RESUMO
OBJECTIVE: In the present study, we analyzed the possible association of inflammasome gene variants and expression to rheumatoid arthritis (RA)'s development and severity in the Brazilian population. MATERIALS AND METHODS: Thirteen single nucleotide polymorphisms within six inflammasome genes (NLRP1, NLRP3, NLRC4, AIM2, CARD8, CASP1) as well as IL1B and IL18 genes in two different Brazilian populations (from Northeast and Southeast Brazil) were analyzed. We also evaluated inflammasome gene expression profile in resting and LPS + ATP-treated monocytes from RA patients and healthy individuals. For genetic association study, 218 patients and 307 healthy controls were genotyped. For gene expression study, inflammasome genes mRNA levels of 12 patients and ten healthy individuals were assessed by qPCR. RESULTS: Our results showed that rs10754558 NLRP3 and rs2043211 CARD8 polymorphisms are associated with RA development (p value = 0.044, OR = 1.77, statistical power = 0.999) and severity measured by Health Assessment Questionnaire (HAQ) (p value = 0.03), respectively. Gene expression analyses showed that RA patients display activation of CASP1, IL1B and IL1R genes independently of LPS + ATP activation. In LPS + ATP-treated monocytes, NLRP3 and NLRC4 expressions were also significantly higher in patients compared with controls. CONCLUSIONS: The first reported results in Brazilian populations support the role of inflammasome in the development of RA.
Assuntos
Artrite Reumatoide/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Inflamassomos/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Proteínas Reguladoras de Apoptose/genética , Brasil , Proteínas de Ligação ao Cálcio/genética , Caspase 1/genética , Proteínas de Ligação a DNA/genética , Feminino , Expressão Gênica , Humanos , Interleucina-18/genética , Interleucina-1beta/genética , Masculino , Pessoa de Meia-Idade , Proteínas NLR , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de DoençaRESUMO
This study evaluated the possible association between SNPs in cytokines coding genes, namely IL10, IL6 and IFNG, cytokines serum levels and clinical assessment' scores in patients with Rheumatoid Arthritis(RA). SNPs genotyping was performed in 126 RA patients and 177 healthy individuals with Taqman probes specific for IL10 -1082 (T>C, rs1800896);INFG -1616 (A>G, rs2069705) and IL6 -174 (G>C, rs1800795) variants,positioned in regulatory regions. Cytokine Bead Array (CBA) was used to measure cytokine levels. We found association between INFG -1616 G allele(pâ¯= 0.0210; OR = 1.605) and INFG -1616 GG genotype (pâ¯= 0.0268; OR =2.609) and RA susceptibility. We also observed association between IL10 -1082 TT genotype and high clinical disease activity index (CDAI) values (pâ¯= 0.026; OR = 1.906; 95% CI = 1.082 - 3.359), IL10 -1082 CC genotype and low CDAI values (pâ¯= 0.016; OR = 0.256) and INFG -1616 AA and high CDAI values (pâ¯= 0.025; OR = 2.919). IL10 -1082 CC also exhibited the lowest IL-10 levels than IL10 -1082 TT (pâ¯= 0.020) and IL10 -1082 TC (pâ¯= 0.032). Finally, we verified higher IL-6 value in the RA patients than healthy control group (pâ¯= 0.007) and an association between high IL-6 levels and increased CDAI (r = 0.4648, pâ¯= 0.0015); DAS 28 (r = 0.3933, p= 0.0091), presence of bone erosions (r = 0.3170, pâ¯= 0.0361), ESR levels(r = 0.3041, pâ¯= 0.0448) and IFN-γ levels (r = 0.3049, pâ¯= 0.0468).Altogether, we suggest that IL10 -1082 (T>C, rs1800896) and INFG -1616(A>G, rs2069705) polymorphisms as well as IL-6 levels alterations may play a role for prognostic and disease follow-up.
Assuntos
Artrite Reumatoide/genética , Interferon gama/genética , Interleucina-10/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Feminino , Frequência do Gene , Genótipo , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Studies performed in the past years showed PTNP22 1858 C > T (rs2476601) polymorphism as associated with systemic lupus erythematosus susceptibility, although conflicting findings are still found. In this context, a powerful statistical study, such as meta-analysis, is necessary to establish a consensus. The aim of this study was to evaluate association studies between the PTPN22 1858 C > T polymorphism and SLE by a meta-analysis update, including three recently published studies in the last three years. A total of 3868 SLE patients and 7458 healthy individuals were considered herein, enclosing 19 studies from Asian, American, European and Latin ethnic groups. Odds ratio (OR) was performed for allelic, dominant and recessive genetic models. Statistically significant association was found between the PTPN22 1858 C > T polymorphism and susceptibility to SLE in all inheritance models. Allelic genetic model data (OR = 1.54, 95% confidence interval (CI) = 1.38-1.72, p value=.000) shows that T allele confers increased SLE susceptibility. As well as recessive genetic model (OR = 2.04, 95% CI = 1.09-3.82, p value = .030) for T/T genotype. Instead, dominant genetic model shows that C/C genotype confers lower susceptibility for SLE development (OR = 0.62, 95% CI = 0.54-0.72, p value = .000). In addition, we provided an ethnicity-derived meta-analysis. The results showed association in Caucasian (OR = 1.47, p value = .000) and Latin (OR = 2.41, p value = .000) ethnic groups. However, rs2476601 polymorphism is not associated nor in Asian (OR= 1.31; p value = .54) and African (OR = 2.04; p value=.22) populations. In conclusion, present meta-analysis update confirms that T allele and T/T genotype in PTPN22 1858 C > T polymorphism confers SLE susceptibility, particular in Caucasian and Latin groups, suggesting PTPN22 1858 C > T as a potential genetic marker in SLE susceptibility.