Mann-Whitney test was used in order to analyze 6MWT variables, whereas the Kruskal-Wallis test was used to determine whether there was an association between the use of oral corticosteroids and respiratory muscle strength. RESULTS: We included 25 patients. Mean FEV1 was 58.8 ± 21.8% of predicted, and mean ACT score was 14.0 ± 3.9 points. No significant difference was found between the median six-minute walk distance recorded for the UCSA patients and that predicted for healthy Brazilians (512 m and 534 m, respectively; p = 0.14). During the 6MWT, there was no significant drop in SpO2. Mean MIP and MEP were normal (72.9 ± 15.2% and 67.6 ± 22.2%, respectively). Comparing the patients treated with at least four courses of oral corticosteroids per year and those treated with three or fewer, we found no significant differences in MIP (p = 0.15) or MEP (p = 0.45). CONCLUSIONS: Our findings suggest that UCSA patients are similar to normal subjects in terms of 6MWT variables and respiratory muscle strength. The use of oral corticosteroids has no apparent impact on respiratory muscle strength.

Mycobacterium tuberculosis epitope-specific interferon-g production in healthy Brazilians reactive and non-reactive to tuberculin skin test.

The interferon (IFN)-γ response to peptides can be a useful diagnostic marker of Mycobacterium tuberculosis (MTB) latent infection. We identified promiscuous and potentially protective CD4+ T-cell epitopes from the most conserved regions of MTB antigenic proteins by scanning the MTB antigenic proteins GroEL2, phosphate-binding protein 1 precursor and 19 kDa antigen with the TEPITOPE algorithm. Seven peptide sequences predicted to bind to multiple human leukocyte antigen (HLA)-DR molecules were synthesised and tested with IFN-γ enzyme-linked immunospot (ELISPOT) assays using peripheral blood mononuclear cells (PBMCs) from 16 Mantoux tuberculin skin test (TST)-positive and 16 TST-negative healthy donors. Eighty-eight percent of TST-positive donors responded to at least one of the peptides, compared to 25% of TST-negative donors. Each individual peptide induced IFN-γ production by PBMCs from at least 31% of the TST-positive donors. The magnitude of the response against all peptides was 182 ± 230 x 106 IFN-γ spot forming cells (SFC) among TST-positive donors and 36 ± 62 x 106 SFC among TST-negative donors (p = 0.007). The response to GroEL2 (463-477) was only observed in the TST-positive group. This combination of novel MTB CD4 T-cell epitopes should be tested in a larger cohort of individuals with latent tuberculosis (TB) to evaluate its potential to diagnose latent TB and it may be included in ELISPOT-based IFN-γ assays to identify individuals with this condition.

Automatic classification of written descriptions by healthy adults: An overview of the application of natural language processing and machine learning techniques to clinical discourse analysis.

Discourse production is an important aspect in the evaluation of brain-injured individuals. We believe that studies comparing the performance of brain-injured subjects with that of healthy controls must use groups with compatible education. A pioneering application of machine learning methods using Brazilian Portuguese for clinical purposes is described, highlighting education as an important variable in the Brazilian scenario.ObjectiveThe aims were to describe how to:(i) develop machine learning classifiers using features generated by natural language processing tools to distinguish descriptions produced by healthy individuals into classes based on their years of education; and(ii) automatically identify the features that best distinguish the groups.MethodsThe approach proposed here extracts linguistic features automatically from the written descriptions with the aid of two Natural Language Processing tools: Coh-Metrix-Port and AIC. It also includes nine task-specific features (three new ones, two extracted manually, besides description time; type of scene described – simple or complex; presentation order – which type of picture was described first; and age). In this study, the descriptions by 144 of the subjects studied in Toledo18 were used,which included 200 healthy Brazilians of both genders.Results and ConclusionA Support Vector Machine (SVM) with a radial basis function (RBF) kernel is the most recommended approach for the binary classification of our data, classifying three of the four initial classes. CfsSubsetEval (CFS) is a strong candidate to replace manual feature selection methods.

