To analyze the relation of matrix metalloproteinase-2(MMP-2) and Fibronection (FN) mRNA expression with metastasis of breast cancer and elucidate the role of MMP-2 and FN in breast cancer metastasis.Methods The expres...To analyze the relation of matrix metalloproteinase-2(MMP-2) and Fibronection (FN) mRNA expression with metastasis of breast cancer and elucidate the role of MMP-2 and FN in breast cancer metastasis.Methods The expression of MMP-2 and FN mRNA in breast cancer cell lines was detected by fluorescence-quantitative RT-PCR.The expression of MMP-2 and FN protein was detected by Western blots.Results The expression of MMP-2 and FN mRNA was down-regulated in high metastatic cell lines MDA-MB-231,MDA-MB-435,but up-regulated in low metastatic cell lines MDA-453,T47D,SK-BR-3 and non-metastatic cell line MCF-7,ZR-75-30.The protein expression of MMP-2 and FN was up-regulated in high mestastic cell lines,and down-regulated in low metastatic cell lines.Conclusion The mRNA and protein expression of MMP-2 and FN was related with breast cancer metastasis.The mRNA expression of MMP-2 and FN is feed-back regulated with protein expression.6 refs,4 figs,2 tabs.展开更多
Genome-wide association study（GWAS） can be used to identify genes that increase the risk of psychiatric diseases.However,much of the disease heritability is still unexplained,suggesting that there are genes to be di...Genome-wide association study（GWAS） can be used to identify genes that increase the risk of psychiatric diseases.However,much of the disease heritability is still unexplained,suggesting that there are genes to be discovered.Functional annotation of the genetic variants may increase the power of GWAS to identify disease genes,by providing prior information that can be used in Bayesian analysis or in reducing the number of tests.Expression quantitative trait loci（eQTLs） are genomic loci that regulate gene expression.Genetic mapping of eQTLs can help reveal novel functional effects of thousands of single nucleotide polymorphisms（SNPs）.The present review mainly focused on the current knowledge on brain eQTL mapping,and discussed some major methodological issues and their possible solutions.The frequently ignored problems of batch effects,covariates,and multiple testing were emphasized,since they can lead to false positives and false negatives.The future application of eQTL data in GWAS analysis was also discussed.展开更多
[Objective] The paper was to analyze the expression and response mechanism of NCED gene of Zoysia japonica in initial infection stage of Rhizoctonia solani. [Method] The NCED gene fragments of Z. japonica‘Zenith＇wer...[Objective] The paper was to analyze the expression and response mechanism of NCED gene of Zoysia japonica in initial infection stage of Rhizoctonia solani. [Method] The NCED gene fragments of Z. japonica‘Zenith＇were screened and cloned on the basis of transcriptome data. The expression patterns of NCED gene in initial infection stage of R. solani（ 0-48 h） were obtained via real-time quantitative PCR. [Result] The expression level of NCED gene in stress treatment was higher than that without infection,which first increased then decreased with the extension of time,and reached the maximum at 36 h. Further detection of ABA level in‘Zenith＇roots showed that the change trend of ABA level within 0-48 h was consistent with the expression pattern of NCED gene,and flattened out after 48 h. [Conclusion] NCED gene regulates the synthesis of phytohormone ABA and probably further involves in plant disease resistance.展开更多
Objective To evaluate the relationship of E cadherin (E CD) expression to cellular DNA content and biological behavior of gastric cancer. Methods E CD expression and cellular DNA content were quantitatively measure...Objective To evaluate the relationship of E cadherin (E CD) expression to cellular DNA content and biological behavior of gastric cancer. Methods E CD expression and cellular DNA content were quantitatively measured by flow cytometry and immunofluorescence methods in 80 cases of formalinfixed, paraffin embedded gastric cancer. Systematic pathological examinations and follow up were performed for all cases. Results E CD expression was significantly reduced in all cases of gastric cancer. Fluorescence Index (FI) of E CD expression was 0.67±0.11 in gastric cancer, 1.0±0.07 in normal gastric mucosa ( P <0.001). The reduction of E CD expression was also found in 2 cases of early gastric cancer. Tumors with a decrease in E CD expression occurred significantly more frequently in undifferentiated, diffuse growth pattern Borrmann 4 type, positive lymph node (LN) metastasis and infiltrated serosa type gastric cancer, of which survival time was within 5 years ( P <0.001). E CD expression was also reduced in gastric cancer with the number of LN metastasis above 5, metastasis to more than group 2. E CD expression was lower in uneuploid cancer than that in diploid cancer ( P <0.01). The value of DI and PI with negative E CD expression was significantly higher than that of positive E CD expression ( P <0.01). Conclusion Down regulation of E CD expression correlates with bad biological behavior and poor prognosis of gastric cancer. The reduction of E CD expression may take place during early time of gastric cancer. Quantitative analysis of E CD expression may have some value in evaluating the intensity of LN metastasis of gastric cancer.展开更多
Epigenetic changes are potentially important for the ontogeny and progression of tumors but are not usually studied because of the complexity of analyzing transcript regulation resulting from epigenetic alterations.Pr...Epigenetic changes are potentially important for the ontogeny and progression of tumors but are not usually studied because of the complexity of analyzing transcript regulation resulting from epigenetic alterations.Prostate cancer(PCa)is characterized by variable clinical manifestations and frequently unpredictable outcomes.We performed an expression quantitative trait loci(eQTL)analysis to identify the genomic regions that regulate gene expression in PCa and identified a relationship between DNA methylation and clinical information.Using multi-level information published in The Cancer Genome Atlas,we performed eQTL-based analyses on DNA methylation and gene expression.To better interpret these data,we correlated loci and clinical indexes to identify the important loci for both PCa development and progression.Our data demonstrated that although only a small proportion of genes are regulated via DNA methylation in PCa,these genes are enriched in important cancer-related groups.In addition,single nucleotide polymorphism analysis identified the locations of CpG sites and genes within at-risk loci,including the 19q13.2-q13.43 and 16q22.2-q23.1 loci.Further,an epigenetic association study of clinical indexes detected risk loci and pyrosequencing for site validation.Although DNA methylation-regulated genes across PCa samples are a small proportion,the associated genes play important roles in PCa carcinogenesis.展开更多
