RESUMO
Assessment of specific antibody (Ab) production to polysaccharide antigens is clinically relevant, identifying patients at risk for infection by encapsulated bacteria and thus enabling a more rigorous selection of patients that can benefit of immunoglobulin replacement therapy. Classically, the gold-standard test is the measurement of antibody production to pure polysaccharide pneumococcal (PPV) immunization. Several factors, including introduction of conjugate vaccination schedule, serotyping analysis, high baseline Ab levels, have hindered the evaluation of polysaccharide antigens. This is even more difficult in secondary immunodeficiencies (SID), where patients can show secondary responses despite lack of primary antibody responses and present with recurrent or severe infections. Assessment of specific Ab production to pure Salmonella typhi Vi polysaccharide (TV) immunization has been proposed as a complementary test to PPV, given its low seroprevalence. To set the optimal cut-off value for PPV and TV response in SID, we tested different biostatistical methodologies, including ROC analysis, Youden index, Union index and Closest-topleft in a cohort of 42 SID patients and 24 healthy controls. The statistically chosen cut-offs value pre-post TV Ab ratio was ≥5, (sensitivity of 90%, specificity of 100%) and a postvaccination TV concentration of 28.5 U/mL (sensitivity of 90%, specificity of 95%), showing relevant clinical correlate.
RESUMO
An increasing healthcare challenge in the management of haematological malignancy (HM) is secondary immunodeficiency. From January 2019, the EMA included the evaluation of specific antibody (Ab) responses to better select patients for immunoglobulin replacement therapy (IgRT). We evaluated Ab responses to pneumococcal and Salmonella typhi pure polysaccharide immunization in a cohort of 42 HM patients and 24 healthy-controls. Pre-post specific Ab concentrations were measured by ELISA at 4â¯weeks. Globally, significantly lower Typhim Vi (TV) seroprevalence (9%) compared to 23-valent pneumococcal polysaccharide vaccine (PPV) (76%) (pâ¯<0.001) was observed. TV non responders (88%) were higher than PPV non responders (62%) (pâ¯<0.0001) and correlated better to infectious history. By ROC analysis, pre-post 5-fold TV increase was the best cut-off to discriminate HM with recurrent infections and controls (sensitivity 91%, specificity 100%). Despite the small sample cohort, our results suggest that specific anti-S typhi Ab response is a useful complementary assay in the diagnosis and management decision of SID to HM.
Assuntos
Neoplasias Hematológicas/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Polissacarídeos Bacterianos/imunologia , Salmonella typhi/fisiologia , Febre Tifoide/imunologia , Vacinas Tíficas-Paratíficas/imunologia , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Formação de Anticorpos , Estudos de Coortes , Feminino , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/imunologia , Humanos , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Estudos Soroepidemiológicos , Espanha/epidemiologiaRESUMO
An important factor affecting the success in the setting of related haploidentical hematopoietic stem cell transplantation (HSCT) is the graft-versus-leukemia effect mediated by natural killer (NK) cells when the donor displays NK alloreactivity versus the recipient. NK cell function is regulated by killer immunoglobulin-like receptors (KIR) and it has been described that donor KIR genotype influences transplantation outcome. This has led to a requirement of laboratories to have a quality assurance program for validation and control of their KIR genotyping methods. The goal of the 1st and 2nd Spanish KIR Genotyping Workshops was to provide an external proficiency testing program in KIR genotyping for Spanish immunology and transplant laboratories. These workshops were conducted during the years 2014-2016 and consisted of 17 participating laboratories typing a set of 20 samples. The presence/absence of 16 mandatory KIR loci (2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 2DP1, 3DL1, 3DL2, 3DL3, 3DS1, and 3DP1) was evaluated per sample. Methods for KIR genotyping included polymerase chain reaction with the use of sequence-specific primers and sequence-specific oligoprobes. Consensus typing was reached in all samples, and the performance of laboratories in external proficiency testing was satisfactory in all cases. The polymorphism detected in the small sample studied in both workshops is indicative of an ample variety of KIR gene profiles in the Spanish population.
