Integrative network analysis reveals different pathophysiological mechanisms of insulin resistance among Caucasians and African Americans
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE65221 | GEO | 2016/01/22
SECONDARY ACCESSION(S): PRJNA273426
REPOSITORIES: GEO
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Project description:Context: Compared with European Americans, African Americans (AAs) are more insulin resistant, have a higher insulin secretion response to glucose, and develop type 2 diabetes more often. Molecular processes and/or genetic variations contributing to altered glucose homeostasis in high-risk AAs remain uncharacterized. Objective: Adipose and muscle transcript expression profiling and genotyping were performed in 260 AAs to identify genetic regulatory mechanisms associated with insulin sensitivity (SI). We hypothesized that: 1) transcription profiles would reveal tissue-specific modulation of physiologic pathways with SI, and 2) a subset of SI-associated transcripts would be controlled by DNA sequence variants as expression quantitative traits, and these variants in turn would be associated with SI. Design and Settings: The cross-sectional research study was performed in a clinical research unit. Participants: Unrelated nondiabetic AAs were recruited for the study. Main Outcome Measures: SI was measured by frequently sampled iv glucose tolerance test. Results: The expression levels of 2212 transcripts in adipose and 145 transcripts in muscle were associated with SI. Genes involved in eIF2, eIF4-p70S6K, and mTOR signaling were modulated with SI in both tissues. Genes involved in leukocyte extravasation signaling showed adipose-specific regulation, and genes involved in oxidative phosphorylation had discordant regulation between tissues. Intersecting cis-expression quantitative trait loci results with data from transcript-SI association analysis identified cis-regulatory single nucleotide polymorphisms for 363 and 42 SI-associated transcripts in adipose and muscle, respectively. Cis-eSNPs for three SI-associated adipose transcripts, NINJ1, AGA, and CLEC10A were associated with SI. Abrogation of NINJ1 induction in THP1 macrophages modulated expression of genes in chemokine signaling, cell adhesion, and angiogenesis pathways. Conclusion: This study identified multiple pathways associated with SI; particularly discordant tissue-specific regulation of the oxidative phosphorylation pathway, and adipose-specific regulation of transcripts in the leukocyte extravasation signaling pathway that seem to be important in insulin resistance. Identification of single nucleotide polymorphisms associated with SI and with modulation of expression of SI-associated transcripts, including NINJ1, reveals novel genetic regulatory mechanisms of insulin resistance in AAs.
2017-03-04 | GSE95674 | GEO
Project description:Context: Compared with European Americans, African Americans (AAs) are more insulin resistant, have a higher insulin secretion response to glucose, and develop type 2 diabetes more often. Molecular processes and/or genetic variations contributing to altered glucose homeostasis in high-risk AAs remain uncharacterized. Objective: Adipose and muscle transcript expression profiling and genotyping were performed in 260 AAs to identify genetic regulatory mechanisms associated with insulin sensitivity (SI). We hypothesized that: 1) transcription profiles would reveal tissue-specific modulation of physiologic pathways with SI, and 2) a subset of SI-associated transcripts would be controlled by DNA sequence variants as expression quantitative traits, and these variants in turn would be associated with SI. Design and Settings: The cross-sectional research study was performed in a clinical research unit. Participants: Unrelated nondiabetic AAs were recruited for the study. Main Outcome Measures: SI was measured by frequently sampled iv glucose tolerance test. Results: The expression levels of 2212 transcripts in adipose and 145 transcripts in muscle were associated with SI. Genes involved in eIF2, eIF4-p70S6K, and mTOR signaling were modulated with SI in both tissues. Genes involved in leukocyte extravasation signaling showed adipose-specific regulation, and genes involved in oxidative phosphorylation had discordant regulation between tissues. Intersecting cis-expression quantitative trait loci results with data from transcript-SI association analysis identified cis-regulatory single nucleotide polymorphisms for 363 and 42 SI-associated transcripts in adipose and muscle, respectively. Cis-eSNPs for three SI-associated adipose transcripts, NINJ1, AGA, and CLEC10A were associated with SI. Abrogation of NINJ1 induction in THP1 macrophages modulated expression of genes in chemokine signaling, cell adhesion, and angiogenesis pathways. Conclusion: This study identified multiple pathways associated with SI; particularly discordant tissue-specific regulation of the oxidative phosphorylation pathway, and adipose-specific regulation of transcripts in the leukocyte extravasation signaling pathway that seem to be important in insulin resistance. Identification of single nucleotide polymorphisms associated with SI and with modulation of expression of SI-associated transcripts, including NINJ1, reveals novel genetic regulatory mechanisms of insulin resistance in AAs.