Objective N6-methyladenosine(m^(6)A)is a common epigenetic modification in eukaryotes.In this study,we explore the potential impact of m^(6)A-associated single nucleotide polymorphisms(m^(6)A-SNPs)on heart failure(HF)...Objective N6-methyladenosine(m^(6)A)is a common epigenetic modification in eukaryotes.In this study,we explore the potential impact of m^(6)A-associated single nucleotide polymorphisms(m^(6)A-SNPs)on heart failure(HF).Methods Data from genome-wide association studies(GWAS)investigating HF in humans and from m^(6)A-SNPs datasets were used to identify HF-associated m^(6)A-SNPs.Their functions were explored using expression quantitative trait locus(eQTL),gene expression,and gene enrichment analyses.Mediation protein quantitative trait locus(pQTL)-Mendelian randomization(MR)was used to investigate the potential mechanism between critical protein levels and risk factors for HF.Results We screened 44 HF-associated m^(6)A-SNPs,including 10 m^(6)A-SNPs that showed eQTL signals and differential expressions in HF.The SNP rs1801270 in CDKN1A showed the strongest association with HF(P=7.75×10^(−6)).Additionally,MR verified the genetic association between the CDKN1A protein and HF,as well as the mediating effect of blood pressure(BP)in this pathway.Higher circulating level of CDKN1A was associated with a lower risk of HF(odds ratio[OR]=0.82,95%confidence interval[CI]:0.69 to 0.99).The proportions of hypertension,systolic BP,and diastolic BP were 48.10%,28.94%,and 18.02%,respectively.Associations of PDIA6(P=1.30×10^(−2))and SMAD3(P=4.80×10^(−2))with HF were also detected.Conclusion Multiple HF-related m^(6)A-SNPs were identified in this study.Genetic associations of CDKN1A and other proteins with HF and its risk factors were demonstrated,providing new ideas for further exploration of the molecular mechanisms of HF.展开更多
Alzheimer's disease(AD)is affected by genetic factors.Polymorphisms in the glutathione S-transfe rase omega-1(Gsto1)gene have been shown by genetic correlation analyses performed in different ethnic populations to...Alzheimer's disease(AD)is affected by genetic factors.Polymorphisms in the glutathione S-transfe rase omega-1(Gsto1)gene have been shown by genetic correlation analyses performed in different ethnic populations to be genetic risk factors for AD.Gene expression profile data from BXD recombinant inbred mice were used in combination with genetic and bioinformatic analyses to chara cterize the mechanisms underlying regulation of Gstol variation regulation and to identify network membe rs that may contribute to AD risk or progression.Allele-specific assays confirmed that variation in Gstol expression is controlled by cis-expression quantitative trait loci.We found that Gstol mRNA levels were related to several central nervous system traits,such as glial acidic fibrillary protein levels in the caudate putamen,co rtical gray matter volume,and hippocampus mossy fiber pathway volume.We identified 2168 genes whose expression was highly correlated with that of Gsto1.Some genes were enriched for the most common neurodegenerative diseases.Some Gsto1-related genes identified in this study had previously been identified as susceptibility genes for AD,such as APP,Grin2 b,Ide,and Psenen.To evaluate the relationships between Gstol and candidate network members,we transfected astrocytes with Gstol siRNA and assessed the effect on putative downstream effecto rs.We confirmed that knockdown of Gstol had a significant influence on Pa2g4 expression,suggesting that Pa2g4 may be a downstream effector of Gstol,and that both genes intera ct with other genes in a network during AD pathogenesis.展开更多
Quantitative analysis of P53 protein expression was performed on paraffin-embedded tissues from 55 smooth muscle tumors of the gastrointestinal tract, using immunofluo-rescence and flow cytometry. No positive expressi...Quantitative analysis of P53 protein expression was performed on paraffin-embedded tissues from 55 smooth muscle tumors of the gastrointestinal tract, using immunofluo-rescence and flow cytometry. No positive expression was found in normal smooth muscle tissues of the gastrointestinal tract. Over-expression of P53 gene was found in a significantly higher proportion in leiomyosarcomas (90%) and potentially malignant smooth muscle tumors (75%) as compared to leiomyomas (14%) (P< 0.005). The quantitation of P53 expression was found to be progressively enhanced in the sequence from leiomyoma through potentially malignant smooth muscle tumor to leiomyosarcoma (P< 0.005). It was markedly over-expressed when the mitotic counts ranged from one to more than one per 10 high power fields (P< 0.005) or the mild cytologic atypia was found (P< 0.005). The five-year survival rate was significantly higher in patients with low-expression of P53 than in those with over-expression of P53 (P< 0.005). It was suggested that P53 over-expression might be associated with the transformation of leiomyoma into leiomyosarcoma and could be used as an objective parameter in distinguishing the malignant from the benign and predicting the prognosis of patients with smooth muscle rumors of the gastrointestinal tract.展开更多
1 Introduction Advances in human genetics have facilitated the investigation of the genetic architecture underlying numerous complex traits.In particular,studies of quantitative expression trait loci(eQTL)have played ...1 Introduction Advances in human genetics have facilitated the investigation of the genetic architecture underlying numerous complex traits.In particular,studies of quantitative expression trait loci(eQTL)have played a pivotal role in elucidating how genetic variants influence gene expression across cell types.This progress has enabled the quantification of effect size for disease genetic risk loci and the construction of binary relational datasets linking diseases to their respective disease genes,such as Fantom5[1]and DisGeNET[2].展开更多
