RESUMO
Ankylosing spondylitis (AS) is a complex inflammatory disease that represents a major health problem both in Algeria and worldwide. Several lines of evidence support that genetic risk factors play a role in AS etiology and the CTLA4 gene has attracted a considerable attention. In this study, we were interested in evaluating the HLA-B27 frequency and in exploring the CTLA4 gene in a sample of the North African population. The dataset of the current study is composed of 81 patients with AS and 123 healthy controls. All samples were genotyped by TaqMan® allelic discrimination assay. The genetic risk of the HLA-B27 specificity and the CTLA4/CT60 polymorphism were assessed by odds ratios (OR) with 95% confidence intervals (CI). High spondylitis risk was detected for HLA-B27 allele (OR= 14.62, p = 10-6 ) in addition to a significant association of the CT60*G allele (OR= 1.89, p = .002). After gender and age stratifications, the association of the CT60*G allele was still significant in females sample (OR= 2.10, p = .001) and when age up to 30 years (OR = 2.21, p = .008). Interestingly, the CT60*G allele revealed an increased spondylitis risk in the B27 negative group (OR= 2.81, p = .006). The present work showed in West Algerian population that the HLA-B27 antigen and the variation in the CTLA4 3'UTR region played an important role in the ankylosing spondylitis susceptibility. The heterogeneity of this disease is deduced by genetic difference found between B27+ and B27- groups.
Assuntos
Antígeno CTLA-4/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Antígeno HLA-B27/genética , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/genética , Adolescente , Adulto , Fatores Etários , Idoso , Argélia/epidemiologia , Alelos , Biomarcadores , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Espondilite Anquilosante/diagnóstico , Adulto JovemRESUMO
Rheumatoid arthritis (RA) patients can be stratified into two subgroups defined by the presence or absence of antibodies against citrullinated circular peptides (anti-CCP) with most of the genetic association found in anti-CCP positive RA. Here we addressed the role of VAV1, previously associated to multiple sclerosis (MS), in the pathogenesis of RA in experimental models and in a genetic association study. Experimental arthritis triggered by pristane or collagen type II was induced in DA rats and in the DA.BN-R25 congenic line that carries a polymorphism in Vav1. Difference in arthritis severity was observed only after immunization with pristane. In a case-control study, 34 SNPs from VAV1 locus were analyzed by Immunochip genotyping in 11475 RA patients (7573 anti-CCP positive and 3902 negative) and 15,870 controls in six cohorts of European Caucasians. A combination of the previous MS-associated haplotype and two additional SNPs was associated with anti-CCP negative RA (alleles G-G-A-A of rs682626-rs2546133-rs2617822-rs12979659, OR=1.13, P=1.27 × 10-5). The same markers also contributed to activity of RA at baseline with the strongest association in the anti-CCP negative group for the rs682626-rs12979659 G-A haplotype (ß=-0.283, P=0.0048). Our study suggests a role for VAV1 and T-cell signaling in the pathology of anti-CCP-negative RA.
Assuntos
Artrite Experimental/genética , Artrite Reumatoide/genética , Doenças Autoimunes/genética , Peptídeos Cíclicos/imunologia , Polimorfismo Genético/genética , Proteínas Proto-Oncogênicas c-vav/genética , Animais , Artrite Experimental/sangue , Artrite Experimental/imunologia , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Biomarcadores/análise , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Prognóstico , Ratos , Ratos Endogâmicos BNRESUMO
OBJECTIVES: The study of polymorphisms of genes differentially expressed may lead to the identification of putative causal genetic variants in multifactorial diseases such as rheumatoid arthritis (RA). Based on preceding transcriptomic results, we genotyped 10 single nucleotide polymorphisms (SNPs) belonging to six genes (S100A8, RNASE2, PGLYRP1, RUNX3, IL2RB, and LY96) showing the highest fold change (> 1.9) when level of expression was compared between RA patients and controls. These SNPs were then analysed to evaluate their role in RA. METHOD: The relationship between gene expression and genotypes of SNPs was first investigated by Kruskal-Wallis and Mann-Whitney tests in RA patients and controls. The genetic association of these SNPs with RA were then analysed using family-based association tests in trio families. RESULTS: We found that RNASE2 gene expression was related to rs2013109 genotypes in 14 RA patients (p = 0.030). The association study in a discovery sample of 200 French trio families revealed a significant association with RA for one SNP, PGLYRP1-rs2041992 (p = 0.019); this association was stronger in trios where RA patients carried the HLA-DRB1 shared epitope (SE) (p = 0.003). However, this association was not found in a replication sample of 240 European trio families (p = 0.6). CONCLUSIONS: Family-based association tests did not reveal an association between RA and any SNP of the candidate genes tested. However, RNASE2 gene expression was differentially expressed in RA patients considering a sequence polymorphism. This result led us to highlight the potential disease-specific regulation for this candidate gene in RA.
