ABSTRACT
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.
Subject(s)
Arthritis, Rheumatoid/genetics , CARD Signaling Adaptor Proteins/genetics , Inflammasomes/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Neoplasm Proteins/genetics , Adaptor Proteins, Signal Transducing/genetics , Adult , Aged , Apoptosis Regulatory Proteins/genetics , Brazil , Calcium-Binding Proteins/genetics , Caspase 1/genetics , DNA-Binding Proteins/genetics , Female , Gene Expression , Humans , Interleukin-18/genetics , Interleukin-1beta/genetics , Male , Middle Aged , NLR Proteins , Polymorphism, Single Nucleotide , Severity of Illness IndexABSTRACT
Systemic lupus erythemathosus (SLE) and rheumatoid arthritis (RA) are complex autoimmune diseases characterized by an immune balance breakdown and by chronic inflammation. Several findings link SLE and RA development with the complement system and ficolin components have emerged as candidates for disease development. Since genetic association studies with ficolin genes in SLE and RA have not yet been conducted in a Brazilian population, the aim of this study was to determine whether polymorphisms of ficolin-1(FCN1) and ficolin-2 (FCN2) genes are associated with SLE and RA susceptibility as well as disease manifestation. Two SNPs within FCN1 (rs2989727 and 1071583) and three in FCN2 (rs17514136, rs3124954, and rs7851696) were studied in 208 SLE and184 RA patients as well as 264 healthy individuals in a Southeast Brazilian population. For SLE patients, the FCN2 rs17514136 SNP was associated with a more severe disease (SLICC) (p = 0.0067). Furthermore, an association between the occurrence of nephritis and the T/T genotype for FCN2 rs3124954 SNP (p = 0.047, OR = 3.17, 95%CI = 1.34-7.5) was observed. No association was observed between the studied polymorphisms and RA development. Thus, our data support involvement of the FCN2 gene in the SLE phenotype.
Subject(s)
Arthritis, Rheumatoid/genetics , Lectins/genetics , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide , Brazil , Case-Control Studies , Genetic Association Studies , Genotype , Humans , Phenotype , FicolinsABSTRACT
Systemic Lupus Erythematosus (SLE) is a multifactorial autoimmune disease affecting different organs or systems. Several genes have been associated with SLE susceptibility so far. A previous study has reported, in SLE patients, a differential expression of Fyn Binding Protein gene (FYB), encoding for a protein participating in the T cells signaling cascade and in the interleukin-2A expression modulation. This study investigates the association of 10 FYB SNPs with differential susceptibility to SLE in 143 SLE patients and 184 controls from Southern Brazil. Significant differences were observed when comparing allele and genotype frequencies distribution in patients and controls: the T allele for rs6863066 C>T SNP and C for rs358501 T>C SNP were significantly more frequent in SLE patients than in controls (p=0.0002 and p=0.008) and associated with an increased risk for SLE (OR=1.93 and OR=1.69). The frequencies of rs6863066 C/T and T/T and rs358501 C/C genotypes were significantly higher in patients than in controls (p=0.001, p=0.006 and p=0.008). A significant association was also found for the rs6863066-rs358501 T-T and T-C haplotypes (OR=2.06, p=0.002 and OR=2.93, p=0.001). When considering clinical and laboratorial manifestations, an association was found between rs2161612 G allele and G/G genotype and hematological alterations (p=0.008) and rs379707 A/C genotype and anti-dsDNA (p=0.01). In conclusion, our findings indicate an association between polymorphisms located in FYB gene and SLE, suggesting their possible involvement in disease susceptibility and clinical manifestations.
