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PubMed2004

Variants in TNFRSF5 locus and association analysis with Hepatitis B virus (HBV) infection.

Human TNFRSF5, a key signaling molecule expressed by antigen-presenting cells of the immune system, might have associations with autoimmune diseases and various infectious diseases. In the present study, we screened single-nucleotide polymorphisms (SNPs) in TNFRSF5 and examined whether they are risk factors for persistent HBV infection or disease severity. We resequenced all 9 exons, the promoter and splicing regions of all introns for 186 Chinese individuals, and identified 11 SNPs. Haplotypes and their frequencies were estimated. The linkage disequilibrium (LD) pattern was also evaluated. Neutrality tests indicated that the variation pattern at TNFRSF5 locus departs from neutrality and may be maintained by positive selection or demography factors such as population growth. Three SNPs (g.53031T>C, g.54068T>C and g.64493A>G) were determined as haplotype-tag SNPs (htSNPs). Furthermore, computer analyses indicated that sequences surrounding g.53031T>C and g.53824T>C were potential binding sites for transcription factors Sp1 and H4TF-2, respectively. We then genotyped these four SNPs for 603 persistent HBV infection patients and 384 spontaneously recovered subjects by PCR direct sequencing. No statistically significant associations were observed between any of the SNPs or haplotypes and persistent HBV infection or disease severity. The information from this study of the TNFRSF5 would be useful for genetic studies of other common diseases.

Adult↗

PubMed2005

Haplotype structure of TNFRSF5-TNFSF5 (CD40-CD40L) and association analysis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is caused by genetic and environmental factors. The tumour necrosis factor (TNF) superfamily of genes play a central role in immune regulation and have been proposed to be involved in the development of SLE. TNFRSF5 (CD40) falls on 20q11-13, a region linked with SLE in three independent genome-wide studies. TNFSF5 (CD40L) falls on Xq26 and is the ligand for TNFRSF5. Seven single-nucleotide polymorphisms (SNPs) in CD40 and eight SNPs in CD40L were looked at for linkage disequilibrium (LD) and haplotype analysis in European-Caucasians. Limited haplotype diversity was observed across CD40 and CD40L, and >97% of the diversity was captured. We also examined the association of SNPs and haplotypes in CD40 and CD40L with SLE in European-Caucasians. There was no evidence of association for CD40 or CD40L in 408 European-Caucasian families with SLE from UK. Haplotype tagging SNPs (htSNPs) are made known, which will facilitate analysis for susceptibility in other autoimmune diseases and risk for infectious disease.

CD40 Antigens↗

PubMed2004

Algorithms for inferring haplotypes.

Haplotype phase information in diploid organisms provides valuable information on human evolutionary history and may lead to the development of more efficient strategies to identify genetic variants that increase susceptibility to human diseases. Molecular haplotyping methods are labor-intensive, low-throughput, and very costly. Therefore, algorithms based on formal statistical theories were shown to be very effective and cost-efficient for haplotype reconstruction. This review covers 1) population-based haplotype inference methods: Clark's algorithm, expectation-maximization (EM) algorithm, coalescence-based algorithms (pseudo-Gibbs sampler and perfect/imperfect phylogeny), and partition-ligation algorithm implemented by a fully Bayesian model (Haplotyper) or by EM (PLEM); 2) family-based haplotype inference methods; 3) the handling of genotype scoring uncertainties (i.e., genotyping errors and raw two-dimensional genotype scatterplots) in inferring haplotypes; and 4) haplotype inference methods for pooled DNA samples. The advantages and limitations of each algorithm are discussed. By using simulations based on empirical data on the G6PD gene and TNFRSF5 gene, I demonstrate that different algorithms have different degrees of sensitivity to various extents of population diversities and genotyping error rates. Future development of statistical algorithms for addressing haplotype reconstruction will resort more and more to ideas based on combinatorial mathematics, graphical models, and machine learning, and they will have profound impacts on population genetics and genetic epidemiology with the advent of the human HapMap.

Algorithms↗

PubMed2006

Analysis of apoptosis-associated genes and pathways in oral cancer cells.

BACKGROUND: Cancer cells can resist apoptosis that is induced by stimuli such as detachment or differentiation, but may be more susceptible to apoptosis when exposed to chemotherapeutic drugs. The pattern of gene expression that produces this phenotype is unknown. METHODS: We compared gene expression patterns of normal human epidermal keratinocytes (NHEK cells) and the oral cancer cell line Tu183 when the cells were exposed to different apoptosis-inducing stimuli. RESULTS: Pathway analysis revealed that the phenotype difference could be best explained by the simultaneous existence of both proapoptosis and antiapoptosis signals in the cancer cells. Microarray analysis, supported by immunoblotting, showed that one gene that was likely to be involved in the proapoptosis signal was TNFRSF5, which encodes the receptor CD40. When Tu183 cells were exposed to the CD40 ligand they showed apoptosis, while NHEK cells did not. CONCLUSIONS: The effects of different apoptotic stimuli on normal cells and oral cancer cells can be explained by expression of proapoptosis genes, including the gene that encodes CD40.

