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1.
PLoS One ; 14(2): e0213073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30818333

RESUMO

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs.

2.
PLoS One ; 13(5): e0196793, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29734345

RESUMO

Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Marcadores Genéticos/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
4.
Gene ; 613: 10-13, 2017 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-28257836

RESUMO

Nowadays, obesity is the greatest scourge worldwide, particularly for the developed countries and is a huge burden for the public health. Over the past decade, GWAS have revealed a number of genes associated with obesity. The fat mass and obesity associated (FTO) gene was the first one associated with obesity in a significant number of populations and recent meta-analysis studies confirm this association. FTO is a N-methyladenosine demethylase and in addition to the genetic association, its biological role in the regulation of body weight has been documented. Due to lack of replication regarding FTO association with obesity in the Greek adult population, we analyzed three SNPs, i.e. rs9939609, rs9930506 and rs3751812 in a cohort of 203 adults, comprising of 95 obese, 58 overweight and 50 control individuals. Analysis has shown a significant association for FTO (rs9930506; A/G) 'G' allele with obesity and a difference by 3.2 BMI units between the two homozygotes (AA versus GG). This association, which was detected for the first time in this population, suggests that FTO rs9930506 is a predisposition marker to obesity in the Greek adults, but the results should be taken cautiously due to the limitation of the relatively small sample size of the subjects.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Obesidade/genética , Sobrepeso/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Feminino , Grécia/epidemiologia , Humanos , Masculino , Obesidade/epidemiologia , Sobrepeso/epidemiologia
5.
Mol Diagn Ther ; 21(2): 137-152, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27905021

RESUMO

Netherton syndrome (OMIM #256500) is a rare but severe autosomal recessive form of ichthyosis that affects the skin, hair, and immune system. The identification of SPINK5, which encodes for the serine protease inhibitor LEKTI, as the gene responsible for Netherton syndrome, enabled the search for causative mutations in Netherton syndrome patients and families. However, information regarding these mutations and their association with the pathological Netherton syndrome phenotype is scarce. Herein, we provide an up-to-date overview of 80 different mutations in exonic as well as intronic regions that have been currently identified in 172 homozygous or compound heterozygous patients from 144 families. Genotypes with mutations located more upstream in LEKTI correlate with more severe phenotypes compared with similar mutations located towards the 3' region. Furthermore, splicing mutations and post-transcriptional mechanism of nonsense-mediated mRNA decay affect LEKTI expression in variable ways. Genotype-phenotype correlations form the basis of prenatal diagnosis in families with a history of Netherton syndrome and when consanguinity is implied.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Síndrome de Netherton/diagnóstico , Síndrome de Netherton/genética , Fenótipo , Alelos , Humanos , Mutação , Proteínas Secretadas Inibidoras de Proteinases/genética , Inibidor de Serinopeptidase do Tipo Kazal 5
7.
Arthritis Res Ther ; 17: 63, 2015 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-25885039

RESUMO

INTRODUCTION: We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA). METHODS: The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria. RESULTS: An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication. CONCLUSIONS: Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA.


Assuntos
Adalimumab/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Imunoglobulina G/genética , Infliximab/genética , Adalimumab/uso terapêutico , Adulto , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Sequência de Bases , Feminino , Genótipo , Humanos , Alótipos de Imunoglobulina , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
8.
Pharmacogenomics ; 16(4): 333-45, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25823782

RESUMO

OBJECTIVES: Reproducible association of a functional polymorphism in FCGR2A with response to a TNF inhibitor (TNFi) in patients with rheumatoid arthritis (RA) led us to explore other FcγR functional polymorphisms. METHODS: Functional polymorphisms FCGR3A F158V, FCGR2B I223T and promoter VNTR in FCGRT were analyzed in up to 429 patients with RA. Response to TNFi was recorded during standard care at 3, 6 and 12 months of follow-up. Fixed effects meta-analysis of studies addressing FCGR3A F158V polymorphism, which is the most studied of these polymorphisms, was conducted with inverse variance weighting. RESULTS: None of the functional polymorphisms were associated with change in DAS28. Meta-analysis of the seven studies (899 patients) with available data addressing association of FCGR3A F158V with response to TNFi in RA showed no association (OR: 1.11, 95% CI: 0.8-1.5; p = 0.5). CONCLUSION: None of the three functional polymorphisms in FcγR genes showed association with response to TNFi in patients with RA. These negative results were obtained in spite of the larger size of this study relative to previous studies addressing the same polymorphisms. In addition, meta-analysis of FCGR3A F158V was also negative against the results provided by previous studies. Original submitted 17 September 2014; Revision submitted 9 December 2014.


