RESUMO
BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic relapsing autoimmune disease characterized by production of autoantibodies against a series of nuclear antigens and by chronic inflammation. The etiology of SLE is the result of interactions between genetic, epigenetic, hormonal, and environmental factors. Changes in histone acetylation and methylation contribute to structural chromatin modifications. OBJECTIVE: We studied the histone demethylase JHDM1D and histone deacetylases HDAC1, HDAC2, and HDAC3 transcript levels in peripheral blood mononuclear cells (PBMCs) from patients diagnosed with systemic lupus erythematosus (SLE). Furthermore, the association of JHDM1D, HDAC1, HDAC2, and HDAC3 transcript levels with gender, age, and major clinical manifestations were analyzed. MATERIALS AND METHODS: Real-time quantitative polymerase chain reaction (RQ-PCR) analysis was used to determine JHDM1D, HDAC1, HDAC2, and HDAC3 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) from 30 patients with SLE and 36 healthy controls. RESULTS: Significantly lower HDAC2 transcript levels (p = 0.006785) and significantly higher JHDM1D (p = 0.0000002) and HDAC1 (p = 0.010581) transcript levels in SLE patients were observed compared with healthy controls. Higher JHDM1D mRNA expression was detected in active SLE patients when compared with inactive patients (p = 0.005). Furthermore, the JHDM1D transcript levels were positively correlated with disease activity (r(s) = 0.368, p = 0.045), while HDAC2 mRNA expression was positively correlated with disease duration (r(s) = 0.502, p = 0.0047). CONCLUSION: Our analyses confirmed the importance of epigenetic alterations (histone demethylation and acetylation) in SLE etiology. Moreover, our results suggest that the presence of some clinical manifestations, like hematological disease and anti-Ro antibody, might be associated with the dysregulation of histone demethylase and deacetylases mRNA expression levels.
Assuntos
Histona Desacetilases/sangue , Histona Desmetilases com o Domínio Jumonji/sangue , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , RNA Mensageiro/sangue , Adulto , Biomarcadores/sangue , Feminino , Predisposição Genética para Doença/genética , Histona Desacetilases/genética , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Lúpus Eritematoso Sistêmico/genética , Masculino , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
There is one study on the association of the CD40 G > T (rs4810485) single nucleotide polymorphism (SNP) as a risk factor of systemic lupus erythematosus (SLE). Therefore, we studied the prevalence of the CD40 G > T SNP in patients with SLE (n = 261) and controls (n = 545) in a Polish population. We did not find significant differences between the CD40 G > T genotype and allele frequency in patients with SLE and healthy individuals. However, the frequency of the CD40 TT and GT genotypes was statistically different between patients with arthritis and neurologic manifestations and patients without these symptoms (OR = 0.2009 (95% CI = 0.07547-0.5348, p = 0.0004, p (corr) = 0.0068) and OR = 0.2876 (95% CI = 0.1371-0.6031, p = 0.0005, p (corr) = 0.0085) respectively). Our observations indicate that the CD40 T variant might be negatively associated with some clinical disease manifestations in patients with SLE.
Assuntos
Antígenos CD40/genética , Lúpus Eritematoso Sistêmico/genética , Adulto , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Pessoa de Meia-Idade , Polônia , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Oestrogens acting via nuclear receptors (encoded by ESR1 or ESR2) are important for pathogenesis of systemic lupus erythematosus (SLE). rs2234693 and rs4986938 are two single nucleotide polymorphisms (SNPs) whose C and A variants increase transcription of ESR1 and ESR2, respectively. The T allele of rs2234693 was associated with early onset SLE, whereas the role of rs4986938 in SLE was not reported. Our aim was to examine the role of rs2234693 and rs4986938 in conferring susceptibility to juvenile and adult SLE (jSLE and aSLE). Genotype distribution of both SNPs was analysed in 84 jSLE, 112 aSLE patients and 1001 controls. Allele C of rs2234693 was associated with jSLE (OR = 1.87, p = 0.006, p(corrected) = 0.02), whereas allele A of rs4986938 showed an association with aSLE (OR = 1.46, p = 0.008, p(corrected) = 0.03). In jSLE, rs2234693 C had lower frequency in patients with central nervous system involvement (OR = 0.39, p = 0.005, p(corrected) = 0.04) and showed a trend for increase among males, patients with renal involvement and those without DR2/3 (p < 0.05, p(corrected) > 0.05). Whereas our results are consistent with a role of ESR1 variation in jSLE, more studies are needed since the direction of association was the opposite of that reported previously. The association between rs4986938 (ESR2) and aSLE is a novel finding, consistent with our recent report associating this variant with Graves' disease.
Assuntos
Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Variação Genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/fisiopatologia , MasculinoRESUMO
It was recently shown that the CD24 Ala57Val (rs 52812045) polymorphism plays a significant role in susceptibility to systemic lupus erythematosus (SLE) in a Spanish population, which has not been confirmed in other ethnic groups. We investigated the distribution of the CD24 Ala57Val polymorphism in patients with SLE (n = 250) and controls (n = 350) in Poland. The odds ratio (OR) for patients with SLE with the Ala/Val genotype compared with Ala/Ala genotype was 1.490 [95% confidence interval (CI) = 1.052-2.111, P = 0.0275], and OR for the Val/Val genotype compared with Ala/Ala genotypes was 2.001 (95% CI = 1.154-3.467, P = 0.0154). Moreover, we observed a significant association between the CD24 Val allele and the presence of anti-Scl-70 antibody (Ab) OR = 2.155 (1.438-3.229, P = 0.0002). There was also an association of Val allele with the presence of anti-snRNP Ab OR = 1.984 (1.266-3.110, P = 0.0034) in patients with SLE. We also found that the CD24 Val/Val and Ala/Val genotypes contribute to immunologic manifestations OR = 2.244 (1.323-3.806, P = 0.0037). Our observations indicate that the CD24 Ala57Val polymorphism may predispose to SLE incidence and can be linked to immunologic manifestations and production of autoantibodies in this disease.