Gene expression regulation plays an important role in controlling plant phenotypes and adaptation. Here, we report a comprehensive assessment of gene expression variation through the transcriptome analyses of a large ...Gene expression regulation plays an important role in controlling plant phenotypes and adaptation. Here, we report a comprehensive assessment of gene expression variation through the transcriptome analyses of a large maize-teosinte experimental population. Genome-wide mapping identified 25 660 expression quantitative trait loci （eQTL） for 17 311 genes, capturing an unprecedented range of expression variation. We found that local eQTL were more frequently mapped to adjacent genes, displaying a mode of expression piggybacking, which consequently created co-regulated gene clusters. Genes within the co-regulated gene clusters tend to have relevant functions and shared chromatin modifications. Distant eQTL formed 125 significant distant eQTL hotspots with their targets significantly enriched in specific functional cate- gories. By integrating different sources of information, we identified putative trans- regulators for a variety of metabolic pathways. We demonstrated that the bHLH transcription factor R1 and hexokinase HEX9 might act as crucial regulators for flavonoid biosynthesis and glycolysis, respectively. Moreover, we showed that domestication or improvement has significantly affected global gene expression, with many genes targeted by selection. Of particular interest, the Bx genes for benzoxazinoid biosynthesis may have undergone coordinated cis-regulatory divergence between maize and teosinte, and a transposon insertion that inactivates Bx12 was under strong selection as maize spread into temperate environments with a distinct herbivore community.展开更多
Neuropsychiatric disorders affect hundreds of millions of patients and families worldwide.To decode the molecular framework of these diseases,many studies use human postmortem brain samples.These studies reveal brain-...Neuropsychiatric disorders affect hundreds of millions of patients and families worldwide.To decode the molecular framework of these diseases,many studies use human postmortem brain samples.These studies reveal brain-specific genetic and epigenetic patterns via highthroughput sequencing technologies.Identifying best practices for the collection of postmortem brain samples,analyzing such large amounts of sequencing data,and interpreting these results are critical to advance neuropsychiatry.We provide an overview of human brain banks worldwide,including progress in China,highlighting some well-known projects using human postmortem brain samples to understand molecular regulation in both normal brains and those with neuropsychiatric disorders.Finally,we discuss future research strategies,as well as state-of-the-art statistical and experimental methods that are drawn upon brain bank resources to improve our understanding of the agents of neuropsychiatric disorders.展开更多
Genome-wide association studies(GWAS)have identified thousands of genomic loci associated with complex diseases and traits,including cancer.The vast majority of common traitassociated variants identified via GWAS fall...Genome-wide association studies(GWAS)have identified thousands of genomic loci associated with complex diseases and traits,including cancer.The vast majority of common traitassociated variants identified via GWAS fall in non-coding regions of the genome,posing a challenge in elucidating the causal variants,genes,and mechanisms involved.Expression quantitative trait locus(eQTL)and other molecular QTL studies have been valuable resources in identifying candidate causal genes from GWAS loci through statistical colocalization methods.While QTL colocalization is becoming a standard analysis in post-GWAS investigation,an easy web tool for users to perform formal colocalization analyses with either user-provided or public GWAS and eQTL datasets has been lacking.Here,we present ezQTL,a web-based bioinformatic application to interactively visualize and analyze genetic association data such as GWAS loci and molecular QTLs under different linkage disequilibrium(LD)patterns(1000 Genomes Project,UK Biobank,or user-provided data).This application allows users to perform data quality control for variants matched between different datasets,LD visualization,and two-trait colocalization analyses using two state-of-the-art methodologies(eCAVIAR and HyPrColoc),including batch processing.ezQTL is a free and publicly available cross-platform web tool,which can be accessed online at https://analysistools.cancer.gov/ezqtl.展开更多
Background and aim:A genome-wide association study has indicated the association of numerous genes in the 6p21.3 region with chronic hepatitis B virus(HBV)infection.In this study,we screened 12 representative single-n...Background and aim:A genome-wide association study has indicated the association of numerous genes in the 6p21.3 region with chronic hepatitis B virus(HBV)infection.In this study,we screened 12 representative single-nucleotide polymorphisms(SNPs)from the 6p21.3 region and investigated their association with the risk of chronic hepatitis B(CHB)to better understand the molecular etiology un-derlying CHB risk in the Han Chinese population.Methods:Between March 2021 and November 2022,we included 183 patients with CHB(case group)and 196 with natural HBV clearance(control group).Allele typing of the selected SNPs was performed using snapshot technology.The correlation between the 12 chosen SNPs and the risk of chronic HBV infection was examined using binary logistic regression analysis.Interacting genes of the variants were identified,and expression quantitative trait loci(eQTL)were analyzed using the 3DSNP database.Results:We validated 12 previously reported CHB susceptibility sites,including rs1419881 of tran-scription factor 19(TCF19),rs3130542 and rs2853953 of human leukocyte antigen(HLA)-C,rs652888 of euchromatic histone-lysine-methyltransferase 2(EHMT2),rs2856718,rs9276370,rs7756516,and rs7453920 of HLA-DQ,rs378352 of HLA-DOA,and rs3077,rs9277535,and rs9366816 of HLA-DP.Logistic regression analyses revealed that polymorphisms such as rs9276370,rs7756516,rs7453920,rs3077,rs9277535,and rs9366816 were positively correlated with natural HBV clearance in the dominant model.Conversely,rs3130542 and rs378352 were identified as risk factors for CHB.Haplotype analysis revealed that rs9276370,rs7756516,and rs7453920 in HLA-DQ were TTG and GCA haplotypes.Although the TTG haplotype was positively correlated with a higher risk of CHB,the GCA haplotype significantly influenced the natural clearance of HBV.Bioinformatics analysis demonstrated that rs378352,rs3077,and rs9366816 were located within enhancer states;rs3077 and rs9366816 overlapped with nine tran-scription factor-binding sites,whereas rs378352 altered five sequence motifs.Furthermore,eQTL analysis demonstrated the functional tendencies of eight statistically significant SNPs(rs3130542,rs9276370,rs7756516,rs7453920,rs378352,rs3077,rs9277535,and rs9366816).Conclusions:Genetic variations within the 6p21.3 region were associated with chronic HBV infection in the Han Chinese population in southern China.Furthermore,the GCA haplotype including rs9276370,rs7756516,and rs7453920 of HLA-DQ contributed significantly to natural HBV clearance,implying that multiple SNPs exert a cumulative allelic effect on HBV infection.展开更多
