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Ponta Delgada, Portugal

Duraes C.,University of Porto | Machado J.C.,University of Porto | Portela F.,University of Coimbra | Rodrigues S.,Hospital of Sao Joao | And 24 more authors.
Inflammatory Bowel Diseases | Year: 2013

Background: About 70 loci are associated with susceptibility to Crohn's disease (CD), particularly in pathways of innate immunity, autophagy, and pathogen recognition. Phenotype-genotype associations are inconsistent. Methods: CD susceptibility polymorphisms ATG16L1 rs2241880, ICAM1 rs5498, IL4 rs2070874, IL17F rs763780, IRGM rs13361189, ITLN1 rs2274910, LRRK2 rs11175593, and TLR4 rs4986790 were genotyped in a Portuguese population (511 CD patients, 626 controls) and assessed for association with CD clinical characteristics. Results: There is a significant association of CD with the single nucleotide polymorphisms (SNPs) in ATG16L1 (odds ratio [OR] 1.36 [1.15-1.60], P 1/4 2.7 · 1024 for allele G), IRGM (OR 1.56 [1.21-1.93], P 1/4 3.9 · 1024 for allele C), and ITLN1 (OR 1.55 [1.28-1.88], P 1/4 4.9 · 1026 for allele C). These SNPs are associated with ileal location (OR, respectively, 1.49, 1.52, and 1.70), ileocolonic location (OR, respectively, 1.31, 1.57, and 1.68), and involvement of the upper digestive tract (OR, respectively for ATG16L1 and IRGM, 1.96 and 1.95). The risk genotype GG in ATG16L1 is associated with patients who respond to steroids (OR 1.89), respond to immunosuppressants (OR 1.77), and to biologic therapy (OR 1.89). The SNPs in ITLN1 and IRGM are both associated with a positive response to biologic therapy. The risk for ileal, ileocolonic, and upper digestive tract locations increases with the number of risk alleles (OR for three alleles, respectively, 7.10, 3.54, and 12.07); the OR for positive response to biologic therapy is 3.66. Conclusions: A multilocus approach using autophagy-related genes provides insight into CD phenotype-genotype associations and genetic markers for predicting therapeutic responses. Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.

Bettencourt C.,University of The Azores | Bettencourt C.,University of Porto | Santos C.,University of The Azores | Santos C.,Autonomous University of Barcelona | And 6 more authors.
European Journal of Human Genetics | Year: 2010

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder of late onset (occurring at a mean age of 40.2 years). The clinical manifestation of MJD is dependent on the presence of an expansion of the (CAG)n motif within exon 10 of the ATXN3 gene, located at 14q32.1. The variance in onset of MJD is only partially correlated (∼ 50-80%) with the extension of the CAG tract in genomic DNA (gDNA). The main aim of this work was to determine whether there are discrepancies in the size of the (CAG) n tract between gDNA and mRNA, and to establish whether there is a better association between age at onset and repeat size at the mRNA level. We typed gDNA and cDNA samples for the (CAG)n tract totalizing 108 wild-type and 52 expanded ATXN3 alleles. In wild-type alleles no differences were found between gDNA and cDNA. In expanded alleles, the CAG repeat size in gDNA was not always directly transcribed into the mRNA; on average there were differences of 1 repeat at the cDNA level. The slight discrepancies obtained were insufficient to cause significant differences in the distribution of the expanded alleles, and therefore no improvement in onset variance explanation was obtained with mRNA. © 2010 Macmillan Publishers Limited All rights reserved.

Albergaria A.,University of Minho | Albergaria A.,University of Porto | Ribeiro A.S.,University of Porto | Pinho S.,Imperial College London | And 9 more authors.
Human Molecular Genetics | Year: 2010