Assuntos
Artrite Reumatoide/genética , Citocinas/genética , Neurotoxina Derivada de Eosinófilo/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Transcriptoma , Adulto , Calgranulina A/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Feminino , Marcadores Genéticos , Genótipo , Humanos , Subunidade beta de Receptor de Interleucina-2/genética , Antígeno 96 de Linfócito/genética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The objective of the study was to investigate the association of caspase activating and recruitment domain 8 (CARD8) and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) polymorphisms with rheumatoid arthritis (RA) in Tunisian and French populations. CARD8 (c.30T>A, rs2043211) and NLRP3 (c.2113C>A, rs35829419) single nucleotide polymorphisms (SNPs) were genotyped in 100 French RA trio families and 141 Tunisian patients with RA and 191 unrelated healthy controls, using TaqMan(®) allelic discrimination assay. The genetic analyses for the association and linkage in French families were performed using the comparison of allelic frequencies (AFBAC), the genotype relative risk (GRR) and the transmission disequilibrium test (TDT). Data for case and control samples were analysed by chi-square-test, GRR and odds ratio (OR). No significant differences between alleles and genotypes frequencies were detected in French trio and Tunisian patients with RA and controls, either with CARD8 or with NLRP3 SNPs both in French and in Tunisian populations. Moreover, stratifying patients according to the presence of rheumatoid factor (RF), anti-cyclic peptides antibodies (ACPA), erosion, nodules, other autoimmune disease or HLA-DRB1*04-positive subgroups did not show any significant association with CARD8 or NLRP3 (P ≥ 0.05). This study suggests that variations in the innate immunity genes CARD8 (p.C10X) and NLRP3 (p.Q705K) have no effect on RA susceptibility either in the Tunisian or in the French population.
Assuntos
Artrite Reumatoide/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Transporte/genética , Proteínas de Neoplasias/genética , Grupos Populacionais/genética , Adulto , Artrite Reumatoide/etnologia , Estudos de Casos e Controles , Feminino , França , Frequência do Gene , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Tunísia , Adulto JovemRESUMO
OBJECTIVES: The signal transducer and activator of transcription 4 (STAT4) gene localised on chromosome 2q32.2-q32.3 is known to be essential for mediating responses to interleukin 12 in lymphocytes and regulating the differentiation of T helper cells. The aim of this study was to investigate the role of the STAT4 gene in susceptibility to rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) in Tunisian case control studies. METHODS: Genotyping of STAT4 rs7574865 single nucleotide polymorphism (SNP) was performed in 140 patients affected with RA, 159 patients affected with AITDs and 200 healthy controls using TaqMan® allelic discrimination assay. Data were analysed by χ2-test, genotype relative risk (GRR) and odds ratio (OR). RESULTS: Our results revealed that frequencies of the T allele and the T/T genotype were significantly higher among RA patients compared to controls (p=0.008; p=0.003, respectively). However, no significant associations with the risk of autoimmune thyroid diseases were detected. Moreover, the stratification of RA patients subgroups revealed a significant association of both T allele and T/T genotype in patients presented erosion (p=0.003; p=0.004, respectively) as well as anti-cyclic peptides-negative RA (ACPA-) (p=0.002; p=0.0003, respectively). Furthermore, genotypic association was found according to the absence of rheumatoid factor antibody (RF) (p=0.0014). But, no significant differences in allele and genotype frequencies of STAT4 rs7574865 polymorphism were detected according to the presence of another autoimmune disease, nodules and in HLA-DRB1*04 and HLA-DRB1*0404 positive subgroups. CONCLUSIONS: Our results support involvement of the STAT4 gene in the genetic susceptibility to RA but not to AITDs in the Tunisian population.