Assessment of gait deviation on the Babinski-Weill test in healthy Brazilians

The aim of this study was to validate a simple and reproducible method for assessing gait deviation on the Babinski-Weill test in a representative sample of healthy Brazilians. Gait deviations were measured in 75 individuals (median=30 years, 41 women) for forward, backwards, and Babinski-Weill steps. The test entailed blindfolded individuals walking 10 paces at a frequency of 1 Hz with deviations subsequently measured by a protractor. Mean gait deviation forward was 0.53° with standard deviation (SD)=4.22 and backwards was 2.14° with SD=4.29. No significant difference in deviation was detected between genders (t test p=0.40 forward and p=0.77 backwards) or for age (ANOVA, p=0.33 forward and p=0.63 backwards). On the Babinski-Weill test, mean gait deviation was 5.26°; SD=16.32 in women and -3.11°; SD=12.41 in men, with no significant difference between genders (t test, p=0.056). Defining normative gait patterns helps distinguish pathological states.

Leprosy Association with Low MASP-2 Levels Generated by MASP2 Haplotypes and Polymorphisms Flanking MAp19 Exon 5

BackgroundThe gene MASP2 (mannan-binding lectin (MBL)-associated serine protease 2) encodes two proteins, MASP-2 and MAp19 (MBL-associated protein of 19 kDa), bound in plasma to MBL and ficolins. The binding of MBL/MASP-2 and ficolin/MASP-2 complexes to microorganisms activates the lectin pathway of complement and may increase the ingestion of intracellular pathogens such as Mycobacterium leprae.MethodsWe haplotyped 11 MASP2 polymorphisms with multiplex sequence-specific PCR in 219 Brazilian leprosy patients (131 lepromatous, 29 borderline, 21 tuberculoid, 14 undetermined, 24 unspecified), 405 healthy Brazilians and 291 Danish blood donors with previously determined MASP-2 and MAp19 levels. We also evaluated MASP-2 levels in further 46 leprosy patients and 69 Brazilian controls.ResultsTwo polymorphisms flanking exon 5 of MASP2 were associated with a dominant effect on high MASP-2 levels and an additive effect on low MAp19 levels. Patients presented lower MASP-2 levels (P = 0.0012) than controls. The frequency of the p.126L variant, associated with low MASP-2 levels (below 200 ng/mL), was higher in the patients (P = 0.0002, OR = 4.92), as was the frequency of genotypes with p.126L (P = 0.00006, OR = 5.96). The *1C2-l [AG] haplotype, which harbors p.126L and the deficiency-causing p.439H variant, has a dominant effect on the susceptibility to the disease (P = 0.007, OR = 4.15). Genotypes composed of the *2B1-i and/or *2B2A-i haplotypes, both associated with intermediate MASP-2 levels (200–600 ng/mL), were found to be protective against the disease (P = 0.0014, OR = 0.6). Low MASP-2 levels (P = 0.022), as well as corresponding genotypes with *1C2-l and/or *2A2-l but without *1B1-h or *1B2-h, were more frequent in the lepromatous than in other patients (P = 0.008, OR = 8.8).ConclusionsIn contrast with MBL, low MASP-2 levels increase the susceptibility to leprosy in general and to lepromatous leprosy in particular. MASP2 genotypes and MASP-2 levels might thus be of prognostic value for leprosy progression.

Application of the F ST statistics to explore pharmacogenomic diversity in the Brazilian population

New drug applications submitted to regulatory agencies in developing countries rarely include data from local clinical trials. We used the F(ST) statistics to explore the pharmacogenomic diversity of the Brazilian population and its potential implications in drug regulatory assessment and decisions. The F(ST) analyses were based on data for 44 polymorphisms in 12 pharmacogenes among 1034 healthy Brazilians, recruited in four different geographical regions and self-identified as branco (white) pardo (brown) or preto (black). Each region/color group comprised 83-89 individuals. The Utah residents of northern and western European ancestry and Yoruba people from Nigeria, Africa, cohorts of the HapMap project were used as proxies of the European and sub-Saharan African ancestral roots of Brazilians, respectively. Allele-specific F(ST) values for the overall Brazilian cohort revealed low genetic divergence between white and brown (F(ST) = 0.005 ± 0.006, mean ± standard deviation), white and black (0.013 ± 0.017) and brown and black (0.004 ± 0.005) individuals. However, the distribution of F(ST) values for white vs brown (p < 0.0001, analysis of variance) and white vs black (p < 0.0001) differed significantly across the geographical regions. Considerably larger pharmacogenomic divergence was observed between black Brazilians and Yoruba people from Nigeria, Africa (F(ST) = 0.028 ± 0.035) compared to white Brazilians vs Utah residents of northern and western European ancestry (0.007 ± 0.010). The present F(ST) analyses highlight the challenge faced by Brazilian regulatory agencies when assessing the relevance to Brazilians of pharmacogenomic data derived from foreign populations, with distinct biogeographical ancestries. This challenge is compounded by the heterogeneity of the Brazilian population with respect to the frequency distribution of pharmacogenomic polymorphisms across color categories and geographical regions.