Alternative splicing exists in most multi-exonic genes,and exploring these complex alternative splicing events and their resultant isoform expressions is essential.However,it has become conventional that RNA sequencin...Alternative splicing exists in most multi-exonic genes,and exploring these complex alternative splicing events and their resultant isoform expressions is essential.However,it has become conventional that RNA sequencing results have often been summarized into gene-level expression counts mainly due to the multiple ambiguous mapping of reads at highly similar regions.Transcript-level quantification and interpretation are often overlooked,and biological interpretations are often deduced based on combined transcript information at the gene level.Here,for the most variable tissue of alternative splicing,the brain,we estimate isoform expressions in 1,191 samples collected by the Genotype-Tissue Expression(GTEx)Consortium using a powerful method that we previously developed.We perform genome-wide association scans on the isoform ratios per gene and identify isoform-ratio quantitative trait loci(irQTL),which could not be detected by studying gene-level expressions alone.By analyzing the genetic architecture of the irQTL,we show that isoform ratios regulate edu-cational attainment via multiple tissues including the frontal cortex(BA9),cortex,cervical spinal cord,and hippocampus.These tissues are also associated with different neuro-related traits,including Alzheimer’s or dementia,mood swings,sleep duration,alcohol intake,intelligence,anxiety or depression,etc.Mendelian randomization(MR)analysis revealed 1,139 pairs of isoforms and neuro-related traits with plausible causal relationships,showing much stronger causal effects than on general diseases measured in the UK Biobank(UKB).Our results highlight essential transcript-level biomarkers in the human brain for neuro-related complex traits and diseases,which could be missed by merely investigating overall gene expressions.展开更多
Gene expression is a critical process in biological system that is influenced and modulated by many factors including genetic variation. Expression Quantitative Trait Loci（e QTL） analysis provides a powerful way to ...Gene expression is a critical process in biological system that is influenced and modulated by many factors including genetic variation. Expression Quantitative Trait Loci（e QTL） analysis provides a powerful way to understand how genetic variants affect gene expression. For genome wide e QTL analysis, the number of genetic variants and that of genes are large and thus the search space is tremendous. Therefore, e QTL analysis brings about computational and statistical challenges. In this paper, we provide a comprehensive review of recent advances in methods for e QTL analysis in population-based studies. We first present traditional pairwise association methods, which are widely used in human genetics. To account for expression heterogeneity, we investigate the methods for correcting confounding factors. Next, we discuss newly developed statistical learning methods including Lasso-based models. In the conclusion, we provide an overview of future method development in analyzing e QTL associations. Although we focus on human genetics in this review, the methods are applicable to many other organisms.展开更多
Background:Rheumatoid arthritis(RA)is a globally prevalent condition that has a significant impact on morbidity and mortality rates.As a result,there is growing interest in understanding its pathogenetic mechanisms,pa...Background:Rheumatoid arthritis(RA)is a globally prevalent condition that has a significant impact on morbidity and mortality rates.As a result,there is growing interest in understanding its pathogenetic mechanisms,particularly genetic susceptibility.To explore the potential genes that may cause RA,we conducted a comprehensive Mendelian randomization analysis and colocalization based on data from large sample size genome-wide association studies.Methods:We used two transcriptome datasets to identify expression quantitative trait loci as the exposure and employed genome-wide association studies data from the FinnGen study as the outcome.We then performed colocalization analysis to confirm that the expression quantitative trait loci and RA share causal genetic variants.Furthermore,we implemented a phenomewide scan to identify other clinical phenotypes associated with significant causal genes.Results:At a Bonferroni significance level of p<2.70×10^(−6),the Mendelian randomization analysis revealed that 20 genes increased the risk of RA,while 16 genes showed a marginally protective effect.Co-localization analyses indicated that AP4B1,GGA2,KEAP1,PTPN22,REG4,and TRAV38-2DV8 were associated with the risk of RA.The phenome-wide scan demonstrated shared genetic determinants between RA and other immune-mediated disorders,including autoimmune thyroid disease,diabetes mellitus,cardiovascular disorders,inflammatory bowel disease,and malignant tumors.Conclusions:Our study identified six risk genes(AP4B1,GGA2,KEAP1,PTPN22,REG4,and TRAV38-2DV8)that may have a causal role in RA.These findings provide novel therapeutic targets for the treatment of RA.Further exploration is required to elucidate the underlying biological mechanisms.展开更多
文摘To analyze the relation of matrix metalloproteinase-2(MMP-2) and Fibronection (FN) mRNA expression with metastasis of breast cancer and elucidate the role of MMP-2 and FN in breast cancer metastasis.Methods The expression of MMP-2 and FN mRNA in breast cancer cell lines was detected by fluorescence-quantitative RT-PCR.The expression of MMP-2 and FN protein was detected by Western blots.Results The expression of MMP-2 and FN mRNA was down-regulated in high metastatic cell lines MDA-MB-231,MDA-MB-435,but up-regulated in low metastatic cell lines MDA-453,T47D,SK-BR-3 and non-metastatic cell line MCF-7,ZR-75-30.The protein expression of MMP-2 and FN was up-regulated in high mestastic cell lines,and down-regulated in low metastatic cell lines.Conclusion The mRNA and protein expression of MMP-2 and FN was related with breast cancer metastasis.The mRNA expression of MMP-2 and FN is feed-back regulated with protein expression.6 refs,4 figs,2 tabs.