2017-03-04 | GSE95675 | GEO
Project description:The incidence and mortality of colorectal cancer (CRC) is higher in African Americans (AAs) than in other ethnic groups in the U. S., but reasons for the disparities are unknown. We performed gene expression profiling and microsatellite instability (MSI) analysis of sporadic CRCs from AAs vs. European Americans (EAs) to assess the contribution to CRC disparities. We evaluated gene expression of 43 AA and 43 EA CRC tumors matched by stage and 40 normal colon tissues using the Agilent human whole genome 4x44K cDNA arrays. Gene and pathway analysis were performed using Significance Analysis of Microarrays (SAM), 10-fold Cross Validation (10-fCV) and Ingenuity Pathway Analysis (IPA). MSI analysis was assessed with five NIH Bethesda markers. SAM revealed that 95 genes were differentially expressed between AA and EA patients at a false discovery rate of <5%. A 10f-CV demonstrated that 9 genes were differentially expressed between AA and EA with an accuracy of 97%. Nine genes (CRYBB2, PSPH, ADAL, VSIG10L, C17orf81, ARSE, ANKRD36B, ZNF835, ARHGAP6) were validated and differential expression confirmed by qRT-PCR in independent test set of 21 patients (10 AA, 11 EA). We also analyzed MSI in 57 of the CRC subjects. Overall, 15.8% of CRC patients had MSI, with a higher rate observed in EA (20%) than in AA (12%). MSI distribution by tumor site was 77% right and 23% left colon. Previously, genetic, epigenetic and environmental factors have been implicated in the etiology of CRC. Our results are the first to implicate differential gene expression in CRC disparities and support the existence of distinct tumor microenvironments in these two patients' populations. 126 total samples: 1) 43 white cancer samples; 2) 43 black cancer samples; 3) 27 white control samples; 4) 13 black control samples.
2012-05-22 | E-GEOD-28000 | biostudies-arrayexpress
Project description:Translational Relevance Historically, African Americans have been underrepresented in clinical cancer research. Diversity helps to ensure equal access to new cancer therapies and better treatment for everyone. Cancer research is increasingly focused on classifying patients according to molecular profiles for particular groups. We provide a detailed molecular analysis from paired NSCLC tissues that identified differential coding and noncoding RNA expression in NSCLC from African Americans (AA) and European Americans (EA). Similar to other tumor types, we determined that race-enriched gene and microRNA expression signatures suggest a more aggressive disease in African Americans. Based on predicted drug resistance to adjuvant chemotherapies, AA may not equally benefit from the same range of clinical drugs as EA. Our findings provide a rationale for integrating coding and noncoding transcriptome profiles, along with clinical, demographic, and genomic data, when determining treatment options. Abstract Purpose: To determine if racial differences in gene and microRNA expression translates to differences in lung tumor biology with clinical relevance in African Americans (AA) and European Americans (EA). Experimental Design: The NCI-Maryland Case Control Study includes seven Baltimore City hospitals and is overrepresented with AA patients (~40%). Patients that underwent curative NSCLC surgery between 1998 and 2014 were enrolled. Comparative molecular profiling used mRNA (n = 22 AAs and n = 19 EAs) and microRNA (n = 42 AAs and n = 55 EAs) expression arrays to track differences in paired fresh frozen normal tissues and lung tumor specimens from AA and EA. Pathway enrichment, predicted drug response, tumor microenvironment infiltration, cancer immunotherapy antigen profiling, and microRNA target enrichment were assessed. Results: AA-enriched differential gene expression was characterized by stem-cell and invasion pathways. Differential gene expression in lung tumors from EA were primarily characterized by cell proliferation pathways. Population-specific gene expression was partly driven by population-specific miRNA expression profiles. Drug susceptibility predictions revealed a strong inverse correlation between AA resistance and EA sensitivity to the same panel of drugs. Statistically significant differences in M1 and M2 macrophage infiltration was observed in AA (P <0.05), however, PD-L1, PD-L2 expression was similar between both. Conclusions: Comparative transcriptomic profiling revealed clear differences in lung tumor biology between AA and EA. Increased participation by AA in lung cancer clinical trials are needed to integrate, and leverage, transcriptomic differences with other clinical information to maximize therapeutic benefit in both AA and EA. GSEA, Connectivity Map, CIBERSORT, cancer immunotherapy antigen profiling, and hypergeometric testing for overlapping miRNA targets were performed.
