Yumin Mao

Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: a meta-analysis

AbstractAssociation studies on the MTHFR polymorphisms (C677T and A1298C) in colorectal cancer (CRC) and colorectal adenoma have shown conflicting results. We performed a meta-analysis to better assess the purported associations. Overall, the 677T allele (10,131 patients and 15,362 controls) showed a small but significant protective effect against CRC compared to the 677C allele [P=0.0003, odds ratio (OR)=0.93; 95% confidence interval (CI) 0.89–0.98, P=0.22 (for heterogeneity)] for a worldwide population. Meta-analyses of other genetic contrasts suggested that the 677T allele is more likely to affect CRC in a recessive genetic model worldwide (P<0.0001, OR=0.86; 95% CI 0.76-0.96, P=0.06) and in Asians (P=0.0005, OR=0.75; 95% CI 0.64-0.88, P=0.71). Similarly, we found a significantly decreased risk of CRC for 1298C polymorphism (4,764 CRC patients and 6,592 controls) for a recessive genetic model worldwide (P=0.005, OR=0.81; 95% CI 0.70-0.94, P=0.40) and in Caucasians (P=0.04, OR=0.75 95% CI 0.57-0.99, P=0.35). No evidence of association of C677T (4,616 patients and 6,338 controls) and A1298C (1,272 patients and 1,684 controls) with colorectal adenoma were found. The evidence accumulated suggests that MTHFR may represent a low-penetrance susceptible gene for CRC, and that the two polymorphisms might protect against colorectal adenoma developing into cancer. A larger single study is required to further evaluate gene-gene and gene-environment interactions for MTHFR polymorphisms and the cancer risk in a specific population.

DNA repair gene XRCC3 polymorphisms and cancer risk: a meta-analysis of 48 case-control studies

The X-ray repair cross-complementing group 3 (XRCC3) is a highly suspected candidate gene for cancer susceptibility. However, association studies on the XRCC3 polymorphisms (4541A>G, Thr241Met, 17893A>G) in cancer have shown conflicting results. Therefore, we performed a meta-analysis to better assess the purported associations. Forty eight eligible case–control studies including 24 975 cancer patients and 34 209 controls were selected for our meta-analysis. Overall, individuals carrying the XRCC3 Met/Met genotype showed a small cancer risk under a recessive genetic model. The subgroup and meta-regression analysis demonstrated different scenarios concerning the XRCC3 Met/Met genotypes role in cancer susceptibility for different subgroups. Specially, there was a significantly increased risk of breast cancer (OR, 1.14; P=0.0004; 95% CI, 1.06–1.23; P=0.37 for heterogeneity), elevated but not significant risk of cancer for head and neck, bladder, surprisingly, a significantly decreased risk of non-melanoma skin cancer (OR, 0.76; P=0.007; 95% CI, 0.62–0.93; P=0.61 for heterogeneity). A significantly elevated risk of cancer was observed in population-based case–control studies but not in nested or hospital based studies. Similarly, we found a significantly increased risk of cancer for A4541G and a decreased risk for A17893G under dominant genetic models. Our meta-analysis results support that the XRCC3 might represent a low-penetrance susceptible gene especially for cancer of breast, bladder, head and neck, and non-melanoma skin cancer. A single larger study should be required to further evaluate gene–gene and gene–environment interactions on XRCC3 polymorphisms and tissue-specific cancer risk in an ethnicity specific population.

Discovery and analysis of hepatocellular carcinoma genes using cDNA microarrays.

Abstract Purpose. Microarray analysis on a genomic scale was used to profile changes in gene expression accompanying hepatocellular carcinoma. Methods. Gene expression profiles of liver tissues from twelve hepatocellular carcinoma samples relative to the gene expression profile of the normal liver tissue were analyzed using 4096 chips and 12800 chips. The results of microarray experiments were verified by the Northern blot technique. Results. A group of 1,820 genes with altered expression were identified in more than 50% of the patients examined. This highly concordant expression profile included human genes encoding proteins involved in the function of peroxisomes, serum control, polycyclic aromatic hydrocarbon carcinogenesis, cell growth and differentiation, metastasis, the function of the immune system, apoptosis, and remodeling of the cytoskeleton. Conclusions. The newly identified genes afford a quantitative view of the changes that accompany liver cancer at the genomic level, enable deeper insights into the molecular basis of disease, and provide an extensive list of potential early-onset molecular markers for improved diagnosis.

Methionine synthase A2756G polymorphism and cancer risk: a meta-analysis.