Epidemiological profile in multiple sclerosis patients, Uberaba, MG, Brazil

Dear Editor, We read with great interest the article published by Ribeiro SBF et al. (Arq Neuropsiquiatr 2011;69:184-187), about the epidemiological characteristics of patients with multiple sclerosis (MS) in the city of Uberaba-MG, Brazil. In this article, the authors comment on the similarity of most of the clinical and epidemiological features found in Uberaba to those presented in other samples in Brazil. However, when considering ethnicity, which in their study was predominantly Caucasian (85.71%), they cite the example of the city of Recife, where the incidence was predominantly in the black population (93.3%). They also mention the difficulties of ethnic classification in the Brazilian population, given the racial characteristics observed in our population. We agree that these difficulties exist but, nonetheless, we believe that ethnic traits need to be better studied in Brazil, with regard to the therapeutic options for multiple sclerosis. This can be seen from a study by Alves-Leon et al., in which they demonstrated the existence of heterogeneous phenotypes of HLA-DRB1*1501 in a population of healthy Brazilians that included both African descendants and white subjects. It is known that these alleles can negatively influence the therapeutic response to interferon. In another study, Brum et al. drew attention to the fact that HLA-DRB1 may exhibit behavior of either resistance or susceptibility in response to ethnic background and environmental factors. Brazil is a country of continental dimensions with a high degree of miscegenation. However, this miscegenation is variable with regard to demographic distribution. Ethnic characteristics need to be reviewed more carefully because surveys on the epidemiology of MS in some Brazilian cities have found that the rate of cases of MS among the black population was greater than that observed in other studies, especially in the cities of Rio de Janeiro (28%) and Cuiaba (26%). This implies that there is a need for regional and multicenter studies on MS in Brazil, especially in relation to the genetic susceptibility and environmental variables observed in a country with the dimensions of Brazil. Our congratulations to the authors.

Frequency of genetic polymorphisms of PXR gene in the Brazilian population

INTRODUCTION:PXR polymorphisms have been implicated in modulating CYP3A4 and PXR expression, potentially accounting for interindividual differences in drug metabolism. The prevalence of PXR polymorphisms varies among ethnic groups and data on the allelic distribution in the highly mixed Brazilian population is lacking. The aim of this study was to analyze genetic variations in the PXR gene in Brazilians and to compare the results to other ethnic groups.METHODS:DNA samples from 117 healthy Brazilians underwent PCR amplification and sequencing.RESULTS:Eleven polymorphisms were identified, 3 of which are highly associated with differences in CYP3A4 expression. We also identified 1 new synonymous variant in 1.3% of the alleles. Among the functional polymorphisms, –25913 C>T and –6994T>C occurred at a higher frequency compared to the African alleles (p < 0.05) but at a lower frequency compared to Caucasian alleles. The 8055 C>T allele was found at a similar frequency to those described in Caucasians and Africans (p > 0.05).CONCLUSION:We observed that functional variants of the PXR were frequent in our sample of the Brazilian population. Our results suggest that PXR gene variants may be of interest in pharmacogenetic studies involving Brazilians.

Polymorphisms in regulatory regions of Cyclooxygenase-2 gene and breast cancer risk in Brazilians: a case-control study