Assuntos
Artrite Reumatoide/genética , Antígenos de Histocompatibilidade Classe I/genética , Receptores Fc/genética , Receptores de IgG/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/antagonistas & inibidores
9.
Pharmacogenet Genomics ; 24(5): 238-45, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24667440

RESUMO

OBJECTIVES: We aimed to assess a functional polymorphism in FCGR2A H131R, for association with the treatment response to Fc-containing inhibitors of tumor necrosis factor (TNF). METHODS: A total of 429 biologic-naive patients with rheumatoid arthritis collected in two sets (299 and 130) were treated during standard care with infliximab (INX), etanercept, or adalimumab. Response to the treatment was evaluated at 3, 6, and 12 months of follow-up as the change in the Disease Activity Score (DAS) 28 from baseline and as the response by the European League Against Rheumatism (EULAR) criteria. These variables were analyzed for association with linear and logistic regression models that included sex, inhibitors of TNF, and baseline DAS28 as covariates. RESULTS: Significant association was found between the FCGR2A H131R polymorphism and the response to treatment with INX, but not with the other two TNF inhibitors. The 131R allele was associated with a lower change in DAS28 (P=0.04-0.008 at different times) in the first set of patients and confirmed in the second group of patients (P=0.026 at 3 months of follow-up). Association was also found in the comparison between nonresponders and responders to INX by the EULAR criteria. CONCLUSION: We found an association of the FCGR2A 131R allele with poor response to INX. This finding could be of utility to understand the mechanisms behind treatment failure and contribute to biomarker panels for INX response prediction.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Artrite Reumatoide/genética , Estudos de Associação Genética , Receptores de IgG/genética , Adalimumab , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
10.
Arthritis Res Ther ; 16(2): R66, 2014 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-24612463

RESUMO

INTRODUCTION: In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. METHODS: The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. RESULTS: None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. CONCLUSION: Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
11.
Cytokine ; 62(1): 38-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23517877

RESUMO

Angiogenesis has been considered to be an important step in the initiation and progression of chronic diseases such as psoriasis. The hypoxia inducible factor 1 alpha (HIF-1α), a critical hypoxia-induced factor that regulates angiogenesis has been shown previously to be over-expressed in psoriasis skin both at the mRNA and protein level. In this report we confirm HIF-1α and IL-6 over-expression in psoriatic patients using immunoenzymometric assay and found that the expression of HIF-1α is closely correlated with IL-6 expression (r = 0.61 and p = 0.005), suggesting a close interaction of HIF-1α and IL-6 in the psoriasis immuno-microenvironment. Our findings merit further in vitro and in vivo work before solid suggestions can be made for therapeutic interventions that target HIF-1α pathway and/or IL-6.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Interleucina-6/sangue , Psoríase/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Gene ; 512(2): 237-9, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23103831

RESUMO

The prevalence of obesity has increased dramatically during the last thirty years in western countries with severe complications for health and economy. Obesity is the outcome of the strong interplay between genetic and environmental factors and is therefore widely expected that the discovery of the many genetic factors underlying the heritable risk of obesity will contribute critically to our basic knowledge of the disease etiopathogenesis and the identification of new targets for therapeutic intervention. The aim of the present study was to assess the genetic contribution of known polymorphisms in two genes that are linked to the pathogenetic mechanism of obesity. Analysis of vitamin D receptor (VDR) TaqI (rs731236; T/C) and fat mass and obesity-associated (FTO) (rs9939609; A/T) [corrected] polymorphisms in 82 obesity subjects and 102 controls showed significant association for VDR TaqI 'T' allele and obesity (OR: 2.07; 1.123-3.816; P=0.019), contributing to an elevated BMI of 3kg/m(2) per risk allele. No association was observed for the FTO polymorphism. These results further support a role for VDR as risk factor for obesity and suggest its further validation in larger independent populations as well as highlight a target for functional analysis towards therapeutic intervention in obese individuals.