Polymorphisms in methionine synthase (MTR) gene may be involved in carcinogenesis by affecting DNA methylation. However, association studies on MTR A2756G polymorphism in cancers have reported conflicting results. Therefore we performed a meta-analysis to better assess the associations. A total of 24 896 cancer patients and 33 862 controls from 52 articles for MTR A2756G were investigated. Overall, individuals carrying MTR 2756GG genotype had a subtly reduced cancer risk under a recessive genetic model (odds ratio (OR), 0.92; P=0.053; 95% confidence interval (95% CI), 0.84–1.00; I2=0.0%; Pheterogeneity=0.61). In the subgroup analyses by ethnicity, 2756GG was associated with a significantly reduced cancer risk in European populations (OR, 0.83; P=0.001; 95% CI, 0.74–0.93; I2=0.0%; Pheterogeneity=0.99). However, in Asian populations, a significantly elevated association between 2756GG genotype and cancer risk was observed (OR, 1.33; P=0.012; 95% CI, 1.06–1.65; I2=0.0%; Pheterogeneity=0.50). In studies stratified by tumor site, there was a significantly reduced risk of acute lymphoblastic leukemia (ALL) (OR, 0.54; P=0.049; 95% CI, 0.29–1.00; I2=10.7%; Pheterogeneity=0.33) and colorectal cancer (OR, 0.63; P=0.004; 95% CI, 0.47–0.87; I2=0.0%; Pheterogeneity=0.73) in European populations. Our study indicates that MTR A2756G polymorphism is a candidate gene polymorphism for cancer susceptibility regardless of environmental factors. Large-scale, well-designed, and population-based studies are required to further investigate gene–gene and gene–environment interactions on MTR A2756G polymorphism and tissue-specific cancer risk in an ethnicity-specific population.

Polymorphisms of tumor necrosis factor-alpha are associated with increased susceptibility to gastric cancer: a meta-analysis

AbstractWe conducted a meta-analysis to assess the association between tumor necrosis factor-alpha (TNF-alpha) gene TNFA-308 (G > A) and TNFA-857 (C > T) polymorphisms and gastric cancer (GC) susceptibility. We also performed subgroup analyses based on ethnicity (Caucasian, east Asian, and other populations) and tumor location [noncardia gastric cancer (NCGC)]. There were 3,335 GC patients and 5,286 controls for TNFA-308, and 1,118 GC patients and 1,591 controls for TNFA-857 in our analysis. Overall, allele contrast (A vs. G) of TNFA-308 polymorphism produced significant results in worldwide populations [Pheterogeneity = 0.05, random-effects (RE) odds ratio (OR) 1.19; 95% confidence interval (CI) 1.03–1.37, P = 0.02] and Caucasian populations (Pheterogeneity = 0.15, fixed-effects (FE), OR 1.27; 95% CI 1.11–1.45, P = 0.0005). Similar results were also obtained in recessive models and homozygote contrasts. No significant association was observed in NCGC and east Asian subgroup analysis. T variant of TNFA-857 produced significant results only in allele contrast (Pheterogeneity = 0.38, FE OR 1.17; 95% CI 1.01–1.35, P = 0.04). In conclusion, TNFA-308 locus of TNF-alpha would be a risk factor for GC, especially in Caucasian populations. Besides, TNFA-857 locus may be related to GC risk, which demonstrated changeability of results in different contrasts.

Meta-analysis of the association of CTLA-4 exon-1 +49A/G polymorphism with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a highly suspected candidate gene for RA susceptibility. However, association studies on the polymorphism of CTLA-4 exon-1 +49A/G in RA have shown conflicting results. Therefore, we performed a meta-analysis to better assess the purported association. In order to look for ethnic effect, we performed subgroup meta-analysis in populations of European descent and Asian descent. Meta-regression analysis was also performed to explore the possible heterogeneity between the two subgroups. Ten studies (11 comparisons) with the CTLA-4 exon-1 +49A/G genotyping on 2,315 patients with RA and 2,536 controls were selected for our meta-analysis. Overall, the fixed-effects odds ratio (OR) for the G versus A allele was 1.11 (P=0.02, 95% confidence interval (CI) 1.02–1.21), with no between-study heterogeneity. Subgroup and meta-regression analysis according to the ethnicity (European or Asian) demonstrated different scenarios concerning the CTLA-4 exon-1 +49A/G polymorphism’s role in RA susceptibility for the two different subgroups. No effect of G on susceptibility was seen in European descent (five comparisons; OR=1.04, P=0.30, 95% CI 0.95–1.19; no significant between-study heterogeneity). However, there is a significant association in Asian descent under both fixed [OR=1.21, 95% CI (1.06–1.39), P=0.005] and random-effect models [OR=1.19, 95% CI (1.01–1.42), P=0.04]. Meta-regression analysis also supports the heterogeneity between the two subgroups (P=0.082). We also explored the role of this polymorphism on RA risk under other various interested genetic contrasts. These results further support that this polymorphism could not be a risk factor for Europeans. Interestingly, we find that in Asians the G allele has a greater tendency to cause RA in a recessive genetic model. However, sensitivity analysis showed that the combined result of Asian populations was unstable. In conclusion, our meta-analysis results suggest that CTLA-4 exon-1 +49G allele would not be a risk factor for RA in Europeans but might play a role in RA susceptibility for Asians.