文摘Genome-wide association study（GWAS） can be used to identify genes that increase the risk of psychiatric diseases.However,much of the disease heritability is still unexplained,suggesting that there are genes to be discovered.Functional annotation of the genetic variants may increase the power of GWAS to identify disease genes,by providing prior information that can be used in Bayesian analysis or in reducing the number of tests.Expression quantitative trait loci（eQTLs） are genomic loci that regulate gene expression.Genetic mapping of eQTLs can help reveal novel functional effects of thousands of single nucleotide polymorphisms（SNPs）.The present review mainly focused on the current knowledge on brain eQTL mapping,and discussed some major methodological issues and their possible solutions.The frequently ignored problems of batch effects,covariates,and multiple testing were emphasized,since they can lead to false positives and false negatives.The future application of eQTL data in GWAS analysis was also discussed.
基金Supported by National High Technology Research and Development Program("863"Program) of China(2013AA102607)
文摘[Objective] The paper was to analyze the expression and response mechanism of NCED gene of Zoysia japonica in initial infection stage of Rhizoctonia solani. [Method] The NCED gene fragments of Z. japonica‘Zenith＇were screened and cloned on the basis of transcriptome data. The expression patterns of NCED gene in initial infection stage of R. solani（ 0-48 h） were obtained via real-time quantitative PCR. [Result] The expression level of NCED gene in stress treatment was higher than that without infection,which first increased then decreased with the extension of time,and reached the maximum at 36 h. Further detection of ABA level in‘Zenith＇roots showed that the change trend of ABA level within 0-48 h was consistent with the expression pattern of NCED gene,and flattened out after 48 h. [Conclusion] NCED gene regulates the synthesis of phytohormone ABA and probably further involves in plant disease resistance.
文摘Objective To evaluate the relationship of E cadherin (E CD) expression to cellular DNA content and biological behavior of gastric cancer. Methods E CD expression and cellular DNA content were quantitatively measured by flow cytometry and immunofluorescence methods in 80 cases of formalinfixed, paraffin embedded gastric cancer. Systematic pathological examinations and follow up were performed for all cases. Results E CD expression was significantly reduced in all cases of gastric cancer. Fluorescence Index (FI) of E CD expression was 0.67±0.11 in gastric cancer, 1.0±0.07 in normal gastric mucosa ( P <0.001). The reduction of E CD expression was also found in 2 cases of early gastric cancer. Tumors with a decrease in E CD expression occurred significantly more frequently in undifferentiated, diffuse growth pattern Borrmann 4 type, positive lymph node (LN) metastasis and infiltrated serosa type gastric cancer, of which survival time was within 5 years ( P <0.001). E CD expression was also reduced in gastric cancer with the number of LN metastasis above 5, metastasis to more than group 2. E CD expression was lower in uneuploid cancer than that in diploid cancer ( P <0.01). The value of DI and PI with negative E CD expression was significantly higher than that of positive E CD expression ( P <0.01). Conclusion Down regulation of E CD expression correlates with bad biological behavior and poor prognosis of gastric cancer. The reduction of E CD expression may take place during early time of gastric cancer. Quantitative analysis of E CD expression may have some value in evaluating the intensity of LN metastasis of gastric cancer.
基金the Projects of National Science Foundation of China(No.81070600 and 81570684)Projects of the Shanghai Committee of Science and Technology,China(No.14430720800,134119a0600,and 11ZR1424100).
文摘Epigenetic changes are potentially important for the ontogeny and progression of tumors but are not usually studied because of the complexity of analyzing transcript regulation resulting from epigenetic alterations.Prostate cancer(PCa)is characterized by variable clinical manifestations and frequently unpredictable outcomes.We performed an expression quantitative trait loci(eQTL)analysis to identify the genomic regions that regulate gene expression in PCa and identified a relationship between DNA methylation and clinical information.Using multi-level information published in The Cancer Genome Atlas,we performed eQTL-based analyses on DNA methylation and gene expression.To better interpret these data,we correlated loci and clinical indexes to identify the important loci for both PCa development and progression.Our data demonstrated that although only a small proportion of genes are regulated via DNA methylation in PCa,these genes are enriched in important cancer-related groups.In addition,single nucleotide polymorphism analysis identified the locations of CpG sites and genes within at-risk loci,including the 19q13.2-q13.43 and 16q22.2-q23.1 loci.Further,an epigenetic association study of clinical indexes detected risk loci and pyrosequencing for site validation.Although DNA methylation-regulated genes across PCa samples are a small proportion,the associated genes play important roles in PCa carcinogenesis.
