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Identifying candidate genes for Type 2 Diabetes Mellitus and obesity through gene expression profiling in multiple tissues or cells.

ABSTRACT: Type 2 Diabetes Mellitus (T2DM) and obesity have become increasingly prevalent in recent years. Recent studies have focused on identifying causal variations or candidate genes for obesity and T2DM via analysis of expression quantitative trait loci (eQTL) within a single tissue. T2DM and obesity are affected by comprehensive sets of genes in multiple tissues. In the current study, gene expression levels in multiple human tissues from GEO datasets were analyzed, and 21 candidate genes displaying high percentages of differential expression were filtered out. Specifically, DENND1B, LYN, MRPL30, POC1B, PRKCB, RP4-655J12.3, HIBADH, and TMBIM4 were identified from the T2DM-control study, and BCAT1, BMP2K, CSRNP2, MYNN, NCKAP5L, SAP30BP, SLC35B4, SP1, BAP1, GRB14, HSP90AB1, ITGA5, and TOMM5 were identified from the obesity-control study. The majority of these genes are known to be involved in T2DM and obesity. Therefore, analysis of gene expression in various tissues using GEO datasets may be an effective and feasible method to determine novel or causal genes associated with T2DM and obesity.

SUBMITTER: Chen J

PROVIDER: S-EPMC3888709 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Identifying candidate genes for Type 2 Diabetes Mellitus and obesity through gene expression profiling in multiple tissues or cells.

Chen Junhui J Meng Yuhuan Y Zhou Jinghui J Zhuo Min M Ling Fei F Zhang Yu Y Du Hongli H Wang Xiaoning X

Journal of diabetes research 20131226

Type 2 Diabetes Mellitus (T2DM) and obesity have become increasingly prevalent in recent years. Recent studies have focused on identifying causal variations or candidate genes for obesity and T2DM via analysis of expression quantitative trait loci (eQTL) within a single tissue. T2DM and obesity are affected by comprehensive sets of genes in multiple tissues. In the current study, gene expression levels in multiple human tissues from GEO datasets were analyzed, and 21 candidate genes displaying h ...[more]

PMID: 24455749

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Project description:BackgroundObesity associated type 2 diabetes mellitus is a metabolic disorder ; however, the etiology of obesity associated type 2 diabetes mellitus remains largely unknown. There is an urgent need to further broaden the understanding of the molecular mechanism associated in obesity associated type 2 diabetes mellitus.MethodsTo screen the differentially expressed genes (DEGs) that might play essential roles in obesity associated type 2 diabetes mellitus, the publicly available expression profiling by high throughput sequencing data (GSE143319) was downloaded and screened for DEGs. Then, Gene Ontology (GO) and REACTOME pathway enrichment analysis were performed. The protein - protein interaction network, miRNA - target genes regulatory network and TF-target gene regulatory network were constructed and analyzed for identification of hub and target genes. The hub genes were validated by receiver operating characteristic (ROC) curve analysis and RT- PCR analysis. Finally, a molecular docking study was performed on over expressed proteins to predict the target small drug molecules.ResultsA total of 820 DEGs were identified between healthy obese and metabolically unhealthy obese, among 409 up regulated and 411 down regulated genes. The GO enrichment analysis results showed that these DEGs were significantly enriched in ion transmembrane transport, intrinsic component of plasma membrane, transferase activity, transferring phosphorus-containing groups, cell adhesion, integral component of plasma membrane and signaling receptor binding, whereas, the REACTOME pathway enrichment analysis results showed that these DEGs were significantly enriched in integration of energy metabolism and extracellular matrix organization. The hub genes CEBPD, TP73, ESR2, TAB1, MAP 3K5, FN1, UBD, RUNX1, PIK3R2 and TNF, which might play an essential role in obesity associated type 2 diabetes mellitus was further screened.ConclusionsThe present study could deepen the understanding of the molecular mechanism of obesity associated type 2 diabetes mellitus, which could be useful in developing therapeutic targets for obesity associated type 2 diabetes mellitus.