Assuntos
Alelos , Obesidade/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Enzimas de Restrição do DNA , Feminino , Grécia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Prevalência , Proteínas/genética , Fatores de Risco
13.
Mol Diagn Ther ; 16(1): 29-34, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22111980

RESUMO

BACKGROUND: Although biologic therapies have revolutionized the treatment of psoriasis, patients exhibit a substantial heterogeneous response that could be due to complex genetic heterogeneity. OBJECTIVE: The aim of this study was to investigate the possible influence of tumor necrosis factor-α (TNF), TNF receptor I (TNFRSF1A), and TNF receptor II (TNFRSF1B) gene polymorphisms on anti-TNF treatment responsiveness in psoriasis patients. METHODS: A Greek multicenter collaboration was established to recruit a cohort of patients (n = 80) with psoriasis treated with anti-TNF drugs. Single nucleotide polymorphisms (SNPs) in TNF (-238G>A, -308G>A, -857C>T), TNFRSF1A (36A>G), and TNFRSF1B (676T>G) were genotyped by PCR-restriction fragment length polymorphism assays. SNPs and haplotypes, including stratification by comorbidity status, were analyzed for association with treatment response after 6 months of therapy, defined as a reduction in the Psoriasis Area and Severity Index (PASI) score by >75% (responders) or ≤50% (nonresponders). RESULTS: Sixty-three patients (78.8%) were defined as responders (PASI score reduction >75%) and 17 patients (21.2%) were defined as nonresponders (PASI score reduction ≤50%). Carriage of TNF -857C or TNFRSF1B 676T alleles was associated with positive response to drug treatment in patients treated with etanercept (p = 0.002 and p = 0.001, respectively). None of the genotyped SNPs were associated with responsiveness to treatment with infliximab or adalimumab. Additionally, when patients were stratified by comorbidity status, none of the genotyped SNPs were alone associated with responsiveness to drug treatment. CONCLUSION: This study is the first in the field of psoriasis demonstrating a strong association between genetic markers and positive response to drug treatment. Validation of this result in larger studies, as well as analysis of other drug treatments, could provide the basis for individually tailored treatment, along with increased cost effectiveness and reduced unnecessary exposure to toxicity.


Assuntos
Polimorfismo de Nucleotídeo Único , Psoríase/tratamento farmacológico , Psoríase/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/antagonistas & inibidores , Fatores de Necrose Tumoral/genética , Adulto , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Grécia , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Farmacogenética , Psoríase/imunologia , Psoríase/patologia , Estudos Retrospectivos , Fatores de Necrose Tumoral/imunologia
14.
Genet Test Mol Biomarkers ; 15(9): 613-7, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21473680

RESUMO

Impaired energy homeostasis and low-grade inflammation have been related to components of the metabolic syndrome (MetS) such as dyslipidemia, obesity, and insulin resistance. Single-nucleotide polymorphisms in the genes encoding for IL-6 (g.-634G>C; c.174G>C), TNFα (g.-308G>A), methylenetetrahydrofolate reductase (MTHFR) (c.677C>T), APOC3 (c.3175C>G), and APOA5 (g.-1131T>C) have been implicated in the processes of inflammation and energy intake that take place in the development of MetS manifestations. The aim of this study was to investigate the association between these polymorphisms and MetS, as defined by the National Cholesterol Education Program-Adult treatment Panel III criteria, in the Greek population. Overall, 30 unrelated subjects who met the criteria of MetS and 60 matched control subjects from central Greece were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. There was a significant association between both MTHFR c.677C>T (odds ratio: 4.02; confidence interval: 1.496-10.777; p=0.003) and APOA5 g.-1131T>C (odds ratio: 3.514; confidence interval: 1.065-11.585; p=0.035) and MetS. Analysis of constructed haplotypes showed a highly significant association between 677C-1131T-3175C haplotype and MetS (p<0.0001). Carriers of both MTHFR c.677T and APOA5 g.-1131C were associated with increased triglyceride levels (p=0.001 and p=0.003, respectively), compared with noncarriers. These results support a role for MTHFR and APOA5 as risk factors for MetS and suggest their further validation in larger independent populations.


