Intake of total and subgroups of fat minimally affect the associations between selected single nucleotide polymorphisms in the PPARγ pathway and changes in anthropometry among European adults from cohorts of the DiOGenes study

BACKGROUND: Although the peroxisome proliferator-activated receptor γ (PPARγ) pathway is central in adipogenesis, it remains unknown whether it influences change in body weight (BW) and whether dietary fat has a modifying effect on the association. OBJECTIVES: We examined whether 27 single nucleotide polymorphisms (SNPs) within 4 genes in the PPARγ pathway are associated with the OR of being a BW gainer or with annual changes in anthropometry and whether intake of total fat, monounsaturated fat, polyunsaturated fat, or saturated fat has a modifying effect on these associations. METHODS: A case-noncase study included 11,048 men and women from cohorts in the European Diet, Obesity and Genes study; 5552 were cases, defined as individuals with the greatest BW gain during follow-up, and 6548 were randomly selected, including 5496 noncases. We selected 4 genes [CCAAT/enhancer binding protein β (CEBPB), phosphoenolpyruvate carboxykinase 2, PPARγ gene (PPARG), and sterol regulatory element binding transcription factor 1] according to evidence about biologic plausibility for interactions with dietary fat in weight regulation. Diet was assessed at baseline, and anthropometry was followed for 7 y. RESULTS: The ORs for being a BW gainer for the 27 genetic variants ranged from 0.87 (95% CI: 0.79, 1.03) to 1.12 (95% CI: 0.96, 1.22) per additional minor allele. Uncorrected, CEBPB rs4253449 had a significant interaction with the intake of total fat and subgroups of fat. The OR for being a BW gainer for each additional rs4253449 minor allele per 100 kcal higher total fat intake was 1.07 (95% CI: 1.02, 1.12; P = 0.008), and similar associations were found for subgroups of fat. CONCLUSIONS: Among European men and women, the influence of dietary fat on associations between SNPs in the PPARγ pathway and anthropometry is likely to be absent or marginal. The observed interaction between rs4253449 and dietary fat needs confirmation.

Polimorfismos genéticos da kappa-caseína e da beta-lactoglobulina e produção de leite em bovinos

As variantes gênicas da beta-lactoglobulina (β-LG) e da kappa-caseína (κ-CN) bovinas são associadas à produção, qualidade e características de processamento do leite. O objetivo deste trabalho foi analisar as frequências dos genótipos AA, AB e BB, por meio da técnica de PCR-RFLP, da β-LG e da κ-CN bovinas, e suas associações com a produção de leite (kg leite/dia) em bovinos das raças Girolanda, Holandesa e Jersey. Para a κ-CN, a frequência do genótipo AA foi maior nos animais das raças Holandesa (37%) e Girolanda (63%). Na raça Jersey, houve predomínio do genótipo BB (60%). Para a β-LG, o genótipo AB foi o mais encontrado nas raças Girolanda (54%) e Holandesa (58%), enquanto nos animais da raça Jersey houve predomínio do genótipo BB (45%). Houve associação do alelo B da κ-CN com maior produtividade leiteira nas raças Girolanda e Holandesa, e do alelo A da β-LG com maior produtividade de leite na raça Jersey. As variantes genéticas da κ-CN podem ser usadas como marcadores na seleção para a produtividade leiteira nas raças Girolanda e Holandesa. Para a raça Jersey, as variantes da β-LG seriam mais adequadas para essa seleção.

Molecular and geographic analyses of vampire bat-transmitted cattle rabies in central Brazil

Background: Vampire bats are important rabies virus vectors, causing critical problems in both the livestock industry and public health sector in Latin America. In order to assess the epidemiological characteristics of vampire bat-transmitted rabies, the authors conducted phylogenetic and geographical analyses using sequence data of a large number of cattle rabies isolates collected from a wide geographical area in Brazil.Methods: Partial nucleoprotein genes of rabies viruses isolated from 666 cattle and 18 vampire bats between 1987 and 2006 were sequenced and used for phylogenetic analysis. The genetic variants were plotted on topographical maps of Brazil.Results: In this study, 593 samples consisting of 24 genetic variants were analyzed. Regional localization of variants was observed, with the distribution of several variants found to be delimited by mountain ranges which served as geographic boundaries. The geographical distributions of vampire-bat and cattle isolates that were classified as the identical phylogenetic group were found to overlap with high certainty. Most of the samples analyzed in this study were isolated from adjacent areas linked by rivers.Conclusion: This study revealed the existence of several dozen regional variants associated with vampire bats in Brazil, with the distribution patterns of these variants found to be affected by mountain ranges and rivers. These results suggest that epidemiological characteristics of vampire bat-related rabies appear to be associated with the topographical and geographical characteristics of areas where cattle are maintained, and the factors affecting vampire bat ecology.

