Browsing by Author "Maciel, P"
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- Study of disease-relevant polymorphisms in the TLR4 and TLR9 genes: a novel method applied to the analysis of the Portuguese populationPublication . Carvalho, A; Marques, A; Maciel, P; Rodrigues, FToll-like receptors (TLRs) are cellular receptors that mediate recognition of microbial challenges and the subsequent inflammatory response. Genetic variations within these inflammation-associated genes may alter host-pathogen defence mechanisms affecting susceptibility towards infectious diseases. Taking into account the significance of these genes, we developed a simple and rapid method based in the bi-directional PCR amplification of specific alleles (Bi-PASA) for genotyping known sequence variants in TLR4 (Asp299Gly and Thr399Ile) and TLR9 (T-1237C) genes. This method allows genotype determination in a single reaction and is amenable to large-scale analysis. We used Bi-PASA to characterize the distribution of these polymorphisms in the Portuguese population. A total of 388 randomly selected blood donors of Portuguese origin (203 females and 185 males) were genotyped and allele frequencies were determined. Among the tested individuals, 11.1% and 10.8% were heterozygous for Asp299Gly and Thr399Ile, respectively. In what concerns the T-1237C variation in TLR9, the variant allele was present in 19.4% of the individuals tested. Besides confirming the usefulness of the Bi-PASA in polymorphism analysis, the data presented provide valuable information on TLR polymorphisms in the Portuguese population that can be used to stratify risk patients with increased susceptibility to infection.
- The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphomaPublication . Carvalho, A; Cunha, C; Almeida, AJ; Osório, NS; Saraiva, M; Teixeira-Coelho, M; Pedreiro, S; Torrado, E; Domingues, N; Gomes-Alves, AG; Marques, A; Silva MG; Lacerda, JF; Gomes, M; Pinto, AC; Torres, F; Rendeiro, P; Tavares, P; Di Ianni, M; Heutink, P; Bracci, PM; Conde, L; Ludovico, P; Pedrosa, J; Maciel, P; Pitzurra, L; Aversa, F; Marques, H; Paiva, A; Skibola, CF; Romani, L; Castro, AG; Rodrigues, FNon-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.
- Whole Gene Deletion of EBF3 Supporting Haploinsufficiency of This Gene as a Mechanism of Neurodevelopmental DiseasePublication . Lopes, F; Soares, G; Gonçalves-Rocha, M; Pinto-Basto, JM; Maciel, PMutations in early B cell factor 3 (EBF3) were recently described in patients with a neurodevelopmental disorder (NDD) that includes developmental delay/intellectual disability, ataxia, hypotonia, speech impairment, strabismus, genitourinary abnormalities, and mild facial dysmorphisms. Several large 10q terminal and interstitial deletions affecting many genes and including EBF3 have been described in the literature. However, small deletions (<1 MB) affecting almost exclusively EBF3 are not commonly reported. We performed array comparative genomic hybridization (aCGH) (Agilent 180K) and quantitative PCR analysis in a female patient with intellectual disability. A clinical comparison between our patient and overlapping cases reported in the literature was also made. The patient carries a de novo 600 Kb deletion at 10q26.3 affecting the MGMT, EBF3, and GLRX genes. The patient has severe intellectual disability, language impairment, conductive hearing loss, hypotonia, vision alterations, triangular face, short stature, and behavior problems. This presentation overlaps that reported for patients carrying EBF3 heterozygous point mutations, as well as literature reports of patients carrying large 10qter deletions. Our results and the literature review suggest that EBF3 haploinsufficiency is a key contributor to the common aspects of the phenotype presented by patients bearing point mutations and indels in this gene, given that deletions affecting the entire gene (alone or in addition to other genes) are causative of a similar syndrome, including intellectual disability (ID) with associated neurological symptoms and particular facial dysmorphisms.
- A whole genome screen for association with multiple sclerosis in Portuguese patientsPublication . Santos, M; Pinto-Basto, J; Rio, ME; Sá, MJ; Valença, A; Sá, A; Dinis, J; Figueiredo, J; Bigotte de Almeida, L; Coelho, I; Sawcer, S; Setakis, E; Compston, A; Sequeiros, J; Maciel, PMultiple sclerosis (MS) is common in Europe affecting up to 1:500 people. In an effort to identify genes influencing susceptibility to the disease, we have performed a population-based whole genome screen for association. In this study, 6000 microsatellite markers were typed in separately pooled DNA samples from MS patients (n=188) and matched controls (n=188). Interpretable data was obtained from 4661 of these markers. Refining analysis of the most promising markers identified 10 showing potential evidence for association.