Assuntos
Apolipoproteínas A/genética , Síndrome Metabólica/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Adulto , Apolipoproteína A-V , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genética Populacional , Genótipo , Grécia/epidemiologia , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
15.
J Hum Genet ; 56(6): 423-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21412248

RESUMO

Psoriasis is an inflammatory skin disorder that exhibits multifactorial mode of inheritance. In addition to the well-known susceptibility locus PSORS1 many other loci have been shown to be implicated in the genetic predisposition for disease. However, interactions between loci have not been thoroughly explored. Thus, we measured the effect of potential interaction between human leukocyte antigen (HLA)-C, CSTA and D1S236 at PSORS1, PSORS4 and PSORS5, respectively, in the development of psoriasis. Analysis of 130 Caucasian psoriatic families showed that the risk to an HLA-Cw6 +ve individual who carries two copies of the risk allele at both the CSTA and D1S2346 is 105 times the risk to an HLA-Cw6 +ve individual who does not carry any risk alleles at the CSTA or D1S2346. This is the first demonstration of an interaction between risk alleles in three susceptibility loci suggesting possible functional interaction between genes in these loci, which might explain the complexity of the pathogenesis of psoriasis.


Assuntos
Alelos , Cistatina A/genética , Predisposição Genética para Doença/genética , Antígenos HLA-C/genética , Proteínas/genética , Psoríase/genética , Adolescente , Adulto , Criança , Pré-Escolar , Epistasia Genética/genética , Frequência do Gene/genética , Genótipo , Humanos , Lactente , Recém-Nascido , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Proteínas/metabolismo , Risco , Adulto Jovem
17.
J Invest Dermatol ; 129(8): 1892-908, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19494826

RESUMO

Atopic dermatitis (AD) is a multifactorial, heterogenous disease that arises as a result of the interaction between both environmental and genetic factors. Changes in at least three groups of genes encoding structural proteins, epidermal proteases, and protease inhibitors predispose to a defective epidermal barrier and increase the risk of developing AD. Loss-of-function mutations found within the FLG gene encoding the structural protein, filaggrin, represent the most significant genetic factor predisposing to AD identified to date. Enhanced protease activity and decreased synthesis of the lipid lamellae lead to exacerbated breakdown of the epidermal barrier. Environmental factors, including the use of soap and detergents, exacerbate epidermal barrier breakdown, attributed to the elevation of stratum corneum pH. A sustained increase in pH enhances the activity of degradatory proteases and decreases the activity of the lipid synthesis enzymes. The strong association between both genetic barrier defects and environmental insults to the barrier with AD suggests that epidermal barrier dysfunction is a primary event in the development of this disease. Our understanding of gene-environment interactions should lead to a better use of some topical products, avoidance of others, and the increased use and development of products that can repair the skin barrier.


Assuntos
Dermatite Atópica/metabolismo , Epiderme/metabolismo , Corticosteroides/administração & dosagem , Animais , Dermatite Atópica/etiologia , Detergentes/farmacologia , Homeostase , Humanos , Concentração de Íons de Hidrogênio , Calicreínas/fisiologia , Mutação , Proteínas Secretadas Inibidoras de Proteinases/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Inibidor de Serinopeptidase do Tipo Kazal 5
18.
Eur J Hum Genet ; 16(8): 1002-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18364739