基金supported by the National Natural Science Foundation of China[82070473,82170480,82030102]Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences[2021-I2M-1-010].
文摘Objective N6-methyladenosine(m^(6)A)is a common epigenetic modification in eukaryotes.In this study,we explore the potential impact of m^(6)A-associated single nucleotide polymorphisms(m^(6)A-SNPs)on heart failure(HF).Methods Data from genome-wide association studies(GWAS)investigating HF in humans and from m^(6)A-SNPs datasets were used to identify HF-associated m^(6)A-SNPs.Their functions were explored using expression quantitative trait locus(eQTL),gene expression,and gene enrichment analyses.Mediation protein quantitative trait locus(pQTL)-Mendelian randomization(MR)was used to investigate the potential mechanism between critical protein levels and risk factors for HF.Results We screened 44 HF-associated m^(6)A-SNPs,including 10 m^(6)A-SNPs that showed eQTL signals and differential expressions in HF.The SNP rs1801270 in CDKN1A showed the strongest association with HF(P=7.75×10^(−6)).Additionally,MR verified the genetic association between the CDKN1A protein and HF,as well as the mediating effect of blood pressure(BP)in this pathway.Higher circulating level of CDKN1A was associated with a lower risk of HF(odds ratio[OR]=0.82,95%confidence interval[CI]:0.69 to 0.99).The proportions of hypertension,systolic BP,and diastolic BP were 48.10%,28.94%,and 18.02%,respectively.Associations of PDIA6(P=1.30×10^(−2))and SMAD3(P=4.80×10^(−2))with HF were also detected.Conclusion Multiple HF-related m^(6)A-SNPs were identified in this study.Genetic associations of CDKN1A and other proteins with HF and its risk factors were demonstrated,providing new ideas for further exploration of the molecular mechanisms of HF.
基金the Natural Science Foundation of China,Nos.81200828(to YC),32070998(to GC)the Key Research and Development Program(Social Development)of Jiangsu Province,No.BE2020667(to GC)+1 种基金the Foundation of Jiangsu Province"333 Project High-level Talents",No.BRA2020076(to GC)the Priority Academic Program Development of Jiangsu Higher Education Institutes(PAPD)。
文摘Alzheimer's disease(AD)is affected by genetic factors.Polymorphisms in the glutathione S-transfe rase omega-1(Gsto1)gene have been shown by genetic correlation analyses performed in different ethnic populations to be genetic risk factors for AD.Gene expression profile data from BXD recombinant inbred mice were used in combination with genetic and bioinformatic analyses to chara cterize the mechanisms underlying regulation of Gstol variation regulation and to identify network membe rs that may contribute to AD risk or progression.Allele-specific assays confirmed that variation in Gstol expression is controlled by cis-expression quantitative trait loci.We found that Gstol mRNA levels were related to several central nervous system traits,such as glial acidic fibrillary protein levels in the caudate putamen,co rtical gray matter volume,and hippocampus mossy fiber pathway volume.We identified 2168 genes whose expression was highly correlated with that of Gsto1.Some genes were enriched for the most common neurodegenerative diseases.Some Gsto1-related genes identified in this study had previously been identified as susceptibility genes for AD,such as APP,Grin2 b,Ide,and Psenen.To evaluate the relationships between Gstol and candidate network members,we transfected astrocytes with Gstol siRNA and assessed the effect on putative downstream effecto rs.We confirmed that knockdown of Gstol had a significant influence on Pa2g4 expression,suggesting that Pa2g4 may be a downstream effector of Gstol,and that both genes intera ct with other genes in a network during AD pathogenesis.
文摘Quantitative analysis of P53 protein expression was performed on paraffin-embedded tissues from 55 smooth muscle tumors of the gastrointestinal tract, using immunofluo-rescence and flow cytometry. No positive expression was found in normal smooth muscle tissues of the gastrointestinal tract. Over-expression of P53 gene was found in a significantly higher proportion in leiomyosarcomas (90%) and potentially malignant smooth muscle tumors (75%) as compared to leiomyomas (14%) (P< 0.005). The quantitation of P53 expression was found to be progressively enhanced in the sequence from leiomyoma through potentially malignant smooth muscle tumor to leiomyosarcoma (P< 0.005). It was markedly over-expressed when the mitotic counts ranged from one to more than one per 10 high power fields (P< 0.005) or the mild cytologic atypia was found (P< 0.005). The five-year survival rate was significantly higher in patients with low-expression of P53 than in those with over-expression of P53 (P< 0.005). It was suggested that P53 over-expression might be associated with the transformation of leiomyoma into leiomyosarcoma and could be used as an objective parameter in distinguishing the malignant from the benign and predicting the prognosis of patients with smooth muscle rumors of the gastrointestinal tract.
基金supported by the National Natural Science Foundation of China(Grant Nos.62172318,62372349,62132015).
文摘1 Introduction Advances in human genetics have facilitated the investigation of the genetic architecture underlying numerous complex traits.In particular,studies of quantitative expression trait loci(eQTL)have played a pivotal role in elucidating how genetic variants influence gene expression across cell types.This progress has enabled the quantification of effect size for disease genetic risk loci and the construction of binary relational datasets linking diseases to their respective disease genes,such as Fantom5[1]and DisGeNET[2].