A meta-analysis of DNA repair gene XPC polymorphisms and cancer risk

AbstractPolymorphisms (A33512C, C21151T and PAT −/+) of the xeroderma pigmentosum group C (XPC) were shown to contribute to genetic susceptibility to cancer. However, association studies on these polymorphisms in cancer have shown conflicting results. Thus, we performed a meta-analysis. Overall, there was no significant association between 33512C (9,091 patients and 11,553 controls) and cancer risk. No significant association was found in stratification analysis by tumor sites and ethnicities except an elevated lung cancer risk under the recessive genetic model in all subjects [P = 0.04, odds ratio (OR) = 1.20, 95% confidence interval (CI) 1.00–1.45, Pheterogeneity= 0.88]. There was no significant association between 21151T (5,227 patients and 5,959 controls) and cancer risk in all subjects but an increased cancer risk in Caucasians under the recessive genetic model (P = 0.006, OR = 1.45, 95% CI 1.11–1.90, Pheterogeneity = 0.75) and homozygote comparison (P = 0.02, OR = 1.41, 95% CI 1.07–1.81, Pheterogeneity = 0.41). It might be that 21151T increases bladder cancer risk under the recessive genetic model (P = 0.02, OR = 1.49, 95% CI 1.06–2.09, Pheterogeneity = 0.47) and homozygote comparison (P = 0.02, OR = 1.49, 95% CI 1.05–2.11, Pheterogeneity = 0.23). There was no significant association between PAT + (4,600 patients and 4,866 controls) and cancer risk in all subjects. An increased cancer risk in Caucasians was found under the recessive genetic model (P = 0.02, OR = 1.20, 95% CI 1.03–1.40, Pheterogeneity = 0.37) and homozygote comparison (P = 0.008, OR = 1.26, 95% CI 1.06–1.50, Pheterogeneity = 0.13). The XPC PAT + allele might increase head and neck cancer risk (P = 0.02, OR = 1.29, 95% CI 1.04–1.59, Pheterogeneity = 0.15). More studies based on larger, stratified, case–control population, especially studies investigate the combined effect of XPC A33512C, C21151T, and PAT, are required to further evaluate the role of these polymorphisms in different cancers.

Androgen-Responsive Gene Database: Integrated Knowledge on Androgen-Responsive Genes

Androgen signaling plays an important role in many biological processes. Androgen Responsive Gene Database (ARGDB) is devoted to providing integrated knowledge on androgen-controlled genes. Gene records were collected on the basis of PubMed literature collections. More than 6000 abstracts and 950 original publications were manually screened, leading to 1785 human genes, 993 mouse genes, and 583 rat genes finally included in the database. All the collected genes were experimentally proved to be regulated by androgen at the expression level or to contain androgen-responsive regions. For each gene important details of the androgen regulation experiments were collected from references, such as expression change, androgen-responsive sequence, response time, tissue/cell type, experimental method, ligand identity, and androgen amount, which will facilitate further evaluation by researchers. Furthermore, the database was integrated with multiple annotation resources, including National Center for Biotechnology Information, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway, to reveal the biological characteristics and significance of androgen-regulated genes. The ARGDB web site is mainly composed of the Browse, Search, Element Scan, and Submission modules. It is user friendly and freely accessible at http://argdb.fudan.edu.cn. Preliminary analysis of the collected data was performed. Many disease pathways, such as prostate carcinogenesis, were found to be enriched in androgen-regulated genes. The discovered androgen-response motifs were similar to those in previous reports. The analysis results are displayed in the web site. In conclusion, ARGDB provides a unified gateway to storage, retrieval, and update of information on androgen-regulated genes.

Cloning and characterization of a human lysyl oxidase-like 3 gene (hLOXL3)

Using the PCR primers generated from human expressed sequence tag (EST), the cDNA of lysyl oxidase-like gene 3 (LOXL3), a new member of human lysyl oxidases gene family, was cloned from the human fetal brain mRNA. The predicted amino acid sequence of the hLOXL3 gene was highly homologous to mLOR2. Bioinformatics analysis shows that hLOXL3 protein is also a member of the scavenger receptor cysteine-rich family, which contains a 25 amino acids signal peptide. The hLOXL3 gene was mapped to human 2p13 locus by BLAST search and at least 14 exons were found. Expression of the hLOXL3 gene was detected in several human tissues and especially high in spleen and testis.

Molecular cloning and characterization of a novel human cAMP response element-binding (CREB) gene (CREB4)

AbstractCyclic adenosine monophosphate (cAMP) response element-binding (CREB) proteins are a family of mammalian transcription activators. We identified a novel human CREB gene (CREB4) that was 1592bp long and encoded a protein of 395 amino acid residues. The protein shared high homology to mouse CREB3 (identity 62%, similarity 72%). The expression pattern of the human CREB4 gene showed transcripts in prostate, brain, pancreas, skeletal muscle, small intestine, testis, leukocyte, and thymus, whereas in heart, lung, liver, kidney, placenta, spleen, ovary, and colon, specific bands of the transcript could not be detected. The CREB4 gene consisted of ten exons and nine introns and was mapped to chromosome 1q21.3 by means of a bioinformatics analysis.