RESUMO

Family-based analysis has revealed several loci for psoriasis and the locus, PSORS5, on chromosome 3q21 has been found in two independent studies. In this region, cystatin A (CSTA) encodes a skin barrier cystein protease inhibitor found in human sweat and it is over-expressed in psoriatic skin. Three CSTA markers at positions -190 (g.-190T>C), +162 (c.162T>C) and +344 (c.344C>T) were analysed in 107 unrelated patients and 216 matched controls. There was a significant trend for association with CSTA c.162T>C and psoriasis (odds ratio (OR)=3.45, P<0.001). Analysis of constructed haplotypes showed a highly significant association between disease and CSTA -190T/+162C/+344C (CSTA TCC) (P=10(-6)). In independent study, a TDT analysis in 126 nuclear families confirmed the over-transmission of CSTA TCC (P=0.0001). The presence of statistical interaction between CSTA TCC haplotype and HLA-Cw6 at PSORS1 locus was detected by performing TDT analysis on CSTA haplotypes stratified by the presence or absence of the risk allele at HLA-Cw6 locus. To estimate the disease risk we employed conditional logistic regression on the family data. The CSTA TCC haplotype is only associated with psoriasis in those individuals carrying the risk allele at the HLA-Cw6 locus (OR=2.22, P=0.0004, 95% CI= 1.42, 3.49). These results represent a major step towards the dissection of genetic factors involved in the pathogenesis of psoriasis.


Assuntos
Cistatinas/genética , Antígenos HLA-C/genética , Psoríase/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 6/genética , Cistatina A , Cistatinas/metabolismo , Família , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA-C/metabolismo , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Psoríase/imunologia , Psoríase/metabolismo
19.
J Allergy Clin Immunol ; 118(1): 3-21; quiz 22-3, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16815133

RESUMO

Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disorder in which genetic mutations and cutaneous hyperreactivity to environmental stimuli play a causative role. Genetic mutations alone might not be enough to cause clinical manifestations of AD, and this review will propose a new perspective on the importance of epidermal barrier dysfunction in genetically predisposed individuals, predisposing them to the harmful effects of environmental agents. The skin barrier is known to be damaged in patients with AD, both in acute eczematous lesions and also in clinically unaffected skin. Skin barrier function can be impaired first by a genetic predisposition to produce increased levels of stratum corneum chymotryptic enzyme. This protease enzyme causes premature breakdown of corneodesmosomes, leading to impairment of the epidermal barrier. The addition of environmental interactions, such as washing with soap and detergents, or long-term application of topical corticosteroids can further increase production of stratum corneum chymotryptic enzyme and impair epidermal barrier function. The epidermal barrier can also be damaged by exogenous proteases from house dust mites and Staphylococcus aureus. One or more of these factors in combination might lead to a defective barrier, thereby increasing the risk of allergen penetration and succeeding inflammatory reaction, thus contributing to exacerbations of this disease.


Assuntos
Dermatite Atópica/metabolismo , Epiderme/metabolismo , Corticosteroides/farmacologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Detergentes/farmacologia , Meio Ambiente , Humanos , Concentração de Íons de Hidrogênio , Calicreínas/genética , Calicreínas/fisiologia , Peptídeo Hidrolases/farmacologia , Proteínas Secretadas Inibidoras de Proteinases , Inibidor de Serinopeptidase do Tipo Kazal 5 , Staphylococcus aureus/enzimologia
20.
Community Pract ; 78(12): 440-2, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16375050

RESUMO

Genes that control the thickness of our skin and its vulnerability to chemicals in the environment play a role in the development of contact dermatitis and atopic eczema. Sensitive skin manifests itself as a burning, stinging or itching sensation following the application of topical products such as soap, bubble baths and cosmetics. The skin may become red and dry after repeated application of these products. New insights into the skin barrier can help us improve treatment of the skin and prevent problems associated with atopic eczema and sensitive skin


Assuntos
Dermatite Atópica/fisiopatologia , Dermatite de Contato/fisiopatologia , Criança , Dermatite Atópica/genética , Dermatite Atópica/prevenção & controle , Dermatite de Contato/genética , Dermatite de Contato/prevenção & controle , Predisposição Genética para Doença , Humanos , Lactente , Higiene da Pele , Fenômenos Fisiológicos da Pele
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