Assuntos
Artrite Reumatoide , Fator de Transcrição STAT4 , Tireoidite Autoimune , Adulto , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/imunologia , Fator de Transcrição STAT4/metabolismo , Tireoidite Autoimune/epidemiologia , Tireoidite Autoimune/genética , Tireoidite Autoimune/imunologia , Tunísia/epidemiologiaRESUMO
OBJECTIVE: We recently showed, using a candidate gene approach in a case-control association study, that a 65-kb block encompassing tumor necrosis factor receptor-associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. METHODS: A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. RESULTS: We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04-1.50). CONCLUSION: Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.
Assuntos
Artrite Reumatoide/genética , Complemento C5/genética , Polimorfismo Genético/genética , Fator 1 Associado a Receptor de TNF/genética , Alelos , Estudos de Casos e Controles , Família , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , População Branca/genéticaRESUMO
OBJECTIVES: The objective of this study was to investigate the association between genes (HLA-DRB1 and PTPN22) and tobacco smoking, separately as well as combined, and serological markers of rheumatoid arthritis (RA) in a French population with RA. METHODS: 274 patients with RA with half of them belonging to RA multicase families, were genotyped for HLA-DRB1 allele and for PTPN22-1858 polymorphism. IgM rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies were determined by ELISA method. The search for association relied on chi(2) test and odds ratio with 95% confidence interval calculation. The interaction study relied on the departure-from-additivity-based method. RESULTS: The presence of at least one shared epitope (SE) allele was associated with anti-CCP antibodies presence (82.5% vs. 68.4%, p = 0.02), particularly with HLA-DRB1*0401 allele (28.0% vs. 16.4%, p = 0.01). Tobacco exposure was associated with anti-CCP antibodies, but only in presence of SE. A tendency toward an interaction was found between tobacco, the presence of at least one HLA-DRB1*0401 allele and anti-CCP antibodies (attributable proportion due to interaction = +0.24 (-0.21+0.76)). The cumulative dose of cigarette smoking was correlated with anti-CCP antibody titres (r = 0.19, p = 0.04). The presence of both SE and 1858T alleles was associated with a higher, but not significantly different, risk for anti-CCP antibodies presence than for each separately. No association was found between PTPN22-1858T allele and tobacco smoking for autoantibody positivity. CONCLUSIONS: Our findings suggest an association between SE alleles and tobacco smoking for anti-CCP positivity and a tendency toward an interaction between the HLA-DRB1*0401 allele and smoking for anti-CCP positivity in this sample of RA.
Assuntos
Artrite Reumatoide/genética , Autoanticorpos/sangue , Fumar/efeitos adversos , Adulto , Alelos , Artrite Reumatoide/etiologia , Artrite Reumatoide/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Fator Reumatoide/sangue , Fumar/genéticaRESUMO
OBJECTIVE: A strong genetic association of rheumatoid arthritis (RA) with the interferon regulatory factor 5 (IRF5) gene has been described previously in a Swedish population, although this result was not confirmed in a French population. We undertook an association study between IRF5 and the RA phenotype, as well as a study with serological markers of RA, in a Tunisian population. METHODS: A single-nucleotide polymorphism (SNP; rs2004640) was genotyped using a Taqman 5' allelic discrimination assay on an ABI 7500 real-time polymerase chain reaction (PCR) instrument in 140 RA patients and 185 controls. Rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) were determined by enzyme-linked immunosorbent assay (ELISA). Association was assessed based on the chi(2) test and odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The frequency of the TT genotype of the IRF5 SNP rs2004640 differed significantly between patients and controls (p = 0.01). This difference was greater when a subgroup of patients with another 'autoimmune' disorder was considered (p = 0.007). A weak but significant association was also found in a subgroup of patients who were positive for ACPA (p = 0.04) or erosion (p = 0.01). CONCLUSIONS: Our results indicate that the TT genotype of the IRF5 (rs2004640) dimorphism is associated with RA in a Tunisian population.