CDH3/P-cadherin is a classical cadherin. Overexpression of which has been associated with proliferative lesions of high histological grade, decreased cell polarity and poor survival of patients with breast cancer. In vitro studies showed that it can be up-regulated by ICI 182,780, suggesting that the lack of ERα signalling is responsible for the aberrant P-cadherin overexpression and for its role in inducing breast cancer cell invasion and migration. However, the mechanism by which ER-signalling inhibition leads to P-cadherin expression is still unknown. The aim of this study was to explore the molecular mechanism linking the ERα-signalling and P-cadherin-regulated expression in breast cancer cell lines. This study showed that ICI 182,780 is able to increase CDH3 promoter activity, inducing high levels of the active chromatin mark H3 lysine 4 dimethylation. We also observed, for the first time, that the transcription factor C/EBPβ is able to up-regulate CDH3 promoter activity in breast cancer cells. Moreover, we showed that the expression of P-cadherin and C/EBPβ are highly associated in human breast carcinomas and linked with a worse prognosis of breast cancer patients. This study demonstrates the existence of an epigenetic regulation by which ICI 182,780 up-regulates P-cadherin expression in MCF-7/AZ breast cancer cells through chromatin remodelling at CDH3 promoter, bringing forward the growing evidence that ERα signalling-abrogation by anti-oestrogens is able to induce the expression of ERα-repressed genes which, in the appropriate cell biology context, may contribute to a breast cancer cell invasion phenotype. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.

Bettencourt C.,University of Porto | Bettencourt C.,University of The Azores | Bettencourt C.,Complutense University of Madrid | Raposo M.,University of The Azores | And 15 more authors.
Archives of Neurology | Year: 2011

Objective: To investigate a modulating effect of the apolipoprotein E (APOE) polymorphism on age at onset of Machado-Joseph disease (MJD). Design: We collected blood samples from 192 patients with MJD and typed the APOE polymorphism. Patients: The 192 patients with MJD included 59 from the Azores, 73 from mainland Portugal, and 60 from Brazil. Setting: Academic research center. Results: Cases with the ε2/ε3 genotype had an earlier onset compared with those with the ε3/ε3 or the ε3/ε4 genotype. In this series of patients, the presence of an APOE ε2 allele implies a decrease of nearly 5 years in the age at onset. When combining several other predictors in a general linear model, namely, the presence/absence of the APOE ε2 allele, with the size of the (CAG) n in expanded alleles, the model was significantly improved and the explanation of onset variance was raised from 59.8% to 66.5%. Furthermore, the presence of the å2 allele was associated with an onset before age 39 years (odds ratio, 5.00; 95% CI, 1.18-21.14). Conclusion: The polymorphism at the APOE gene plays a role as a genetic modifier of MJD phenotype. ©2011 American Medical Association. All rights reserved.

Gonzalez C.,Hospital Divino Espirito Santo | Gomes E.,systemIC | Kazachkova N.,University of The Azores | Kazachkova N.,University of Porto | And 9 more authors.
Genetic Testing and Molecular Biomarkers | Year: 2012

The present study on long-term outcome of presymptomatic testing for Machado-Joseph disease (MJD) aimed to evaluate the psychological well-being and the familial satisfaction of subjects that 5 years prior received an unfavorable result in the predictive testing (PT). The study included 47 testees of Azorean origin (23 from the island of Flores and 24 from S. Miguel) that completed the fourth evaluation session of the MJD protocol, and undertook a neurological examination at the moment of participation in the study. Nearly 50% of testees were symptomatic at the time of the study. Psychological well-being of the 47 participants was evaluated using the Psychological General Well-Being Index (PGWB). The family satisfaction scale by adjectives was applied to obtain information on family dynamics. The average PGWB score of the total participants was of 73.3, a value indicative of psychological well-being. Nearly half of the testees presented scores indicating psychological well-being, whereas scores indicating moderate (28.9%) or severe (23.7%) stress were found in the remaining. The average score in the PGWB scale was lower in symptomatic than in asymptomatic subjects; moreover, the distinct distribution of the well-being categories seen in the two groups shows an impact of the appearance of first symptoms on the psychological state. Motives for undertaking the test, provided 5 years prior, failed to show an impact in well-being. The average score for familial satisfaction was of 134, a value compatible with high familial satisfaction, which represented the most frequent category (59.6%). Results demonstrate that well-being and family satisfaction need to be monitored in confirmed carriers of the MJD mutation. The inclusion of acceptance studies, after PT, as well as the development of acceptance training actions, should be of major importance to anticipate the possibility of psychological damage. © Copyright 2012, Mary Ann Liebert, Inc.

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