Project description:Multiple symmetric lipomatosis (MSL) is a rare disorder characterized by aberrant multiple and symmetric subcutaneous adipose tissue accumulation in the face, neck, shoulders, back, chest and abdomen, severely affecting the quality of life of patients. At present, precise MSL etiology and pathogenesis remain to be elucidated. The present study first utilized a digital gene expression technique with a next‑generation sequencing platform to profile differentially expressed genes in three cases of MSL vs. normal control tissue. cDNA libraries from these tissue specimens were constructed and DNA sequenced for identification of differentially expressed genes, which underwent bioinformatic analysis using the Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein‑protein interaction (PPI) network analyses. As a result, a total of 859 differentially expressed genes were identified, including 308 upregulated genes (C19orf80, Apelin, C21orf33, FAM166B and HSD11B2 were mostly upregulated 6.984‑, 4.670‑, 4.412‑, 3.693‑ and 3.561‑fold, respectively) and 551 downregulated genes [FosB proto‑oncogene, AP‑1 transcription factor subunit (FOSB), selectin (SEL) E, RAR related orphan receptor (ROR) B, salt inducible kinase (SIK)1 and epidermal growth factor‑like protein (EGFL)6 were mostly downregulated ‑9.845, ‑8.243, ‑8.123, ‑7.702 and ‑7.664 fold, respectively). The GO functional enrichment analysis demonstrated these differentially expressed genes were predominantly involved in biological processes and cellular components, while the KEGG pathway enrichment analysis demonstrated that ribosome, non‑alcoholic fatty liver disease, human T‑lymphotropic virus type 1 (HTLV‑I) infection and Alzheimer's disease pathways were altered in MSL. The PPI network data demonstrated ubiquitin C (UBC), translocator protein (TSPO), Jun Proto‑Oncogene, AP‑1 Transcription Factor (JUN) and FOS were among these differentially expressed genes that participated in regulation of adipocyte differentiation, although no previous study has linked them to MSL. In conclusion, the present study profiled differentially expressed genes in MSL and identified gene pathways that may be associated with MSL development and progression.

Project description:Background:Certain candidate genes have been associated with obesity. The goal of this study is to determine the association between thirteen neuroendocrine disorder-related candidate genes and pre-pregnancy obesity among gestational diabetes mellitus (GDM) patients using the stratification approach defined the Asian and International criteria-based body mass index (BMI). Methods:This was a post-hoc case-control exploratory sub-analysis of a cross-sectional study among GDM women to determine which candidate single nucleotide polymorphisms (SNPs) related to neuroendocrine disorders may be associated with obesity. Factors were adjusted for socio-demographic characteristics and concurrent medical problems in this particular population. Pre-pregnancy BMI and concurrent medical profiles were obtained from maternal health records. Obesity is defined as BMI of ?27.5 kg/m2 for Asian criteria-based BMI and >30 kg/m2 for International criteria-based BMI. Thirteen candidate genes were genotyped using Agena® MassARRAY and examined for association with pre-pregnancy obesity using multiple logistic regression analysis. The significant difference threshold was set at P value <0.05. Results:Three hundred and twelve GDM women were included in this study; 60.9% and 44.2% of GDM patients were obese using Asian and International criteria-based BMI, respectively. GDM patients with AA or AG genotypes in specific SNP of brain-derived neurotrophic factor (BDNF) (G > A in rs6265) are more likely to be obese (adjusted odd ratio =2.209, 95% CI, 1.305, 3.739, P=0.003) compared to those who carry the GG genotype in the SNP adjusted for parity, underlying with asthma, heart disease, anaemia, education background in the International criteria-based BMI stratification group. On the other hand, there were no associations between other candidate genes (NRG1, FKBP5, RORA, OXTR, PLEKHG1, HTR2C, LHPP, SDK2, TEX51, EPHX2, NPY5R and ANO2) and maternal obesity. Conclusions:In summary, BDNF rs6265 is significantly associated with pre-pregnancy obesity among GDM patients. The exact role of BDNF adjusted for diet intake and lifestyle factors merits further investigation.