Assuntos
Seleção do Doador/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Receptores KIR/genética , Frequência do Gene , Genótipo , Humanos , Células Matadoras Naturais/imunologia , Reação em Cadeia da Polimerase/métodos , Polimorfismo Genético , Controle de QualidadeRESUMO
Celiac disease (CD) is developed after gluten ingestion in genetically susceptible individuals. It can appear at any time in life, but some differences are commonly observed between individuals with onset early in life or in adulthood. We aimed to investigate the molecular basis underlying those differences. We collected 19 duodenal biopsies of children and adults with CD and compared the expression of 38 selected genes between each other and with the observed in 13 non-CD controls matched by age. A Bayesian methodology was used to analyze the differences of gene expression between groups. We found seven genes with a similarly altered expression in children and adults with CD when compared to controls (C2orf74, CCR6, FASLG, JAK2, IL23A, TAGAP and UBE2L3). Differences were observed in 13 genes: six genes being altered only in adults (IL1RL1, CD28, STAT3, TMEM187, VAMP3 and ZFP36L1) and two only in children (TNFSF18 and ICOSLG); and four genes showing a significantly higher alteration in adults (CCR4, IL6, IL18RAP and PLEK) and one in children (C1orf106). This is the first extensive study comparing gene expression in children and adults with CD. Differences in the expression level of several genes were found between groups, being notorious the higher alteration observed in adults. Further research is needed to evaluate the possible genetic influence underlying these changes and the specific functional consequences of the reported differences.
Assuntos
Doença Celíaca/genética , Perfilação da Expressão Gênica , Adulto , Estudos de Casos e Controles , Doença Celíaca/imunologia , Criança , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Humanos , Células Th17/imunologiaRESUMO
BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) cases have arisen amongst multiple sclerosis patients treated with natalizumab. Our objective was to gain a better understanding of the mechanisms that underlie the John Cunningham virus (JCV) infection which causes PML. METHODS: A study was made of (i) the quarterly JCV DNA levels in peripheral blood mononuclear cells (PBMCs), serum and urine samples in 100 multiple sclerosis patients during their natalizumab treatment (3-39 months), (ii) the association between human leukocyte antigen (HLA) class II and the previous viral detection and (iii) the identification of the JCV variants in those patients suspected of having PML. RESULTS: (i) JCV DNA in PBMCs and/or serum was detected in 23% of our cohort. Patients with an intermittent JCV excretion in urine had a significant increase of the viral load and prevalence in this compartment during natalizumab treatment. (ii) The frequency of the DRB1*07/DQA1*02:01/DQB1*02:02 haplotype tended to be higher in patients with detectable versus undetectable JCV DNA in PBMCs (P(corrected) = 0.108). (iii) The variants in PBMCs and serum of the non-PML patient matched the archetype. In the patient with non-fatal PML, the archetype and the same neurotropic variant in PBMCs, serum and cerebrospinal fluid was identified at the time PML was diagnosed, whereas in the patient with a worse PML prognosis, four neurotropic variants in the three previous compartments were found by the PML diagnosis. CONCLUSIONS: The detection of the neurotropic variant in blood during natalizumab treatment could be critical in the prevention of the development of severe PML, since this variant appears simultaneously with the clinical symptoms of PML and mutates quickly.
