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  • 1
    Keywords: CELLS ; EXPRESSION ; BLOOD ; CELL ; THERAPY ; POPULATION ; RISK ; GENE ; PROTEIN ; PROTEINS ; MOLECULES ; LIGAND ; RESPONSES ; DNA ; MECHANISM ; DENDRITIC CELLS ; mechanisms ; T-CELLS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; MOLECULE ; LYMPHOMA ; GRAVES-DISEASE ; WOMEN ; case-control studies ; IMMUNE-RESPONSE ; B-CELL LYMPHOMA ; NON-HODGKINS-LYMPHOMA ; case-control study ; SAN-FRANCISCO ; VARIANT ; INCREASE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; non-Hodgkin lymphoma ; dendritic cell ; single-nucleotide polymorphism ; USA ; population-based ; B-CELL ; FRANCISCO BAY AREA ; non Hodgkin lymphoma ; interactions ; NUCLEOTIDE ; SOLUBLE CD40 LIGAND
    Abstract: CD40 and its ligand, CD154, are major costimulatory molecules whose interactions are important in humoral and cellular immunity. We hypothesized that single nucleotide polymorphisms (SNPs) in TNFRSF5 and TNFSF5 encoding the CD40 and CD154 proteins, respectively, influence lymphoma risk, particularly a functional TNFRSF5 SNP (-1C〉T, rs1883832) associated with reduced B-cell CD40 expression. TNFRSF5 and TNFSF5 SNPs were examined in a population-based case-control study of non-Hodgkin lymphoma (376 cases/801 controls with DNA), and compelling findings were followed up in 2 independent populations. Pooled analyses of all 3 case-control studies (total N = 1776 non-Hodgkin lymphoma cases, N = 2482 controls) revealed an increased risk of follicular lymphoma (FL) associated with the TNFRSF5-1TT genotype (odds ratio = 1.6; 95% confidence interval, 1.1-2.4). In addition, among women, an inverse association was found between the variant A allele for a TNFSF5 6809G〉A SNP and FL risk (OR=.61; 95% Cl, 0.36-0.98). In genotype-phenotype studies, significantly reduced circulating soluble CD40 was observed in TNFRSF5-1TT compared with -1CC carriers. Further, dendritic cells from those with -1TT versus -1CC genotypes exhibited lower CD40 cell surface expression. These results suggest that the TNFRSF5 -1C〉T polymorphism may increase FL susceptibility through mechanisms that hinder cellular immune responses. Further studies are needed to explore these findings
    Type of Publication: Journal article published
    PubMed ID: 18287517
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  • 2
    Keywords: RISK ; GENE ; GENES ; ASSOCIATION ; polymorphism ; SUSCEPTIBILITY ; LYMPHOMA ; PROMOTER ; meta-analysis ; FOLLICULAR LYMPHOMA ; SYSTEMIC-LUPUS-ERYTHEMATOSUS ; VARIANT ; RHEUMATOID-ARTHRITIS ; ALLELES ; pooled analysis ; B-CELL ; SUBGROUPS ; INTERLEUKIN-10 ; SUN EXPOSURE ; GENETIC-VARIATION ; non-Hodgkin ; Genetic ; IMMUNE ; single nucleotide ; lymphotoxin-alpha ; tumor necrosis factor-alpha
    Abstract: In an International Lymphoma Epidemiology Consortium pooled analysis, polymorphisms in 2 immune-system-related genes, tumor necrosis factor (TNF) and interleukin-10 (IL10), were associated with non-Hodgkin lymphoma (NHL) risk. Here, 8,847 participants were added to previous data (patients diagnosed from 1989 to 2005 in 14 case-control studies; 7,999 cases, 8,452 controls) for testing of polymorphisms in the TNF -308G 〉 A (rs1800629), lymphotoxin-alpha (LTA) 252A 〉 G (rs909253), IL10 -3575T 〉 A (rs1800890, rs1800896), and nucleotide-binding oligomerization domain containing 2 (NOD2) 3020insC (rs2066847) genes. Odds ratios were estimated for non-Hispanic whites and several ethnic subgroups using 2-sided tests. Consistent with previous findings, odds ratios were increased for "new" participant TNF -308A carriers (NHL: per-allele odds ratio (ORallelic) = 1.10, P-trend = 0.001; diffuse large B-cell lymphoma (DLBCL): ORallelic = 1.23, P-trend = 0.004). In the combined population, odds ratios were increased for TNF -308A carriers (NHL: ORallelic = 1.13, P-trend = 0.0001; DLBCL: ORallelic = 1.25, P-trend = 3.7 x 10(-6); marginal zone lymphoma: ORallelic = 1.35, P-trend = 0.004) and LTA 252G carriers (DLBCL: ORallelic = 1.12, P-trend = 0.006; mycosis fungoides: ORallelic = 1.44, P-trend = 0.015). The LTA 252A 〉 G/TNF -308G 〉 A haplotype containing the LTA/TNF variant alleles was strongly associated with DLBCL (P = 2.9 x 10(-8)). Results suggested associations between IL10 -3575T 〉 A and DLBCL (P-trend = 0.02) and IL10 -1082A 〉 G and mantle cell lymphoma (P-trend = 0.04). These findings strengthen previous results for DLBCL and the LTA 252A 〉 G/TNF -308A locus and provide robust evidence that these TNF/LTA gene variants, or others in linkage disequilibrium, are involved in NHL etiology
    Type of Publication: Journal article published
    PubMed ID: 20047977
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