Assuntos
Artrite Reumatoide/genética , Fatores Reguladores de Interferon/genética , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , TunísiaRESUMO
The MMP2 rs243865-T allele was recently suggested to be associated with rheumatoid arthritis (RA) in a case-control study. MMP2 is a positional RA candidate gene. Our aim was to test rs243865 in a French family based study. No significant result was shown. The MMP2 rs243865-T allele is not a major rheumatoid arthritis genetic factor in this population.
Assuntos
Alelos , Artrite Reumatoide/genética , Metaloproteinase 2 da Matriz/genética , Feminino , França , Predisposição Genética para Doença , Humanos , Masculino , População BrancaRESUMO
In multiple sclerosis (MS) MBP is heavily citrullinated by peptidylarginine deiminase (PAD). This post-translational modification may be crucial for its pathogenesis. PADI4 is the isoform expressed in inflammatory infiltrates. The aim of this study was to analyse the role of PADI4 gene in conferring susceptibility to MS, by means of a family-based association study, testing three SNPs by RFLP. No association was found either with single SNPs or haplotypes. Similarly no significant association was detected partitioning the patients according to DRB1*15 positivity or disease severity. These results do not support a major role of the PADI4 gene, but further studies may contribute to clarify the genetic factors that regulate deimination.
Assuntos
Sistema Nervoso Central/imunologia , Predisposição Genética para Doença/genética , Hidrolases/genética , Esclerose Múltipla/genética , Proteína Básica da Mielina/metabolismo , Adulto , Biomarcadores/análise , Biomarcadores/metabolismo , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Mapeamento Cromossômico , Citrulina/metabolismo , Análise Mutacional de DNA , Feminino , França , Marcadores Genéticos/genética , Marcadores Genéticos/imunologia , Testes Genéticos , Genótipo , Haplótipos/genética , Haplótipos/imunologia , Humanos , Masculino , Esclerose Múltipla/etnologia , Esclerose Múltipla/imunologia , Proteína Básica da Mielina/imunologia , Bainha de Mielina/imunologia , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/imunologia , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/imunologia , Proteína-Arginina Desiminase do Tipo 4 , Desiminases de Arginina em Proteínas , População Branca/genéticaRESUMO
AIM: The aim of the present study was to replicate the association of five risk gene polymorphisms (PTPN22-rs2476601, STAT4-rs7574865, 6q23-rs6927172, IRF5-rs2004640 and TRAF1/C5-rs10818488) with RA in a specific population of the Western Algeria. MATERIAL AND METHODS: The study group comprised 110 patients with RA and 197 ethnically matched healthy control subjects. All polymorphisms were genotyped using predesigned TaqMan® assays. Allele and genotype frequencies in patients and control subjects were compared by chi-square test and odds ratios with 95% confidence intervals. Correction for multiple testing was carried out using the Bonferroni adjustment. RESULTS: Statistically significant associations with RA were detected. The strongest signal was obtained for PTPN22-rs2476601 with an allelic Pvalue 3.32 x 10(-11) (OR = 9.83, 95% CI [4.28 - 22.56]). A second significant association was obtained with STAT4-rs7574865 (allelic Pvalue = 4 x 10(-3); OR = 1.75, 95% CI [1.16 - 2.63]). The third SNP, 6q23-rs6927172, showed a significant result of association with RA, but missed our criteria for significance at allelic level after Bonferroni's correction (allelic Pvalue = 0.027; OR = 0.64, 95% CI [0.42 - 0.97]). Finally, IRF5-rs2004640 and TRAF1/C5-rs10818488 showed a significant association only at genotypic level (Pvalues: 3 x 10(-4) and 2.9 x 10(-3) respectively) but did not reach statistical significance when comparing allele frequencies (Pvalues: 0.96 and 0.21 respectively). CONCLUSIONS: From this initial study, we can conclude that PTPN22-rs2476601 and STAT4-rs7574865 polymorphisms are clearly associated with the risk of RA in the Western Algerian population.