Apoptosis↗

PubMedDate not supplied

Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines.

Curcumin (diferuloyl methane), the yellow-colored dietary pigment from the rhizomes of turmeric, has been recognized as a chemopreventive agent because of its antitumor, antioxidant and antiproliferative effects. The cytotoxic, apoptotic and gene regulatory effects of both turmeric and curcumin were investigated in the MCF-7 human breast cancer carcinoma cell line and compared with the effects in MCF-10A human mammary epithelial cells. MCF-7 cells were more sensitive to turmeric and curcumin than MCF-10A cells. MCF-10A cells retained comparatively less curcumin in the medium than MCF- 7 cells after 24 h, thereby reducing the cytotoxic effect. Curcumin induced a significantly higher percentage of apoptosis in MCF-7 than MCF-10A cells at all doses. Microarray hybridization of Clonetech apoptotic arrays with labeled first-strand probes of total RNA was performed to identify and characterize the genes regulated by curcumin in tumor cells. Of the 214 apoptosis-associated genes in the array, the expression of 104 genes was altered by curcumin treatment. The gene expression was altered up to 14-fold levels in MCF-7 as compared to only up to 1.5-fold in the MCF-10A cell line by curcumin. Curcumin up-regulated (>3 fold) 22 genes and down-regulated (<3-fold) 17 genes at both 25 microg/ml and 50 microg/ml doses in the MCF-7 cell line. The up-regulated genes include HIAP1, CRAF1, TRAF6, CASP1, CASP2, CASP3, CASP4, HPRT, GADD45, MCL-1, NIP1, BCL2L2, TRAP3, GSTP1, DAXX, PIG11, UBC, PIG3, PCNA, CDC10, JNK1 and RBP2. The down-regulated genes were TRAIL, TNFR, AP13, IGFBP3, SARP3, PKB, IGFBP, CASP7, CASP9, TNFSF6, TRICK2A, CAS, TRAIL-R2, RATS1, hTRIP, TNFb and TNFRSF5. While a dose-dependent gene expression change was noticed in some genes, opposite regulatory effects were induced by different curcumin doses in three apoptotic genes. These results suggest that curcumin induces apoptosis in breast cancer cells by regulation of multiple signaling pathways, indicating its potential use for prevention and treatment of cancer.

Antineoplastic Agents↗

PubMed2025

CD40 transcriptomic expression patterns across malignancies: implications for clinical trials of CD40 agonists.

BACKGROUND: CD40 is a T-cell co-stimulatory receptor targeted by next-generation immunotherapies. We conducted a pan-cancer transcriptome analysis of CD40, its ligand, and related immune markers to evaluate co-expression patterns and clinical outcomes. METHODS: We analyzed transcriptome data for CD40, its ligand, and other common checkpoints and co-stimulators (PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, ICOS, CD27, CD28, OX40, and GITR). RNA expression was classified as high (75-100th percentile), moderate (25-74th), or low (0-24th) against a reference population of 735 previously tested solid tumors. RESULTS: Of 514 patients, 114 (22%) showed high, 247 (48%) moderate, and 153 (30%) low CD40 RNA expression. High CD40 expression was most frequent in liver and bile duct (42%), pancreatic (42%), and ovarian (40%) cancers. Both high CD40 and low-moderate CD40 ligand expression-potentially conducive to CD40 agonist therapy-was most frequent in ovarian (33%) and pancreatic (24%) cancer. In both UCSD (N = 514) and TCGA (N = 10,953) cohorts, high CD40 expression significantly correlated with high CD28 and GITR. High CD40 RNA levels were not prognostic for overall survival (OS) from metastatic disease (P = 0.2) (n = 272 immune checkpoint inhibitor (ICI)-naïve patients). High CD40 expression correlated with longer OS from immunotherapy initiation (n = 217 ICI-treated patients; P = 0.04, univariable analysis), but not multivariable analysis, suggesting it may not be an independent predictive biomarker. CONCLUSION: High CD40 expression correlated with liver and bile duct, pancreatic, and ovarian cancers, as well as with CD28 and GITR transcripts. Immune marker co-expression in individual patients merits further exploration for the development of CD40-based and other immunotherapy interventions.

Humans↗