Assuntos
DNA Viral/sangue , Fatores Imunológicos/uso terapêutico , Vírus JC , Leucoencefalopatia Multifocal Progressiva/sangue , Esclerose Múltipla/sangue , Natalizumab/uso terapêutico , Adulto , DNA Viral/urina , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/urina , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/urina , Natalizumab/efeitos adversosRESUMO
AIMS/HYPOTHESIS: A complex region covering numerous genes in 12q13 was first associated with type 1 diabetes in the Wellcome Trust Case-Control Consortium (WTCCC) study. Two studies performed in a white population have tested the association of polymorphisms within this region with age at onset of the disease, with seemingly contradictory results. We aimed at replicating three of the strongest signals in a group of patients with early and late disease onset. METHODS: Polymorphisms rs773107, rs2292239 and rs10876864 were genotyped in 444 type 1 diabetic Spanish participants (age at onset 0-65 years) and 861 controls. The influence of single nucleotide polymorphisms (SNPs) on age at onset was tested through stratified and continuous analyses. RESULTS: rs773107 and rs2292239 were significantly associated with the disease, while rs10876864 showed a trend towards statistical significance in the whole population analyses. Comparison of early-onset patients to controls was significant for the three polymorphisms (allelic p < 0.006). Late-onset patients and controls did not reveal statistical differences. Analysis of age at onset in both rs773107 and rs2292239 showed differences between genotypes (p ≤ 0.002), alleles (p ≤ 0.013) and homozygotes for the risk genotype (p ≤ 4 × 10(-4)). Polymorphism rs10876864 showed trends towards statistical significance in the allelic frequencies (p = 0.051) and homozygotes for the risk genotype (p = 0.056). Subjects with risk genotypes had a disease onset between 2 and 5 years earlier than carriers of protective alleles. CONCLUSIONS/INTERPRETATION: We replicate two of the previously studied associations in a Spanish population and find new evidence of the influence of the 12q13 region on age at onset of type 1 diabetes.
Assuntos
Cromossomos Humanos Par 12/genética , Diabetes Mellitus Tipo 1/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Adulto JovemRESUMO
Alterations in intestinal epithelial permeability could underlie inflammatory bowel disease (IBD) and celiac disease (CeD) etiology, as supported by previous association studies. One related gene, DLG5 [discs, large homologue 5 (Drosophila)], has been associated with IBD in several populations and with CeD in the Dutch population. We tried to confirm the involvement of DLG5 in CeD performing a case-control study (725 CeD patients and 803 controls) by analysing the R30Q variant (rs1248696). Genetic frequencies did not significantly differ between groups (P > 0.80) and the meta-analysis with the Dutch data did not show any association. Additionally, we evaluated the effect of R30Q in IBD risk (858 patients), as discordant results were previously obtained. No association was detected. Our study does not support the effect of the R30Q DLG5 variant in CeD or IBD predisposition in the Spanish population.
Assuntos
Doença Celíaca/genética , Doenças Inflamatórias Intestinais/genética , Proteínas de Membrana/genética , Proteínas Supressoras de Tumor/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , EspanhaRESUMO
In recent reports, IRF5 polymorphisms showed significant association with multiple sclerosis (MS) susceptibility in three studied populations and Irf5-deficient mice exhibited an increased susceptibility to viral infection, linked to a significant decrease in the induction of serum type I interferon (IFN). In the present study, we evaluated the association of two IRF5 polymorphisms with MS predisposition and we also addressed whether these polymorphisms were associated with active replication of human herpes virus-6 (HHV-6) observed in a subgroup of MS patients, and/or with response to IFN-ß therapy. A total of 1494 MS patients and 1506 ethnically matched controls were genotyped for rs4728142 and rs3807306 with TaqMan pre-designed assays. One hundred and six patients were classified as responders to IFN-ß therapy (no relapses/increases in EDSS over the 2-year follow-up) and 112 as non-responders (at least two relapses or an increase in expanded disability status scale (EDSS) of at least one point during the same period). The combined analysis of available datasets yielded an effect size on MS with odds ratio (OR)(Mantel-Haenszel)=1.14 (P<0.002) for the IRF5 polymorphisms rs4728142 and rs3807306. Additionally, trends for association were observed between rs3807306T and infection with HHV-6 [p=0.05, OR (95% CI)=1.56 (1.00-2.44)] and response to IFN-ß therapy [P=0.09, OR (95% CI)=1.39 (0.95-2.05)].
