RESUMO
Objectives: The aim of our study was to investigate whether TNFAIP3, PTPN22, and TRAF1-5 single nucleotide polymorphisms (SNPs) are associated with susceptibility, severity, or serological markers in primary Sjögren's syndrome (pSS). Patients and methods: The cases and controls study was conducted between December 2021 and June 2022. TNFAIP3 rs10499194C/T, rs6920220G/A, and rs2230926T/G, PTPN22 rs2476601C/T and rs33996649G/A, and TRAF1-C5 rs10818488G/A polymorphisms were genotyped in 154 female pSS patients (mean age: 45.2±6.8 years) and 313 female control subjects (mean age: 50.3±7.5 years) using the TaqMan® SNP genotyping assay. An association analysis between TNFAIP3, PTPN22, and TRAF1-C5 SNPs and susceptibility, clinical characteristics, and serological markers of pSS was performed. Interactions between TNFAIP3, PTPN22, and TRAF1-C5 SNPs were also evaluated in patients and controls. Results: The genotype and allele frequencies showed no association with susceptibility, severity, or serological markers of pSS. Nevertheless, several interactions between TNFAIP3 and TRAF1-C5 or TNFAIP3, PTPN22, and TRAF1-C5 genotypes were associated with susceptibility to pSS (p<0.01). Conclusion: Individual TNFAIP3, PTPN22, and TRAF1-C5 SNPs are not associated with susceptibility, severity, or serological markers of pSS. However, genetic interactions between TRAF1-C5 and TNFAIP3 or TNFAIP3, PTPN22, and TRAF1-C5 SNPs are risk factors for pSS.
RESUMO
TNFAIP3 is a classical systemic lupus erythematosus (SLE)-associated risk locus identified by genome-wide association studies (GWASs) and replicated by candidate gene association studies primarily in Caucasians and Asians. However, in Latin American populations, its role on SLE susceptibility is not known. We conducted a case-control study to evaluate whether the TNFAIP3 rs2230926T/G (Phe127Cys) variant is associated with risk of developing SLE in a cohort of Mexican patients. The TNFAIP3 rs2230926T/G variant was analyzed in 561 patients with SLE and 499 control subjects, using TaqMan probes. We found that the G allele was associated with susceptibility to SLE under the allelic (OR 2.09, p = 0.005) and genotypic (OR 2.14, p = 0.004) models. In conclusion, our results show that TNFAIP3 rs2230926T/G is a risk factor for the development of SLE in the Mexican population.
Assuntos
Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico , Humanos , Estudos de Casos e Controles , América Latina , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a DNA/genética , Lúpus Eritematoso Sistêmico/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genéticaRESUMO
Rheumatoid arthritis (RA) is a chronic inflammatory disease of autoimmune origin with many associated genetic traits, including genes related to the control of inflammation. The A20 protein, encoded by the TNFAIP3 gene, is a negative regulator of NF-kB mediated inflammation. Several single nucleotide variants (SNVs) of TNFAIP3 are associated with susceptibility to RA in different ethnic groups, none of which has been evaluated in Mexican patients. OBJECTIVE: To examine the possible association of eight TNFAIP3 SNVs in Mexican patients with RA. MATERIALS: We studied 471 patients with RA and 500 controls, as well as eight TNFAIP3 SNVs: including, rs10499194C/T, rs6920220G/A, and rs2230926T/G, which have been associated with RA in European or Asian patients, in addition to rs373421182G/C, rs139054966T/G, rs5029924C/T, rs59693083A/G and rs61593413T/A, not previously examined in RA. All SNVs were evaluated by means of an allelic discrimination assay using TaqMan probes. RESULTS: The allelic and genotypic frequencies of all SNVs examined were similar between cases and controls, and none of them was associated with RA under the allelic, codominant, dominant, and recessive models, as well as in haplotype combinations. CONCLUSION: Our data indicate that TNFAIP3 SNVs evaluated herein are not risk factors for RA in Mexican subjects.