文摘Gene expression regulation plays an important role in controlling plant phenotypes and adaptation. Here, we report a comprehensive assessment of gene expression variation through the transcriptome analyses of a large maize-teosinte experimental population. Genome-wide mapping identified 25 660 expression quantitative trait loci （eQTL） for 17 311 genes, capturing an unprecedented range of expression variation. We found that local eQTL were more frequently mapped to adjacent genes, displaying a mode of expression piggybacking, which consequently created co-regulated gene clusters. Genes within the co-regulated gene clusters tend to have relevant functions and shared chromatin modifications. Distant eQTL formed 125 significant distant eQTL hotspots with their targets significantly enriched in specific functional cate- gories. By integrating different sources of information, we identified putative trans- regulators for a variety of metabolic pathways. We demonstrated that the bHLH transcription factor R1 and hexokinase HEX9 might act as crucial regulators for flavonoid biosynthesis and glycolysis, respectively. Moreover, we showed that domestication or improvement has significantly affected global gene expression, with many genes targeted by selection. Of particular interest, the Bx genes for benzoxazinoid biosynthesis may have undergone coordinated cis-regulatory divergence between maize and teosinte, and a transposon insertion that inactivates Bx12 was under strong selection as maize spread into temperate environments with a distinct herbivore community.
基金supported by the National Natural Science Foundation of China(Grant Nos.31571312,31970572,and81401114)the National Key R&D Project of China(Grant No.2016YFC1306000)Innovation-driven Project of Central South University(Grant Nos.2015CXS034 and 2018CX033)to CC
文摘Neuropsychiatric disorders affect hundreds of millions of patients and families worldwide.To decode the molecular framework of these diseases,many studies use human postmortem brain samples.These studies reveal brain-specific genetic and epigenetic patterns via highthroughput sequencing technologies.Identifying best practices for the collection of postmortem brain samples,analyzing such large amounts of sequencing data,and interpreting these results are critical to advance neuropsychiatry.We provide an overview of human brain banks worldwide,including progress in China,highlighting some well-known projects using human postmortem brain samples to understand molecular regulation in both normal brains and those with neuropsychiatric disorders.Finally,we discuss future research strategies,as well as state-of-the-art statistical and experimental methods that are drawn upon brain bank resources to improve our understanding of the agents of neuropsychiatric disorders.
基金the Intramural Research Program(Grant No.1ZIACP010201)the Division of Cancer Epidemiology and Genetics Informatics Tool Challenge of NCI.
文摘Genome-wide association studies(GWAS)have identified thousands of genomic loci associated with complex diseases and traits,including cancer.The vast majority of common traitassociated variants identified via GWAS fall in non-coding regions of the genome,posing a challenge in elucidating the causal variants,genes,and mechanisms involved.Expression quantitative trait locus(eQTL)and other molecular QTL studies have been valuable resources in identifying candidate causal genes from GWAS loci through statistical colocalization methods.While QTL colocalization is becoming a standard analysis in post-GWAS investigation,an easy web tool for users to perform formal colocalization analyses with either user-provided or public GWAS and eQTL datasets has been lacking.Here,we present ezQTL,a web-based bioinformatic application to interactively visualize and analyze genetic association data such as GWAS loci and molecular QTLs under different linkage disequilibrium(LD)patterns(1000 Genomes Project,UK Biobank,or user-provided data).This application allows users to perform data quality control for variants matched between different datasets,LD visualization,and two-trait colocalization analyses using two state-of-the-art methodologies(eCAVIAR and HyPrColoc),including batch processing.ezQTL is a free and publicly available cross-platform web tool,which can be accessed online at https://analysistools.cancer.gov/ezqtl.
基金funded by The Ningde Science and Technology Plan Project of China(Grant No.20170013).
文摘Background and aim:A genome-wide association study has indicated the association of numerous genes in the 6p21.3 region with chronic hepatitis B virus(HBV)infection.In this study,we screened 12 representative single-nucleotide polymorphisms(SNPs)from the 6p21.3 region and investigated their association with the risk of chronic hepatitis B(CHB)to better understand the molecular etiology un-derlying CHB risk in the Han Chinese population.Methods:Between March 2021 and November 2022,we included 183 patients with CHB(case group)and 196 with natural HBV clearance(control group).Allele typing of the selected SNPs was performed using snapshot technology.The correlation between the 12 chosen SNPs and the risk of chronic HBV infection was examined using binary logistic regression analysis.Interacting genes of the variants were identified,and expression quantitative trait loci(eQTL)were analyzed using the 3DSNP database.Results:We validated 12 previously reported CHB susceptibility sites,including rs1419881 of tran-scription factor 19(TCF19),rs3130542 and rs2853953 of human leukocyte antigen(HLA)-C,rs652888 of euchromatic histone-lysine-methyltransferase 2(EHMT2),rs2856718,rs9276370,rs7756516,and rs7453920 of HLA-DQ,rs378352 of HLA-DOA,and rs3077,rs9277535,and rs9366816 of HLA-DP.Logistic regression analyses revealed that polymorphisms such as rs9276370,rs7756516,rs7453920,rs3077,rs9277535,and rs9366816 were positively correlated with natural HBV clearance in the dominant model.Conversely,rs3130542 and rs378352 were identified as risk factors for CHB.Haplotype analysis revealed that rs9276370,rs7756516,and rs7453920 in HLA-DQ were TTG and GCA haplotypes.Although the TTG haplotype was positively correlated with a higher risk of CHB,the GCA haplotype significantly influenced the natural clearance of HBV.Bioinformatics analysis demonstrated that rs378352,rs3077,and rs9366816 were located within enhancer states;rs3077 and rs9366816 overlapped with nine tran-scription factor-binding sites,whereas rs378352 altered five sequence motifs.Furthermore,eQTL analysis demonstrated the functional tendencies of eight statistically significant SNPs(rs3130542,rs9276370,rs7756516,rs7453920,rs378352,rs3077,rs9277535,and rs9366816).Conclusions:Genetic variations within the 6p21.3 region were associated with chronic HBV infection in the Han Chinese population in southern China.Furthermore,the GCA haplotype including rs9276370,rs7756516,and rs7453920 of HLA-DQ contributed significantly to natural HBV clearance,implying that multiple SNPs exert a cumulative allelic effect on HBV infection.