Assuntos
Fatores Reguladores de Interferon/genética , Interferon beta/uso terapêutico , Esclerose Múltipla/genética , Infecções por Roseolovirus/tratamento farmacológico , Estudos de Casos e Controles , Herpesvirus Humano 6/fisiologia , HumanosRESUMO
BACKGROUND: Idiopathic achalasia is a primary esophageal motor disorder of unknown etiology. Different evidences have been reported in support of achalasia as the result of an autoimmune and inflammatory process leading to neuronal cell loss. According to this, idiopathic achalasia has been significantly associated with specific alleles of the human leukocyte antigen system class II, although few reports studying association with other loci can be found in the literature. Recent studies have shown association of a non-synonymous polymorphism within the IL23R gene with different chronic inflammatory disorders, including Barrett's esophagus. The purpose of this study was to assess whether the IL23R coding variant Arg381Gln polymorphism is involved in susceptibility to idiopathic achalasia. METHODS: We performed a case-control study including 262 patients with idiopathic achalasia and 802 healthy subjects, all of them white Spaniards. Achalasia patients were diagnosed on the basis of clinical, radiographic, endoscopic, and manometric criteria. All samples were genotyped for the IL23R Arg381Gln polymorphism using TaqMan technology. KEY RESULTS: The minor allele of the Arg381Gln polymorphism was significantly increased in patients compared with healthy controls (OR = 1.46, 95% CI = 1.01-2.11, P = 0.036). This association seems to be specific to male patients with disease onset after 40 years (OR = 2.33, 95% CI = 1.29-4.16, P = 0.002). CONCLUSIONS & INFERENCES: Our results suggest a role of IL23R in idiopathic achalasia predisposition and extend the evidence of the general influence of this gene in autoimmune and inflammatory diseases.
Assuntos
Acalasia Esofágica/genética , Receptores de Interleucina/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Estudos de Coortes , DNA/genética , Acalasia Esofágica/epidemiologia , Feminino , Genes MHC da Classe II/genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores Sexuais , Espanha/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: Genome-wide studies have identified the chromosomal region 16p13 in the susceptibility to type 1 diabetes (T1D) and multiple sclerosis (MS). This region includes the CLEC16A/KIAA0350 gene and an adjacent gene, MHC2TA (MHC class II transactivator), previously associated with susceptibility to MS and rheumatoid arthritis (RA). The role of CLEC16A polymorphisms in the pathogenesis of T1D, MS and RA and its relationship with the association reported with a MHC2TA haplotype were investigated. METHODS: CLEC16A (rs2903692/rs6498169/rs11074956) polymorphisms were analysed in 435 patients with MS, 316 with T1D and 600 with RA and in 550 ethnically matched controls. The MHC2TA rs3087456G/rs4774C risk haplotype was studied in an independent RA cohort. RESULTS: rs2903692 conferred a protective effect on patients with T1D, MS and RA. The described association of rs6498169 with MS was replicated in MS and RA cohorts. The effect of the MHC2TA rs3087456G/rs4774C haplotype on RA susceptibility was confirmed, and the haplotype was found to be in negative linkage disequilibrium with the CLEC16A rs2903692A/rs6498169A haplotype. CONCLUSIONS: Associations of CLEC16A polymorphisms with T1D and MS were successfully replicated in a Spanish population. A novel association of rs6498169 with a predisposition to RA was described which is consistent with previous MHC2TA results. These data provide evidence for the influence of variants within this chromosomal region on the development of complex diseases.