Assuntos
Artrite Reumatoide , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único/genética , Proteínas Nucleares/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Ligação a DNA/genética , Estudos de Casos e Controles , Artrite Reumatoide/genética , Genótipo , Inflamação , Nucleotídeos , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genéticaRESUMO
PURPOSE: To investigate the role and mechanism of TNF-inducible protein 3(TNFAIP3) in breast cancer angiogenesis induced by fibroblast growth factor receptor1 (FGFR1) activation. METHODS: The immunohistochemical assay was used to detect the expression of vascular endothelial cell marker CD31 and CD105 in mice DCIS.COM-iFGFR1 transplanted tumor (previously established by our group). The effects of TNFAIP3 knockout/knockdown breast cancer cell lines on angiogenesis, migration, and invasion of Human Umbilical Vein Endothelial Cells (HUVEC) were detected by the tubulogenesis and Trewells assay. RNA-seq analysis of TNFAIP3 downstreams differential genes after TNFAIP3 knockdown. The expression and secretion of VEGFA after FGFR1 activation in breast cancer cells were detected by qPCR, Western blot, and ELISA. RESULTS: Immunohistochemistry showed that TNFAIP3 knockout inhibited the expression of CD31 and CD105 in DCIS grafted tumors promoted by FGFR1 activation. Tubulogenesis and Trewells experiments showed that TNFAIP3 gene knockout/knockdown inhibited the angiogenesis, migration, and invasion of HUVEC cells promoted by FGFR1 activation. qPCR assay showed that VEGFA mRNA level in the TNFAIP3 knockdown cell line was significantly down-regulated (p < 0.05). qPCR, Western blot and ELISA results showed that TNFAIP3 gene knockout/knockdown could inhibit the expression and secretion of VEGFA in breast cancer cells induced by FGFR1 activation. CONCLUSION: TNFAIP3 promotes breast cancer angiogenesis induced by FGFR1 activation through the expression and secretion of VEGFA.
Assuntos
Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Fatores de Crescimento de Fibroblastos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Camundongos , Neovascularização Patológica , RNA Mensageiro , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Takayasu arteritis (TAK) is considered a rare disease characterized by nonspecific inflammation of the large arteries, especially the aorta and its major branches. Because TAK is an autoimmune disease (AD), it could share susceptibility loci with other pathologies such as systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), among others. Widely explored polymorphisms in non-HLA genes, including TNFAIP3, STAT4, TNFSF4, BANK1, and BLK have been consistently associated with both SLE and RA, but they have not been evaluated in TAK. OBJECTIVE: The aim of our study was to investigate whether TNFAIP3, STAT4, BANK1, BLK, and TNFSF4 polymorphisms are associated with susceptibility to TAK. METHODS: The TNFAIP3 rs2230926T/G and rs5029924C/T, STAT4 rs7574865G/T, BANK1 10516487G/A, BLK rs2736340T/C, rs13277113A/G, and TNFS4 rs2205960G/T polymorphisms were genotyped in 101 cases and 276 controls by using a TaqMan SNP genotyping assay. An association analysis was performed. RESULTS: The TNFAIP3 rs2230926T/G and rs5029924C/T polymorphisms were in complete linkage disequilibrium and turned out to be risk factors for TAK (OR = 4.88, p = 0.0001). The STAT4, BANK1, BLK, and TNFSF4 polymorphisms were not associated with the disease. CONCLUSIONS: This is the first study documenting an association of TNFAIP3 rs2230926T/G and rs5029924C/T with TAK. Our results provide new information on the genetic bases of TAK.
Assuntos
Genótipo , Arterite de Takayasu/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Ligante OX40/genética , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT4/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Quinases da Família src/genéticaRESUMO
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Very few therapeutic options are currently available in this neoplasia. The use of 5-Aza-2'-deoxycytidine (5-AZAdC) was approved for the treatment of myelodysplastic syndromes, and this drug can treat solid tumours at low doses. Epigenetic manipulation of GC cell lines is a useful tool to better understand gene expression regulatory mechanisms for clinical applications. Therefore, we compared the gene expression profile of 5-AZAdC-treated and untreated GC cell lines by a microarray assay. Among the genes identified in this analysis, we selected NRN1 and TNFAIP3 to be evaluated for gene expression by RT-qPCR and DNA methylation by bisulfite DNA next-generation sequencing in 43 and 52 pairs of GC and adjacent non-neoplastic tissue samples, respectively. We identified 83 candidate genes modulated by DNA methylation in GC cell lines. Increased expression of NRN1 and TNFAIP3 was associated with advanced tumours (P < 0.05). We showed that increased NRN1 and TNFAIP3 expression seems to be regulated by DNA demethylation in GC samples: inverse correlations between the mRNA and DNA methylation levels in the promoter of NRN1 (P < 0.05) and the intron of TNFAIP3 (P < 0.05) were detected. Reduced NRN1 promoter methylation was associated with III/IV TNM stage tumours (P = 0.03) and the presence of Helicobacter pylori infection (P = 0.02). The identification of demethylated activated genes in GC may be useful in clinical practice, stratifying patients who are less likely to benefit from 5-AZAdC-based therapies. KEY MESSAGES: Higher expression of NRN1 and TNFAIP3 is associated with advanced gastric cancer (GC). NRN1 promoter hypomethylation contributes to gene upregulation in advanced GC. TNFAIP3 intronic-specific CpG site demethylation contributes to gene upregulation in GC. These findings may be useful to stratify GC patients who are less likely to benefit from DNA demethylating-based therapies.