基金Funding XS was in receipt of a National Natural Science Foundation of China(NSFC)grant(No.12171495)a Natural Science Foundation of Guangdong Province grant(No.2114050001435)+3 种基金a National Key Research and Development Program grant(No.2022YFF1202105)Swedish Research Council(Vetenskapsraet)grants(No.2017-02543&No.2022-01309)supported by the Swedish Research Council grant(No.2017-02543)XS The Swedish National Infrastructure for Computing(SNIC)utilized was partially funded by the Swedish Research Council through grant agreement No.2018-05973.
文摘Alternative splicing exists in most multi-exonic genes,and exploring these complex alternative splicing events and their resultant isoform expressions is essential.However,it has become conventional that RNA sequencing results have often been summarized into gene-level expression counts mainly due to the multiple ambiguous mapping of reads at highly similar regions.Transcript-level quantification and interpretation are often overlooked,and biological interpretations are often deduced based on combined transcript information at the gene level.Here,for the most variable tissue of alternative splicing,the brain,we estimate isoform expressions in 1,191 samples collected by the Genotype-Tissue Expression(GTEx)Consortium using a powerful method that we previously developed.We perform genome-wide association scans on the isoform ratios per gene and identify isoform-ratio quantitative trait loci(irQTL),which could not be detected by studying gene-level expressions alone.By analyzing the genetic architecture of the irQTL,we show that isoform ratios regulate edu-cational attainment via multiple tissues including the frontal cortex(BA9),cortex,cervical spinal cord,and hippocampus.These tissues are also associated with different neuro-related traits,including Alzheimer’s or dementia,mood swings,sleep duration,alcohol intake,intelligence,anxiety or depression,etc.Mendelian randomization(MR)analysis revealed 1,139 pairs of isoforms and neuro-related traits with plausible causal relationships,showing much stronger causal effects than on general diseases measured in the UK Biobank(UKB).Our results highlight essential transcript-level biomarkers in the human brain for neuro-related complex traits and diseases,which could be missed by merely investigating overall gene expressions.
基金supported in part by a Faculty Research Grant from the University of North Carolina at Charlotte
文摘Gene expression is a critical process in biological system that is influenced and modulated by many factors including genetic variation. Expression Quantitative Trait Loci（e QTL） analysis provides a powerful way to understand how genetic variants affect gene expression. For genome wide e QTL analysis, the number of genetic variants and that of genes are large and thus the search space is tremendous. Therefore, e QTL analysis brings about computational and statistical challenges. In this paper, we provide a comprehensive review of recent advances in methods for e QTL analysis in population-based studies. We first present traditional pairwise association methods, which are widely used in human genetics. To account for expression heterogeneity, we investigate the methods for correcting confounding factors. Next, we discuss newly developed statistical learning methods including Lasso-based models. In the conclusion, we provide an overview of future method development in analyzing e QTL associations. Although we focus on human genetics in this review, the methods are applicable to many other organisms.
基金Basic and Applied Basic Research Foundation of Guangdong Province,Grant/Award Numbers:2023A1515011768,2020A1515010221,2021A1515010535National Natural Science Foundation of China,Grant/Award Numbers:82271818,81871275,82071831,82001714,81671591,81501389,81373182。
文摘Background:Rheumatoid arthritis(RA)is a globally prevalent condition that has a significant impact on morbidity and mortality rates.As a result,there is growing interest in understanding its pathogenetic mechanisms,particularly genetic susceptibility.To explore the potential genes that may cause RA,we conducted a comprehensive Mendelian randomization analysis and colocalization based on data from large sample size genome-wide association studies.Methods:We used two transcriptome datasets to identify expression quantitative trait loci as the exposure and employed genome-wide association studies data from the FinnGen study as the outcome.We then performed colocalization analysis to confirm that the expression quantitative trait loci and RA share causal genetic variants.Furthermore,we implemented a phenomewide scan to identify other clinical phenotypes associated with significant causal genes.Results:At a Bonferroni significance level of p<2.70×10^(−6),the Mendelian randomization analysis revealed that 20 genes increased the risk of RA,while 16 genes showed a marginally protective effect.Co-localization analyses indicated that AP4B1,GGA2,KEAP1,PTPN22,REG4,and TRAV38-2DV8 were associated with the risk of RA.The phenome-wide scan demonstrated shared genetic determinants between RA and other immune-mediated disorders,including autoimmune thyroid disease,diabetes mellitus,cardiovascular disorders,inflammatory bowel disease,and malignant tumors.Conclusions:Our study identified six risk genes(AP4B1,GGA2,KEAP1,PTPN22,REG4,and TRAV38-2DV8)that may have a causal role in RA.These findings provide novel therapeutic targets for the treatment of RA.Further exploration is required to elucidate the underlying biological mechanisms.