Effect of beta-lactoglobulin polymorphism and seasonality on bovine milk composition

The objective was to evaluate the effect of beta-lactoglobulin (beta-lg) polymorphism and seasonality on milk composition (fat, lactose, total solids, milk urea nitrogen, total protein, true protein, casein and somatic cell counts) of Holstein and Girolando cows. Milk and blood samples from 278 Holsteins cows and 156 Girolando cows were taken during two dry seasons and two rainy seasons, for milk composition analysis and to determine beta-lg genotypes, respectively. BB genotype was the most frequent for both breeds, followed by AA genotype for Holstein (BB>AA>AB) and by AB for Girolando cows (BB>AB>AA). No differences were found in milk compositional characteristics among genetic variants of beta-lg (AA, AB and BB) either between Holstein or Girolando cows. No association between milk composition and beta-lg genetic polymorphism was observed. During the dry season, independently of the breed considered, higher contents of lactose, true protein, casein and casein :true protein ratio were found.

Polimorfismo da beta-lactoglobulina não afeta as caracterí sticas físico-químicas e a estabilidade do leite bovino

The objective of this study was to evaluate the effect of beta-lactoglobulin polymorphism, breed and seasonality on physico-chemical characteristics and stability of bovine milk. Six Holstein-Zebu (H-Z) and five Holstein dairy herds were selected, of which 660 Holstein and 293 crossbred Holstein-Zebu milk and blood samples were collected, adding up 953 samples, distributed in two collecting periods at rainy and two at dry seasons. Each milk sample was analyzed for titratable acidity, pH, freezing point and milk ethanol stability, at the following ethanol concentrations: 70, 76, 80 and 84GL. Individual blood samples were submitted to polymerase chain reaction (PCR) for the determination of beta-lactoglobulin polymorphism. No effect of beta-lactoglobulin polymorphism was observed in physico-chemical characteristics of milk, in both studied breed. Breed effect for Holstein and H-Z, respectively, was observed on titratable acidity (16.16 and 17.07°D, while effect of seasonality (for rainy and dry seasons, respectively) was also observed on freezing point (-0.5411 and -0.5376°H). Effects of breed and seasonality on milk stability were observed (Holstein-Zebu milk was less stable on dry season), however, no effect of beta-lactoglobulin on milk stability was observed.

Locus no cromossomo 19 influencia positivamente o número de oócitos recuperados em ciclos estimulados

Objective: To evaluate if identified loci associated with normal age of menopause variation and early menopause can account for the poor response to controlled ovarian stimulation. Methods: A total of 71 patients, with age ≤ 35 years old, undergoing intracytoplasmic sperm injection were tested for three of the four newly identified genetic variants associated with normal variation in menopausal age and early menopause. Patients were divided into two groups: poor responder group (PR group, n=21) and normoresponder group (NR group, n=50). The influence of risk allele frequency on the response to controlled ovarian stimulation (COS) was evaluated. Logistic regression models were used. Results: There was no significant difference in the incidence of the genetic variants between NR and PR group. The risk allele for chromosome 19 variant (rs4806660) demonstrated a protective effect. The presence of a risk allele, either in homozygosis or in heterozygosis, was associated with an increased response to COS, resulting in an elevated number of follicles (Coef: 2.54, P= 0.041) and retrieved oocytes (Coef: 1.41, P= 0.041). Conclusions: Genetic variants rs244715, rs9379896 and rs4806660 are not risk factors for poor ovarian response. Instead, rs4806660 is associated with higher number of follicles and retrieved oocytes. It could be hypothesized that rs4806660 is associated with an increased response to gonadotrophin stimulus. © Todos os direitos reservados a SBRA - Sociedade Brasileira de Reprodução Assistida.

Caracterização molecular dos genótipos G e P de rotavírus tipo G9 provenientes de crianças com gastrenterite aguda na região metropolitana de Belém, Pará, no período de 1999 a 2007