Assuntos
Doenças Autoimunes/genética , Cromossomos Humanos Par 16/genética , Artrite Reumatoide/genética , Diabetes Mellitus Tipo 1/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: The immune monitoring of transplant patients may allow us to minimize adverse events of immunosuppression and predict risks of rejection. Herein we have evaluated the capacity of an immune cell function assay to predict episodes of rejection and infections as well as its correlation with immunosuppressive drug trough levels and CD4, CD8, CD25, and DR cell counts. PATIENTS AND METHODS: This prospective study of 38 kidney transplant patients was performed from January to June 2008. Blood samples were obtained at several times posttransplantation until the sixth month. We measured intracellular adenosine triphosphate (iATP) levels following CD4 cell activation for comparison with the clinical courses. RESULTS: Patients with >or=525 ng/mL levels of iATP in the first week posttransplantation were 6.6 times more likely to develop an acute rejection episode (ARE) than those with lower immune response values (P = .014). Those who had an ARE with iATP < 525 ng/mL were generally highly sensitized (4/5). Statistically significant variations in iATP levels were observed among patients who had an ARE (P = .006). There was a relationship between infections and iATP levels also. Infections were more frequent with iATP Assuntos
Trifosfato de Adenosina/metabolismo
, Linfócitos T CD4-Positivos/imunologia
, Rejeição de Enxerto/epidemiologia
, Infecções/epidemiologia
, Transplante de Rim/efeitos adversos
, Soro Antilinfocitário/uso terapêutico
, Biomarcadores/metabolismo
, Contagem de Linfócito CD4
, Cadáver
, Rejeição de Enxerto/prevenção & controle
, Humanos
, Terapia de Imunossupressão
, Imunossupressores/uso terapêutico
, Transplante de Rim/imunologia
, Luciferases
, Ativação Linfocitária
, Monitorização Fisiológica/métodos
, Ácido Micofenólico/análogos & derivados
, Ácido Micofenólico/uso terapêutico
, Complicações Pós-Operatórias/sangue
, Complicações Pós-Operatórias/epidemiologia
, Probabilidade
, Estudos Prospectivos
, Tacrolimo/uso terapêutico
, Doadores de Tecidos
RESUMO
Genome-wide studies highlighted the effect in Crohn's disease (CD) and ulcerative colitis (UC) susceptibility of single nucleotide polymorphisms (SNPs) in 3p21, where BSN (bassoon), MST1 (macrophage stimulating-1) and MST1R (MST1 Receptor) genes map. MST1R expression was significantly downregulated in multiple sclerosis (MS) compared with control brains, resembling findings in the MS mouse model. We pursued to replicate the effect of this locus on inflammatory bowel diseases and to evaluate its contribution to MS risk. Polymorphisms rs9858542, rs2131109 and rs1128535 were analysed by TaqMan assays in Spanish patients (370 CD, 405 UC and 415 MS) and 800 ethnically matched controls. Allele frequencies of these SNPs were significantly different in CD patients compared with controls [rs9858542: P=0.001, Odds ratio (OR)=1.35; rs2131109: P=0.0005, OR=1.37; rs1128535: P=0.007, OR=0.78] and, specifically, in the ileal phenotype [rs9858542: P=0.0004, OR=1.47; rs2131109: P=0.00009, OR=1.52; rs1128535: P=0.02, OR=0.69]. No differences were detected between UC or MS patients and control individuals. The effect of this locus on CD predisposition was replicated, but no influence on UC or MS predisposition could be detected. This susceptibility locus seems to affect mainly to the ileal CD subphenotype, although this point awaits further corroboration in independent cohorts.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Predisposição Genética para Doença , Fator de Crescimento de Hepatócito/genética , Esclerose Múltipla/genética , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Alelos , Animais , Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Frequência do Gene , Genótipo , Haplótipos/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Camundongos , Esclerose Múltipla/epidemiologia , Proteínas do Tecido Nervoso/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas/metabolismo , Espanha/epidemiologiaRESUMO