BackgroundCyclooxygenase-2 (COX-2) is up-regulated in several types of cancer, and it is hypothesized that COX-2 expression may be genetically influenced. Here, we evaluate the association between single-nucleotide polymorphisms (SNPs) in the COX-2 gene (PTGS2) and the occurrence of breast cancer among Brazilian women.MethodsThe study was conducted prospectively in two steps: First, we screened the promoter region and three fragments of the 3'-untranslated region of PTGS2 from 67 healthy Brazilians to identify SNPs and to select those with a minor allele frequency (MAF) of at least 0.10. The MAF of these selected SNPs was further characterized in 402 healthy volunteers to evaluate potential differences related to heterogeneous racial admixture and to estimate the existence of linkage disequilibrium among the SNPs. The second step was a case-control study with 318 patients and 273 controls designed to evaluate PTGS2 genotype- or haplotype-associated risk of breast cancer.ResultsThe screening analysis indicated nine SNPs with the following MAFs: rs689465 (0.22), rs689466 (0.15), rs20415 (0.007), rs20417 (0.32), rs20419 (0.015), rs5270 (0.02), rs20424 (0.007), rs5275 (0.22) and rs4648298 (0.01). The SNPs rs689465, rs689466, rs20417 and rs5275 were further studied: Their genotypic distributions followed Hardy-Weinberg equilibrium and the MAFs were not affected by gender or skin color. Strong linkage disequilibrium was detected for rs689465, rs20417 and rs5275 in the three possible pairwise combinations. In the case-control study, there was a significant increase of rs5275TC heterozygotes in cases compared to controls (OR = 1.44, 95% CI = 1.01-2.06; P = 0.043), and the haplotype formed by rs689465G, rs689466A, rs20417G and rs5275C was only detected in cases. The apparent association with breast cancer was not confirmed for rs5275CC homozygotes or for the most frequent rs5275C-containing haplotypes.ConclusionsOur results indicate no strong association between the four most frequent PTGS2 SNPs and the risk of breast cancer.

Distribution of the GNB3 825C&gt;T polymorphism among Brazilians: impact of population structure

To describe the impact of population admixture on the distribution of the GNB3 825C>T polymorphism in the heterogeneous Brazilian population. Individual DNA from 236 healthy Brazilians, self-identified as White, Intermediate and Black, was genotyped for a set of insertion/deletion polymorphisms that have been previously validated as ancestry informative markers (AIMs). The GNB3 825C>T polymorphism was detected by PCR-RFLP. Non-linear logistic regression modeling was applied to describe the association between the GNB3 825C>T polymorphisms and the African component of ancestry (ACA) estimated by the AIMs. The GNB3 825C>T allele and genotype distribution differed significantly across the three self-reported groups (P < 0.0001, chi(2) test), with a trend for increasing frequency of both the GNB3 825T allele and the TT genotype from White to Intermediate to Black individuals (P < 0.0001, chi(2) test for trend in proportions). Non-linear logistic regression showed that the odds of having the GNB3 825C>T allele increase monotonically (P < 0.0001, Wald statistics) with increasing ACA throughout the ACA range (0.136-0.897) observed in the overall population sample, irrespective of "racial/color" self-identification. The present data on the GNB3 825C>T polymorphism support the notion that interethnic admixture, which is a source of spurious genotype-phenotype associations in pharmacogenetic/-genomic studies, must be dealt with as a continuous variable, rather than proportioned in arbitrary sub-categories for the convenience of data quantification and analysis.

Impact of Population Admixture on the Distribution of the CYP3A5*3 Polymorphism

To compare the effectiveness of self-identified ethnic/color and marker-based biogeographical ancestry classifications in genotyping the CYP3A5*3 polymorphism in the Brazilian population. Individual DNA from 308 healthy Brazilians, self-identified as white, intermediate and black was genotyped for the CYP3A5*3 polymorphism and for a set of insertion-deletion polymorphisms, validated as ancestry informative markers (AIMs). The Structure software was used to analyze the AIMs data and to obtain estimates of the African component of ancestry (ACA). Nonlinear logistic regression modeling was developed to describe the association between the CYP3A5*3 polymorphism and the individual ACA values. The CYP3A5*3 allele and genotype distribution differed significantly across the self-reported 'color' groups (p < 0.0001, Fisher exact test), with a trend for decreasing frequency of both the CYP3A5*3 allele and the *3/*3 genotype from white to intermediate to black individuals (p < 0.0001, chi(2) test for trend in proportions). When the population sample was proportioned in quartiles according to the individual ACA values, the frequency of the CYP3A5*3 allele and the *3/*3 genotype declined progressively from the lowest (<0.25 ACA) to the highest (>0.75 ACA) quartile. Nonlinear logistic regression showed that the odds of having the CYP3A5*3 allele decreases monotonically (p < 0.0001, Wald statistics) with the increase of the ACA, throughout the ACA range (0.15-0.93) observed in the overall population sample. Interethnic admixture is a source of cryptic population structure that may lead to spurious genotype-phenotype associations in pharmacogenetic/-genomic studies. Logistic regression modeling of CYP3A5*3 polymorphism shows that admixture must be dealt with as a continuous variable, rather than proportioned in arbitrary subcategories for the convenience of data quantification and analysis.