O rotavírus (RV) é o principal agente viral associado às gastrenterites, ocasionando em média 39% dos casos diarreicos que culminam em hospitalizações, sendo responsável por cerca de 520.000 óbitos entre crianças menores de cinco anos de idade a cada ano. Pertencem à família Reoviridae, gênero Rotavirus, possui RNA de dupla fita (dsRNA) com 11 segmentos codificando 12 proteínas, sendo seis estruturais (VPs) e seis não estruturais (NSPs). A proteína VP4, juntamente com a VP7, compõem a camada externa do RV, designando os genótipos P e G, respectivamente. Até o momento foram descritos 23 tipos G e 31 tipos P. O genótipo G9 emergiu em escala global e é possivelmente associado a manifestação clínica mais grave, estando geralmente acompanhado do genótipo P[8]. O genótipo G9 possui 6 linhagens distintas e o P[8] 4 linhagens. Este estudo objetivou caracterizar os genes VP7 e VP4 de RV do genótipo G9, circulantes na região metropolitana de Belém, Pará, no período de 1999 a 2007. O dsRNA viral de 38 amostras selecionadas foi extraído a partir das suspensões fecais e submetido à eletroforese em gel de poliacrilamida para determinação dos eletroferotipos, seguido da reação de seqüenciamento. Na presente investigação, foi possível a análise de 32 amostras selecionadas, sendo todas genótipo G9P[8] associadas ao eletroferotipo longo. A análise filogenética do gene VP7 demonstrou que as amostras G9 agruparam na linhagem 3 com elevados índices de similaridade, apresentando 8 substituições nucleotídicas. Contudo, apenas três modificações aminoacídicas foram observadas nas posições 43 (I→V), 66 (A→V) e 73 (Q→R), sendo estes resíduos 43 e 73 exclusivos das amostras do ano de 2007. A análise do gene VP4 demonstrou que as amostras P[8] agruparam na linhagem 3, identificando-se 15 substituições nucleotídicas, as quais ocasionaram quatro modificações aminoacídicas nos resíduos 108 (V→I), 172 (R→K), 173 (I→V) e 275 (K→R). As modificações nos resíduos 172 e 275 são exclusivos das amostras dos anos de 1999 a 2002. As amostras do presente estudo apresentaram elevada similaridade ao longo do tempo estudado. As amostras de 2007 foram as mais divergentes, tanto para o gene VP4 quanto para o gene VP7. É importante se proceder ao contínuo monitoramento do genótipo G9 na região metropolitana de Belém, a fim de detectar possíveis variantes emergentes que possam representar um desafio as estratégias de imunização atuais.

Polimorfismos dos genes ADA e CNTNAP2 em indivíduos com Transtornos do Espectro do Autismo

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

An update on the pharmacogenetics of treating hypertension

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Estudo das alterações genéticas da Interleucina 28B em Astrocitomas

Pós-graduação em Pesquisa e Desenvolvimento (Biotecnologia Médica) - FMB

Effects of Matrix Metalloproteinase (MMP)-2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy

Imbalanced matrix metalloproteinase (MMP) expression, including MMP-2, has been demonstrated in pre-eclampsia. However, little is known about the effect of polymorphisms in MMP-2 gene on hypertensive disorders of pregnancy. We examined whether two functional MMP-2 polymorphisms (g.-1306C>T and g.-735C>T) are associated with pre-eclampsia and/or gestational hypertension and whether these polymorphisms affect therapeutic responses in women with these conditions. We studied 216 healthy pregnant women (HP), 185 patients with gestational hypertension (GH) and 216 patients with pre-eclampsia (PE). They were stratified as responsive or non-responsive to antihypertensive therapy according to clinical and laboratorial parameters of therapeutic responsiveness. Genomic DNA was extracted from whole blood and genotypes for g-1306C>T and g.-735C>T polymorphisms were determined by real-time PCR using Taqman allele discrimination assays. Haplotype frequencies were inferred using the PHASE 2.1 program. The distributions of MMP-2 genotypes and haplotypes were similar in HP, GH and PE patients (p > 0.05). In addition, we found no significant differences in MMP-2 genotype or haplotype frequencies when GH or PE patients were classified as responsive or non-responsive to antihypertensive therapy (p > 0.05). Our results suggest that MMP-2 polymorphisms do not affect the susceptibility to hypertensive disorders of pregnancy. In parallel, MMP-2 polymorphisms apparently do not affect the responsiveness to antihypertensive therapy of women with these hypertensive disorders of pregnancy.

IRF6 is a Risk Factor for Nonsyndromic Cleft Lip in the Brazilian Population

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a complex disorder with a worldwide incidence estimated at 1:700. Among the putative susceptibility loci, the IRF6 gene and a region at 8q24.21 have been corroborated in different populations. To test the role of IRF6 in NSCL/P predisposition in the Brazilian population, we conducted a structured association study with the SNPs rs642961 and rs590223, respectively, located at 5' and 3' of the IRF6 gene and not in strong linkage disequilibrium (LD), in patients from five different Brazilian locations. We also evaluated the effect of these SNPs in IRF6 expression in mesenchymal stem cells (MSC). We observed association between rs642961 and cleft lip only (CLO) (P = 0.009; odds ratio (OR) for AA genotype = 1.83 [95% Confidence interval (CI), 0.64-5.31]; OR for AG genotype = 1.72 [95% CI, 1.03-2.84]). This association seems to be driven by the affected patients from Barbalha, a location which presents the highest heritability estimate (H-2 = 0.85), and the A allele at rs642961 is acting through a dominant model. No association was detected for the SNP rs590223. We did not find any correlation between expression levels and genotypes of the two loci, and it is possible that these SNPs have a functional role in some specific period of embryogenesis. (C) 2012 Wiley Periodicals, Inc.