Project description:We will explore the genetic (including APC, k-ras, p53, MSI, etc.) and environmental (including family history, life style, diet, nutritional status, DM, serum IGF-I, IGFBP-3, etc.) risk factors of colorectal tumorigenesis. We will accrue approximately 1000 patients as experimental group. The control group consists of 2000 individuals who were confirmed without colorectal cancer or polyps by colonoscopy. We estimated the statistical power of this study will reach more than 90%. In the second year, we will explore the association between various environmental risk factors with the epigenetic changes of various oncogenes and tumor suppressor genes. Firstly, we will study the correlation between hypermethylation of promoter region of hMLH1 gene with various environmental factors. Next, we will explore the genetic polymorphisms of promoter of E-cadherin gene. Recently, it has been reported that the C→A genetic polymorphism in the promoter region of E-cadherin gene in prostate cancer. Since this phenomenon has not been reported in colorectal cancer, it is mandatory for us to extend our research to the E-cadherin polymorphisms of colorectal cancer. Moreover, this project will focus on exploration of the association between the genetic polymorphisms of promoter of TS gene with chemosensitivity to 5-Fu-based therapy. We speculated that the better prognosis in colorectal tumors with MSI is related to their expression of TS gene. In summary, the second year of this project will extend our accumulated experience in the study of genetic polymorphisms to further clarify the association between genetic polymorphisms of TS gene with the prognosis of colorectal cancers after chemotherapy. We believe that this project will facilitate: (1) the further clarification of colorectal cancer tumorigenesis; (2) the establishment of domestic epidemiological data of colorectal cancer of Taiwan, and (3) the improvement of the quality of clinical management of patients with colorectal cancer.

Project description:BACKGROUND:Lipid intermediates produced during triacylglycerols (TAGs) synthesis and lipolysis in adipocytes interfere with the intracellular insulin signaling pathway and development of insulin resistance. This study aims to compare TAG species and their fatty acid composition in adipose tissues from insulin sensitive (IS), insulin resistant (IR) and type 2 diabetes mellitus (T2DM) obese individuals. METHODS:Human subcutaneous and omental adipose tissue biopsies were obtained from 64 clinically characterized obese individuals during weight reduction surgery. TAGs were extracted from the adipose tissues using the Bligh and Dyer method, then were subjected to non-aqueous reverse phase ultra-high performance liquid chromatography and full scan mass spectrometry acquisition and data dependent MS/MS on LTQ dual cell linear ion trap. TAGs and their fatty acid contents were identified and compared between IS, IR and T2DM individuals and their levels were correlated with metabolic traits of participants and the adipogenic potential of preadipocyte cultures established from their adipose tissues. RESULTS:Data revealed 76 unique TAG species in adipose tissues identified based on their exact mass. Analysis of TAG levels revealed a number of TAGs that were significantly altered with disease progression including C46:4, C48:5, C48:4, C38:1, C50:3, C40:2, C56:3, C56:4, C56:7 and C58:7. Enrichment analysis revealed C12:0 fatty acid to be associated with TAGs least abundant in T2DM whereas C18:3 was found in both depleted and enriched TAGs in T2DM. Significant correlations of various adipose tissue-derived TAG species and metabolic traits were observed, including age and body mass index, systemic total cholesterol, TAGs, and interleukin-6 in addition to adipogenic potential of preadipocytes derived from the same adipose tissues. CONCLUSION:Pilot data suggest that adipose tissues from obese IR and T2DM individuals exhibit TAG-specific signatures that may contribute to their increased risk compared to their IS counterparts. Future experiments are warranted to investigate the functional relevance of these specific lipidomic profiles.

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Identifying candidate genes for Type 2 Diabetes Mellitus and obesity through gene expression profiling in multiple tissues or cells.

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Identifying candidate genes for Type 2 Diabetes Mellitus and obesity through gene expression profiling in multiple tissues or cells.

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