Browsing by Author "Silva, B.M."
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- Apoe isoforms in patients with psoriasisPublication . Ferreira, J.C.P.; Torres, T.; Carvalho, C.A.; Bettencourt, A.; Leal, B.; Vasconcelos, C.; Costa, P.P.; Selores, M.; Silva, B.M.Introduction: Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the world population. Patients with psoriasis (Ps) have higher prevalence of lipid disorders when compared to unaffected individuals. These patients, especially those with severe and prolonged disease, have an increased morbidity and mortality from cardiovascular events. Apolipoprotein E (ApoE), a protein involved in lipid metabolism, cholesterol and phospholipid transport, has functionally relevant gene variants. It has been described that the e4 allele may increase the risk to develop atherosclerosis, and the e2 allele has been associated with hyperlipoproteinemia type III. An increased risk of psoriasis among persons with these two alleles has also been reported. Nevertheless, the role of ApoE in Psoriasis remains controversial. Objectives: The aim of this work was to investigate the relationship between APOE-e2/e3/e4 variants and psoriasis in a Portuguese population. Materials and Methods: A cohort of 178 unrelated (74 females, 104 males) severe psoriatic patients [according to the Psoriasis Area and Severity Index (PASI)] from Centro Hospitalar do Porto/Hospital de Santo Ant onio and 285 ethnically-matched healthy controls were studied. Genotyping of APOE was performed using a Polymerase chain reaction restriction fragment-length polymorphism (PCR-RFLP) assay. Results: The frequency of the e4 allele was significantly higher in patients than in controls [(11.5% vs. 7.6%), p = 0.044, OR=1.57 (1.01–2.45)]. Conclusion: The ApoE e4 isoform could be a risk factor for psoriatic disease in this population. Our result is in agreement with previous studies in a Spanish population that associated the e4 isoform with severe psoriasis. These results support the hypothesis that ApoE has a modulatory role in inflammatory conditions.
- Association between vitamin D receptor (VDR) gene polymorphisms and systemic lupus erythematosus in Portuguese patientsPublication . Carvalho, C.; Marinho, A.; Leal, B.; Bettencourt, A.; Boleixa, D.; Almeida, I.; Farinha, F.; Costa, P.P.; Vasconcelos, C.; Silva, B.M.Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown origin, in which both genetic and environmental factors are involved. One such environmental factor is vitamin D, a vital hormone that plays a specific function in the immune system homeostasis, acting through a nuclear receptor (VDR) expressed in all immune cells. Several polymorphisms of the gene that encodes this receptor have been described. Though inconsistently, these polymorphisms have been associated with clinical manifestations and SLE development.The aim of this study was to determine the possible association between VDR gene polymorphisms (BsmI, ApaI, TaqI e FokI) and SLE susceptibility and severity, in a cohort of lupus patients from the north of Portugal.A total of 170 patients (F = 155, M = 15; age = 45 ± 13.4 years) with SLE (diagnosed according the American College of Rheumatology criteria) with at least five years of disease evolution and followed in the Autoimmune Disease Clinical Immunology Unit of Centro Hospitalar do Porto were studied. Patients and 192 ethnicity-matched controls were genotyped for BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236) and FokI (rs2228570) polymorphisms by TaqMan allelic discrimination assay. Disease severity was assessed by SLICC damage score, number of affected organs, number of severe flares and pharmacological history.SLE patients with the CT genotype of FokI polymorphism have a higher SLICC value (p = 0.031). The same result was observed for the group of patients with the TT genotype of TaqI polymorphism (p = 0.046). No differences were observed in VDR genotype between patients and controls. Also, we observed that the other clinical features analysed were not influenced by VDR polymorphisms.Our study confirms a possible role of VDR gene polymorphisms in SLE. A positive association was found between VDR polymorphisms and SLE severity (chronic damage). The presence of CT genotype of FokI and TT genotype of TaqI seems to confer a worse prognosis and may constitute a risk factor for higher long-term cumulative damage in SLE patients.
- CCR5-Delta32: Implications in SLE developmentPublication . Carvalho, C.; Calvisi, S.L.; Leal, B.; Bettencourt, A.; Marinho, A.; Almeida, I.; Farinha, F.; Pinho-Costa, P.; Silva, B.M.; Vasconcelos, C.Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with strong genetic and environmental components. Previous studies have shown increased levels of several chemokines in active SLE. C-C chemokine receptor type 5 (CCR5) is involved in the recruitment of inflammatory cells into tissues, and mechanisms modulating CCR5 expression and function may interfere in SLE development, influencing the clinical course of the disease. The aim of this study was to evaluate the possible association between the CCR5{increment}32 base-pair deletion polymorphism and SLE disease in a group of Portuguese patients. A total of 219 patients with SLE and 205 healthy individuals were studied. The frequency of CCR5[del]32 heterozygotes was lower in patients with SLE than in controls (8% vs. 15% OR = 0.5162; P = 0.0319), suggesting a protective association between CCR5[del]32 allele and SLE. These results highlight the protective role of Th1 cells that express CCR5 in SLE pathogenesis.