Region 8q24 Is a Susceptibility Locus for Nonsyndromic Oral Clefting in Brazil

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate is a relatively common craniofacial defect with multifactorial inheritance. The association of the rs987525 single nucleotide variant, located in a gene desert at 8q24.21 region, has been consistently replicated in European populations. We performed a structured association approach combined with transcriptional analysis of the MYC gene to dissect the role of rs987525 in oral clefting susceptibility in the ethnically admixed Brazilian population. METHODS: We performed the association study conditioned on the individual ancestry proportions in a sample of 563 patients and 336 controls, and in an independent sample of 221 patients and 261 controls. The correlation between rs987525 genotypes and MYC transcriptional levels in orbicularis oris muscle mesenchymal stem cells was also investigated in 42 patients and 4 controls. RESULTS: We found a significant association in the larger sample (p = 0.0016; OR = 1.80 [95% confidence interval {CI}, 1.21-2.69], for heterozygous genotype, and 2.71 [95% CI, 1.47-4.96] for homozygous genotype). We did not find a significant correlation between rs987525 genotypes and MYC transcriptional levels (p = 0.14; r = -0.22, Spearman Correlation). CONCLUSIONS: We present a positive association of rs987525 in the Brazilian population for the first time, and it is likely that the European contribution to our population is driving this association. We also cannot discard a role of rs987515 in MYC regulation, because this locus behaves as an expression quantitative locus of MYC in another tissue. Birth Defects Research (Part A) 94:464-468, 2012. (C) 2012 Wiley Periodicals, Inc.

Matrix metalloproteinase-9 polymorphisms affect plasma MMP-9 levels and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy

Abnormal matrix metalloproteinase (MMP)-9 levels may have a role in hypertensive disorders of pregnancy. We examined whether MMP-9 genetic polymorphisms (g.-1562C>T and g.-90(CA)(13-25)) modify plasma MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 levels and the responses to antihypertensive therapy in 214 patients with preeclampsia (PE), 185 patients with gestational hypertension (GH) and a control group of 214 healthy pregnant (HP). Alleles for the g.-90(CA)(13-25) polymorphism were grouped L (low) (<21 CA repeats) or H (high) (>= 21 CA repeats). Plasma MMP-9 and TIMP-1 concentrations were measured by enzyme-linked immunosorbent assay. Plasma MMP-9 concentrations were not affected by genotypes or haplotypes in HP and PE groups, except for the g.-90(CA)(13-25) polymorphism: GH patients with the LH genotype for this polymorphism have higher MMP-9 levels than those with other genotypes. The T allele for the g.-1562C>T polymorphism and the H4 haplotype (combining T and H alleles) are associated with GH and lack of responsiveness to antihypertensive therapy in GH. The H2 haplotype (combining C and H alleles) was associated with lack of responsiveness to antihypertensive therapy in PE, but not in GH. In conclusion, our results show that MMP-9 genetic variants are associated with GH and suggest that MMP-9 haplotypes affect the responsiveness to antihypertensive therapy in hypertensive disorders of pregnancy. The Pharmacogenomics Journal (2012) 12, 489-498; doi: 10.1038/tpj.2011.31; published online 19 July 2011

Thioredoxin interacting protein (TXNIP) rs7212 polymorphism is associated with arterial stiffness in the Brazilian general population

Thioredoxin interacting protein plays a pivotal role in several important processes of cardiovascular homeostasis by functioning as a biological sensor for biomechanical and oxidative stress. However, the effects of genetic variants in the modulation of arterial stiffness are unknown. In this scenario, the present study evaluated the relationship between the TXNIP rs7212 polymorphism and arterial stiffness. In the overall sample and in the diabetic group, individuals carrying CG + GG genotypes had higher PWV values compared with CC genotype group ( 10.0 vs 9.8 ms(-1), P = 0.03; 12.3 vs 11.2 ms(-1), P = 0.01; respectively). Our findings indicated that the G allele may contribute to increased arterial stiffness in the Brazilian general population and suggest a possible interaction with diabetes.