Celiac disease (CD) is an inflammatory condition affecting small bowel and triggered by gluten (or related proteins) ingestion in genetic susceptible individuals. Polymorphisms in three genes, SERPINE2, PPP6C and PBX3, have recently been associated with CD in the Spanish population. However, this association could not be replicated in the UK population using imputed data. As this second study analyzed a different population, we aimed at reevaluating the role of those polymorphisms using an independent Spanish sample. We genotyped three single nucleotide polymorphisms: rs6747096 in SERPINE2, rs458046 in PPP6C and rs7040561 in PBX3, in 417 CD patients, 527 ethnically matched healthy controls and parents of 304 CD patients. A case-control study using the chi(2)-test and a familial study using the transmission disequilibrium test were performed. No association was detected in those analyses. Therefore, our results seem to discard the role of the previously described polymorphisms in SERPINE2, PPP6C and PBX3 in CD susceptibility.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Doença Celíaca/genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Fosfoproteínas Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Receptores de Superfície Celular/genética , Estudos de Casos e Controles , Frequência do Gene , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Nexinas de Proteases , Serpina E2RESUMO
BACKGROUND AND AIMS: Genome-wide association studies in coeliac disease (CD) have resulted in the finding of eight new genetic regions associated with disease susceptibility. However, a replication study performed in the Italian population could not confirm two of those new regions: 2q12 (IL18RAP) and 3p21 (CCR3). The aim of this study was to investigate the role of those regions in CD risk in a different Mediterranean population, the Spanish population. METHODS: A case-control study with 722 patients with CD and 794 ethnically matched healthy controls was performed. Two single-nucleotide polymorphisms, rs917997 (2q12) and rs6441961 (3p21), were genotyped and their genetic frequencies were compared between both groups using the chi(2) test. RESULTS: An association was found with rs6441961 (p = 0.0004, OR = 1.32, 95% CI 1.13 to 1.54). A non-significant result (but concordant with the initial study) was obtained for rs917997. CONCLUSION: The association of the 3p21 genetic region with CD susceptibility in the Spanish population was confirmed. In 2q12, the initially described OR is most probably overestimated and therefore the real situation may be the existence of a genuine but weak risk factor, which generates statistical power limitations.
Assuntos
Doença Celíaca/genética , Subunidade beta de Receptor de Interleucina-18/genética , Receptores CCR3/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genoma Humano , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , EspanhaRESUMO
In the present study, we investigated the influence of HLA class I and class II genes in the response to interferon-beta (IFNbeta) in multiple sclerosis (MS) patients. HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 DNA typing was performed by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) in a cohort of 149 relapsing-remitting MS patients classified into IFNbeta responders (n=74) and non-responders (n=75) based on stringent clinical criteria. Distribution of HLA class I and class II alleles individually and the HLA-DR2 haplotype was similar between responders and non-responders to treatment. These findings do not support a role of the HLA class I and class II genes as modifiers of the response to IFNbeta.
Assuntos
Resistência a Medicamentos/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Interferon beta/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/genética , Adulto , Estudos de Coortes , Análise Mutacional de DNA , Resistência a Medicamentos/imunologia , Feminino , Frequência do Gene/genética , Testes Genéticos , Genótipo , Haplótipos/genética , Antígenos de Histocompatibilidade Classe I/análise , Antígenos de Histocompatibilidade Classe I/sangue , Antígenos de Histocompatibilidade Classe II/análise , Antígenos de Histocompatibilidade Classe II/sangue , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Esclerose Múltipla Recidivante-Remitente/sangue , Valor Preditivo dos TestesRESUMO
Mutations in the TNFRSF13B (TACI) gene have been associated with common variable immunodeficiency, and a role in immunoglobulin A deficiency (IgAD) has also been suggested. We aimed at studying the role of several polymorphisms along this gene in IgAD susceptibility. Three TNFRSF13B mutations (C104R, A181E and R202H) and eight additional single nucleotide polymorphisms in the gene were genotyped in 338 Spanish IgAD patients and 553 ethnically matched healthy controls and tested for association. Data from parents of 114 IgAD patients were also collected and used for additional analysis. No statistically significant differences were observed after comparing patients and controls for any single nucleotide polymorphism analysed. Therefore, our work seems to discard a role of TNFRSF13B mutations in IgAD, concordantly with the most recent published studies.