- Circulating microRNAs as potential biomarkers for genetic generalized epilepsies: a three microRNA panelPublication . Martins‐Ferreira, R.; Chaves, J.; Carvalho, C.; Bettencourt, A.; Chorão, R.; Freitas, J.; Samões, R.; Boleixa, D.; Lopes, J.; Ramalheira, J.; Silva, B.M.; Martins da Silva, A.; Costa, P. P.; Leal, B.Background and purpose: Genetic generalized epilepsies (GGEs) encompass a group of syndromes of mainly genetic causes, characterized by the involvement of both hemispheres. MicroRNAs (miRNAs) are small non-coding RNAs with a critical role in the regulation of neuronal biological processes through gene expression modulation. Dysregulated miRNA expression has been shown in epilepsy. Due to their stability in biological fluids like serum, miRNAs have assumed a prominent role in biomarker research. Our aim was to evaluate circulating levels of three miRNAs in GGE patients and assess their putative diagnostic value. Methods: MiR-146a, miR-155 and miR-132 were quantified by real-time polymerase chain reaction in the serum of 79 GGE patients (47 women, 32 men, 35.1 ± 12.4 years) and 67 healthy individuals (41 women, 26 men, 42.4 ± 10.1 years). Relative expression values were calculated using the 2-ΔΔCt method. Receiver operating characteristic curve analysis was performed to assess diagnostic value. MiRNA expression was correlated with clinicopathological features. Results: Serum levels of miR-146a and miR-155 were significantly upregulated in GGE patients relative to controls (3.13 and 6.05, respectively). Combined miR-146a, miR-155 and miR-132 serum levels performed well as a diagnostic biomarker, discriminating GGE patients from controls with an area under the curve of 0.85, 80% specificity and 73% sensitivity. Conclusions: Our results indicate that miR-146a, miR-155 and miR-132 may partake in GGE epileptogenesis. A panel of three circulating miRNAs with potential value as a GGE biomarker is reported for the first time. Novel biomarkers may help to identify new treatment targets and contribute to improved patients' quality of life through earlier diagnosis and a more precise prognosis.
- Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1APublication . Kasperavičiute, D.; Catarino, C.B.; Matarin, M.; Leu, C.; Novy, J.; Tostevin, A.; Leal, B.; Hessel, E.V.S.; Hallmann, K.; Hildebrand, M.S.; Dahl, H-H.M.; Ryten, M.; Trabzuni, D.; Ramasamy, A.; Alhusaini, S.; Doherty, C.P.; Dorn, T.; Hansen, J.; Krämer, G.; Steinhoff, B.J.; Zumsteg, D.; Duncan, S.; Kälviäinen, R.K.; Eriksson, K.J.; Kantanen, A-M; Pandolfo, M.; Gruber-Sedlmayr, U.; Schlachter, K.; Reinthaler, E.M.; Stogmann, E.; Zimprich, F.; Theatre, E.; Smith, C.; Obrien, T.J.; Tan, K.M.; Petrovski, S.; Robbiano, A.; Paravidino, R.; Zara, F.; Striano, P.; Sperling, M.R.; Buono, R.J.; Hakonarson, H.; Chaves, J.; Costa, P.P.; Silva, B.M.; Da Silva, A.M.; De Graan, P.N.E.; Koeleman, B.P.C.; Becker, A.; Schoch, S.; Von Lehe, M.; Reif, P.S.; Rosenow, F.; Becker, F.; Weber, Y.; Lerche, H.; Roessler, K.; Buchfelder, M.; Hamer, H.M.; Kobow, K.; Coras, R.; Blumcke, I.; Scheffer, I.E.; Berkovic, S.F.; Weale, M.E.; Delanty, N.; Depondt, C.; Cavalleri, G.L.; Kunz, W.S.; Sisodiya, S.M.Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
- How genetic characterization of Narcolepsy and hypersomnia is useful on phenotype definitionPublication . Martins da Silva, A.; Lopes, J.; Ramalheira, J.; Carvalho, C.; Costa, P.P.; Silva, B.M.Introduction. The determination of HLA class II genotype is widely used to confirm the diagnosis of narcolepsy with or without cataplexy. It is known from studies carried out in the 80’s and 90’s that genetic markers, particularly HLA-DR2 (HLA-DRB1*15) and later DQB1*06:02, are strongly associated with susceptibility to narcolepsy (N). First studies in 1984 showed values of 100% of positive HLA-DR2 (Langdon et al; Lancet 1984) in narcoleptic patients with cataplexy (NC). Mignot et al (Sleep 1997) found values of 76.1% of HLA-DQB1*06:02 positive in NC and 40.9% in N. More recent studies emphasize difference between children and adults for HLA-DQB1*06:02. Values of 93.7% (adults) vs 92.6% (children) in NC and a frequency of 78,6% in adults vs 52.9% in children were found in N (Nevsimalova et al; J Neurol 2013). The dissemination of HLA genotyping was the result of two convergent reasons: i) the method is reliable, easy to perform and reassures the clinician; ii) the assay is less invasive than other methodologies, namely those involving cerebrospinal fluid (CSF) samples. Another contributing factor is the wide acceptance of the hypothesis of an autoimmune origin for Narcolepsy (a clinical field in which the relevance of HLA system is generally accepted). This hypothesis finds support in the virtually absent levels of hypocretin peptides in the CSF of patients with NC, which is postulated to be due to the autoimmune destruction of hypocretin producing neurons (Burgess et al; J Neurosci 2012). Aims. To evaluate the contribution of genetic markers (HLA) to the differential diagnosis between narcolepsy with (NC) or without cataplexy (N) and