Assuntos
Antígeno CD24/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Adulto , Alanina/genética , Substituição de Aminoácidos , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Polônia , Risco , Valina/genéticaRESUMO
Recently, a family-based association analysis showed that the haplotype carrying a low expression of the variant CD3Z 844 T>A (rs1052231) polymorphism located in the 3'-untranslated region of CD3Z predisposes to systemic lupus erythematosus (SLE) incidence. We analyzed the prevalence of the CD3Z 844 T>A polymorphism in SLE patients (n = 152) and controls (n = 304) in Poland. We observed that women with the CD3Z AA and CD3Z AT genotypes exhibited a 1.845-fold increased risk of SLE [95% confidence intervals (95% CI) = 1.222-2.787, P = 0.0038]. However, we did not find an increased risk for the homozygous CD3Z AA genotype (odds ratio = 1.204, 95% CI = 0.2838-5.108, P = 1.0000). This observation confers that genetic factors causing a decreased level of CD3-zeta in T cells may predispose to SLE incidence.
Assuntos
Regiões 3' não Traduzidas/genética , Complexo CD3/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Adulto , Alelos , Feminino , Frequência do Gene , Genótipo , Haplótipos/genética , Humanos , Incidência , Pessoa de Meia-Idade , Polônia/epidemiologia , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Numerous investigations indicated that the programmed cell death 1 (PDCD1) gene polymorphisms contribute to the development of systemic lupus erythematosus (SLE). However, their association with SLE has been found to be controversial. Therefore, in patients with SLE (n=102) and controls (n=140) we examined the association of six polymorphisms of this gene with susceptibility to SLE in the Polish population. We found that PDCD1 7209 CT or 7209 TT genotype exhibited 3.282-fold increased risk of SLE (95% CI=1.553 - 6.935; p=0.0017). The allele and genotype frequencies of the remaining polymorphisms: 5708 C>T, 6438 G>A, 7146 G>A and 8737 G>A did not exhibit statistical differences between SLE patients and controls. Our results confirmed the association of 7209 C>T polymorphism of PDCD1 gene with SLE that was previously observed in the Taiwanese population.
Assuntos
Antígenos CD/genética , Proteínas Reguladoras de Apoptose/genética , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Polônia , Receptor de Morte Celular Programada 1 , Fatores de RiscoRESUMO
The protein tyrosine phosphatase non-receptor 22 (PTPN22) 1858 C>T poly-morphic variant gene (rs2476601) displays an association with systemic lupus erythematosus (SLE) and other autoimmune diseases. However, its contribution to SLE has been found to be disputable. We therefore examined the association of PTPN22 1858 C>T polymorphism with susceptibility to SLE in the Polish population, among patients with SLE (n=150) and controls (n=300). We found a contribution of the PTPN22 1858 C>T polymorphism to the incidence of SLE. Women with the PTPN22 TT and PTPN22 CT genotypes displayed a 2.016-fold increased risk of SLE (95% CI=1.324 - 3.070, P=0.0014). However, we did not observe an increased risk for the homozygous PTPN22 TT genotype OR= 2.552 (95% CI=0.6748-9.64, p=0.1675). Our results confirm an association of the 1858 C>T polymorphism of the PTPN22 gene with SLE, which was previously observed in other populations.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Adulto , Feminino , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Pessoa de Meia-Idade , Mutação Puntual , Polônia/epidemiologia , Polimorfismo Genético , Fatores de RiscoRESUMO
The contribution of the p53 Arg72Pro polymorphism in the development of systemic lupus erythematosus (SLE) remains controversial. We investigated the frequency of the p53 Arg72Pro genotype in patients with SLE (n = 155) and in controls (n = 150) in Poland. We found a weak contribution of the Arg/Arg genotype to the morbidity of SLE. Odds ratio (OR) for patients with SLE and p53 Arg/Arg genotype was 1.875 [95% CI = 1.180-2.979], P = 0.0075 and OR of the Arg/Arg and Arg/Pro genotypes was 1.549 [95% CI = 0.752-3.195], P = 0.2328. Since the p53Arg variant supports apoptosis better than the p53Pro variant, our findings can be linked to an increase in the number of apoptotic leucocytes in SLE patients. The distinction between various populations may be because of differences in racial composition and/or exposure to distinct environmental factors that have a different impact on SLE incidence along with the changed Argp53Pro genotype.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético/genética , Proteína Supressora de Tumor p53/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Polônia , População Branca/genéticaRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by overexpression of cytokines and T cell accessory molecules, which is due to a reduction of DNA regulatory region methylation in T cells. It has been shown that polymorphic variants of genes encoding key enzymes of folate and methionine metabolism may have an effect on DNA methylation. Therefore, in patients with SLE (n = 106) and controls (n = 141) we examined the distribution of polymorphisms of genes encoding methionine synthase (MTR); 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1); and methylenetetrahydrofolate reductase (MTHFR). We found that MTR 2756AG (919DG) or GG (919GG) genotype exhibited 2.005-fold increased risk of SLE (95% CI = 1.177-3.416, P = 0.0146). However, MTHFR 677C > T (A222V) and MTHFD1 1958G > A (R653Q) allele and genotype frequencies did not exhibit statistical differences between SLE patients and controls. Since MTR is located on 1q43, our findings confirm the significance of the role of 1q region and the methyl cycle in etiopathogenesis of SLE.