Assuntos
Frequência do Gene/genética , Deficiência de IgA/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Deficiência de IgA/epidemiologia , Íntrons , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , Espanha/epidemiologiaRESUMO
Celiac disease (CD) is a multifactorial disease characterized by intestinal inflammation after gluten exposure in genetically susceptible individuals. A strong influence of certain human leukocyte antigen (HLA) alleles (those coding the HLA-DQ2 and DQ8 heterodimers) is well established, but they cannot explain the overall genetic risk. CIITA could be a good candidate gene for CD because it is mainly transcriptionally regulated, and it encodes the master regulator of major histocompatibilty complex class II gene transcription. CIITA is located in 16p13, a region also containing KIAA0350 (CLEC16A), associated with two autoimmune diseases in genome-wide association studies. We aimed at studying the involvement of polymorphisms in CIITA and KIAA0350 in CD susceptibility, with special attention to evaluate the possible presence of more than one risk factor in the region. We performed a case-control study with 607 CD patients and up to 794 healthy controls, all Spaniards. All samples were genotyped for five single nucleotide polymorphisms: rs3087456 (-168A/G) and rs4774 in CIITA and rs7203459, rs6498169 and rs2903692 in KIAA0350. No significant results were obtained when comparing genotypic, allelic or haplotypic frequencies between patients and controls. Our results seem to discard the influence in CD susceptibility of CIITA and KIAA0350 markers previously associated with other autoimmune diseases.
Assuntos
Doenças Autoimunes/genética , Doença Celíaca/genética , Lectinas Tipo C/genética , Proteínas de Transporte de Monossacarídeos/genética , Proteínas Nucleares/genética , Transativadores/genética , Alelos , Estudos de Casos e Controles , Doença Celíaca/imunologia , Suscetibilidade a Doenças , Predisposição Genética para Doença , Haplótipos , Humanos , Lectinas Tipo C/metabolismo , Desequilíbrio de Ligação , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Transativadores/metabolismoRESUMO
OBJECTIVE: The STAT4 gene encodes a transcription factor involved in the signaling pathways of several cytokines, including interleukin-12 (IL-12), the type I interferons, and IL-23. Recently, the association of a STAT4 haplotype marked by rs7574865 with rheumatoid arthritis (RA) and systemic lupus erythematosus was reported. The aim of this study was to investigate the role of this STAT4 tagging polymorphism in other immune-mediated diseases. METHODS: The study group comprised 2,776 consecutively recruited Spanish individuals: 575 with RA, 440 with multiple sclerosis, 700 with inflammatory bowel disease, 311 with type 1 diabetes, and 723 ethnically matched healthy control subjects. The STAT4 polymorphism rs7574865 was genotyped using a predesigned TaqMan assay. Allele and genotype frequencies in patients and control subjects were compared by chi-square test. RESULTS: The association of STAT4 polymorphism rs7574865 with RA was validated in patients of Spanish origin (for T versus G, P = 1.2 x 10(-6), odds ratio [OR] 1.59, 95% confidence interval [95% CI] 1.31-1.92), and the association was described for the first time in both clinical forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis (for T versus G, P = 0.006, OR 1.29, 95% CI 1.07-1.55), and in type 1 diabetes mellitus (for T versus G, P = 0.008, OR 1.36, 95% CI 1.07-1.71). In contrast, the genotypic distribution of this polymorphism showed no difference between patients with multiple sclerosis and healthy control subjects (for T versus G, P = 0.83, OR 1.02, 95% CI 0.82-1.28). CONCLUSION: The STAT4 gene is emerging as a novel common risk factor for diverse complex diseases.