hypersomnia (H) and their relevance in the context of our population (Northern Portugal). Patients and methods. A cohort of 113 patients with sleep and hypersomnia complaints were observed at the Outpatient Sleep Clinic from Hospital Santo Antonio/CH Porto and were assessed by clinical, night sleep polygraphic recording, MSLT on the following day, blood sampling in a routine method. Data from laboratory parameters was confronted with the clinical diagnostic hypothesis. Clinical reevaluation of the patients was considered if results did not match. Of these patients, classified as NC, N or H (according to ICSD2, 2005), 38 were NC (age at testing: mean, 32.8 years; median, 30 years); 13 N (age at testing: mean, 34.2 years; median: 36 years); 62 patients had H (age at testing: mean, 38.2 years; median, 40 years). We used a control population (CP) of 206 reportedly healthy individuals from the same geographic origin. The allele frequencies of the control population were confirmed and compared with a larger cohort of another population (2500 individuals) from the central and south regions of the country. Results. The frequency of HLA-DQB1*06:02 allele was overrepresented in N and NC patients (46% and 71% respectively), as expected, and the p value is extremely significant for NC (p < 0.0000). HLA-DQB1*02 frequency was also increased in the population with H when compared with the CP (55% vs 34%; p = 0.00396). Interestingly the frequency of the HLADQB1*03 allele was decreased in the NC vs CP group (34% vs 56%; p =0.012153). No differences were found in the HLA-DQB1*06:03 frequency between the cohort of patients and the control population. Conclusions. The HLA-DQB1*06:02 allele, a susceptibility factor to other autoimmune disorders (e.g.: MS, SLE, sarcoidosis, sclerosing cholangitis), was confirmed as a susceptibility allele also to NC in our population. The frequency of this allele in our NC patients (71%) is within the range of other studies. This value is lower when compared to studies concerning only patients with severe cataplexy (frequencies between 85-95%). Some of the differences could be due to phenotypic uncertainty or to the clinical picture evolution in different age groups (Nevsimalova et al; J Neurol 2013). Also a modification of hypocretin levels, by circadian or other oscillations and the influence of environmental factors (infections, head trauma, immunization) can be involved. The role of the potential regeneration of CNS tissue is also a subject to be explored. Given these uncertainties, genetic characterization has the potential to enhance the ability to carry out differential diagnosis among diverse excessive daytime sleepiness phenotypes, helping in the distinction of diverse entities corresponding to fundamentally different biological processes. Finally a matter to be explored is the role of HLADQB1*06:03 allele, considered by some authors as a protective factor to NC (Hor et al; Nat Genet 2010) (Van der Heide et al; Sleep 2012). Our study did not confirm this assumption.
- IL-6 and TNF-alpha polymorphisms in portuguese psoriatic patientsPublication . Ferreira, J.P.; Torres, T.; Carvalho, C.; Bettencourt, A.; Leal, B.; Vasconcelos, C.; Costa, P.P.; Selores, M.; Silva, B.M.Introduction: Cytokines regulate the growth, function and differentiation of cells and help to steer immune response and inflammation. In this study we focused our attention in two proinflammatory cytokines: IL-6 and TNFa. It is known that their overexpression is responsible for initiation, maintenance and recurrence of skin lesions in psoriatic patients. Therefore, it is important to investigate genetic biomarkers with functional effects in the genes of those cytokines that could help to predict the severity of Psoriasis. Objectives: To investigate the hypothesis that allelic variants in IL-6 and TNF-a genes are a risk factor for the developing of severe Psoriasis. Materials and Methods: A cohort of 178 (74 females, 104 males) psoriatic patients with severe plaque type psoriasis [according to the Psoriasis Area and Severity Index (PASI)] and 206 healthy individuals were selected. Several polymorphisms in the IL-6 gene (rs1800795, rs1800796, rs2069827, rs2069840) and TNF-a (rs361525, rs1799964, rs1800629) promoter region were genotyped. SNP genotyping was performed using Mass Spectrometry (MassARRAY iPLEX–Sequenom). Results: We observed a lower frequency in the minor allele (C) of the TNFa rs1799964 SNP in psoriatic patients, compared with controls [(21.9% vs. 29.4%), p = 0.02, OR = 0.675 (0.49–0.94)]. The frequency of the CC genotype in patients was 3.93% while in the healthy control group it was 9.22% [(p = 0.04, OR = 0.403 (0.17–0.98)]. No statistical significant differences were found in the other polymorphisms. Conclusion: Our data suggest that the rs1799964 C allele could be a protective factor for developing severe psoriasis. These results were similar to the findings of Gallo et al (2012) in a Spanish population. The mechanism to explain this association remains elusive, given the lack of evidence of a functional association.