Assuntos
Artrite Reumatoide/genética , Polimorfismo Genético , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Fator de Transcrição STAT4/genética , Adulto , Argélia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease that results in a chronic systemic inflammation. A few genetic epidemiologic studies found a potential association between genetic polymorphisms C677T (rs1801133) and A1298C (rs1801131) of methylenetatrahydrofolate reductase (MTHFR) gene and C3435T (rs1045642) of ATP-Binding cassette (ABCB1) gene and the increased risk for RA. The aim of this case-control study was to determine the relationship between these polymorphisms and RA susceptibility in West Algerian population. The dataset of the current study is composed of 110 RA patients and 101 healthy controls. All samples were genotyped for theses polymorphisms by TaqMan® allelic discrimination assay. Data were compared between cases and controls by the calculation of the odds ratio (OR) with a confidence interval at 95%. After age and RA erosion-stratified analyzes, no differences in genotypes or alleles frequencies distribution were found for MTHFR C677T (rs1801133) and ABCB1 C3435T (rs1045642) polymorphisms between RA cases and controls. However, the MTHFR A1298C (rs1801131) polymorphism presented a significant distribution in RA with age ≥ 40 (Genotypic data: p=0.007, OR=13.53[1.44-63.31], Allelic data: p=0.001, OR=2.39[1.39-4.1]), and in RA erosive form (Genotypic data: p=0.002, OR=6.92[1.68-30.23], Allelic data: p=0.0001, OR=2.43[1.54-3.85]).These results were confirmed after the Bonferroni correction. In this study we have showed, for the first time in the West Algerian population, that the MTHFR A1298C (rs1801131) polymorphism can be associated with rheumatoid arthritis.
Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Argélia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoAssuntos
Complemento C5/genética , Pênfigo/genética , Polimorfismo Genético/genética , Fator 1 Associado a Receptor de TNF/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Estatística como Assunto , Tunísia , Adulto JovemAssuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/epidemiologia , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Alelos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/epidemiologia , Estudos de Casos e Controles , Intervalos de Confiança , Família , Feminino , Genótipo , Humanos , Incidência , Masculino , Razão de Chances , Linhagem , Probabilidade , Medição de Risco , Sensibilidade e Especificidade , Distribuição por SexoRESUMO
Vitamin D is a potent regulator of calcium homeostasis and may have immunomodulatory effects. The influence of vitamin D on human autoimmune disease is controversial. The aim of this study was to investigate the role of vitamin D receptor gene (VDR) in rheumatoid arthritis (RA). Three polymorphisms for VDR gene FokI T>C (rs 10735810), BsmI A>G (rs 1544410) and TaqI C>T (rs 731236) were genotyped in 100 RA French nuclear families (set 1) and 100 additional French nuclear families for replication (set 2). The association analysis was performed using comparison of alleles frequencies (AFBAC), transmission disequilibrium test and genotype relative risk. Our results revealed a significant difference of F allele of FokI polymorphism between transmitted and nontransmitted frequencies (P=0.01) in set 1. Furthermore, the F/F genotype was more frequent in RA patients compared to controls (P=0.01) in set 1. The replication in set 2 showed similar patterns of transmission with a nonsignificant association. Association with FokI was found to be significant when the two sets were combined (P=0.006). These data suggest that the F allele and F/F VDR genotype are associated with RA. The mechanisms by which distinct receptor variants might confer disease susceptibility remain to be elucidated.