2017-07-28 | GSE101929 | GEO
Project description:Translational Relevance Historically, African Americans have been underrepresented in clinical cancer research. Diversity helps to ensure equal access to new cancer therapies and better treatment for everyone. Cancer research is increasingly focused on classifying patients according to molecular profiles for particular groups. We provide a detailed molecular analysis from paired NSCLC tissues that identified differential coding and noncoding RNA expression in NSCLC from African Americans (AA) and European Americans (EA). Similar to other tumor types, we determined that race-enriched gene and microRNA expression signatures suggest a more aggressive disease in African Americans. Based on predicted drug resistance to adjuvant chemotherapies, AA may not equally benefit from the same range of clinical drugs as EA. Our findings provide a rationale for integrating coding and noncoding transcriptome profiles, along with clinical, demographic, and genomic data, when determining treatment options. Abstract Purpose: To determine if racial differences in gene and microRNA expression translates to differences in lung tumor biology with clinical relevance in African Americans (AA) and European Americans (EA). Experimental Design: The NCI-Maryland Case Control Study includes seven Baltimore City hospitals and is overrepresented with AA patients (~40%). Patients that underwent curative NSCLC surgery between 1998 and 2014 were enrolled. Comparative molecular profiling used mRNA (n = 22 AAs and n = 19 EAs) and microRNA (n = 42 AAs and n = 55 EAs) expression arrays to track differences in paired fresh frozen normal tissues and lung tumor specimens from AA and EA. Pathway enrichment, predicted drug response, tumor microenvironment infiltration, cancer immunotherapy antigen profiling, and microRNA target enrichment were assessed. Results: AA-enriched differential gene expression was characterized by stem-cell and invasion pathways. Differential gene expression in lung tumors from EA were primarily characterized by cell proliferation pathways. Population-specific gene expression was partly driven by population-specific miRNA expression profiles. Drug susceptibility predictions revealed a strong inverse correlation between AA resistance and EA sensitivity to the same panel of drugs. Statistically significant differences in M1 and M2 macrophage infiltration was observed in AA (P <0.05), however, PD-L1, PD-L2 expression was similar between both. Conclusions: Comparative transcriptomic profiling revealed clear differences in lung tumor biology between AA and EA. Increased participation by AA in lung cancer clinical trials are needed to integrate, and leverage, transcriptomic differences with other clinical information to maximize therapeutic benefit in both AA and EA.
2017-08-04 | GSE102286 | GEO
Project description:The incidence and mortality of colorectal cancer (CRC) is higher in African Americans (AAs) than in other ethnic groups in the U. S., but reasons for the disparities are unknown. We performed gene expression profiling and microsatellite instability (MSI) analysis of sporadic CRCs from AAs vs. European Americans (EAs) to assess the contribution to CRC disparities. We evaluated gene expression of 43 AA and 43 EA CRC tumors matched by stage and 40 normal colon tissues using the Agilent human whole genome 4x44K cDNA arrays. Gene and pathway analysis were performed using Significance Analysis of Microarrays (SAM), 10-fold Cross Validation (10-fCV) and Ingenuity Pathway Analysis (IPA). MSI analysis was assessed with five NIH Bethesda markers. SAM revealed that 95 genes were differentially expressed between AA and EA patients at a false discovery rate of <5%. A 10f-CV demonstrated that 9 genes were differentially expressed between AA and EA with an accuracy of 97%. Nine genes (CRYBB2, PSPH, ADAL, VSIG10L, C17orf81, ARSE, ANKRD36B, ZNF835, ARHGAP6) were validated and differential expression confirmed by qRT-PCR in independent test set of 21 patients (10 AA, 11 EA). We also analyzed MSI in 57 of the CRC subjects. Overall, 15.8% of CRC patients had MSI, with a higher rate observed in EA (20%) than in AA (12%). MSI distribution by tumor site was 77% right and 23% left colon. Previously, genetic, epigenetic and environmental factors have been implicated in the etiology of CRC. Our results are the first to implicate differential gene expression in CRC disparities and support the existence of distinct tumor microenvironments in these two patients' populations.
2012-05-23 | GSE28000 | GEO
Project description:Approximately 90% of colorectal cancer (CRC) develop over the age of 50, highlighting the im-portant role of aging in CRC risk. African Americans (AAs) shoulder a greater CRC burden than European Americans (EA), and are more likely to develop CRC at a younger age. The effects of aging in AA and EA normal rectal tissue have yet to be defined. Here, we performed epige-nome-wide DNA methylation analysis in the first, large-scale biracial cohort of normal rectum (n=140 samples)
2022-12-23 | GSE216024 | GEO
Project description:Background: Colorectal cancer is the third most deadly cancer among African Americans (AA). When compared to Caucasian Americans (CA), AA present with more advanced disease and lower survival rates. Here, we investigated if differences in tumor immunology could contribute to the disparities observed between these populations. Methods: We examined gene expression of 20 tumor and 20 non-tumor adjacent tissues from AA and the same number from CA by whole transcriptome sequencing and generated scores for immune cell populations by NanoString. In addition, we utilized “The Cancer Genome Atlas” (TCGA) database from AA (n = 55) and CA (n = 193) as a validation cohort. Finally, we measured the secretion of cytokines characteristic of effector T helper cell (Th) subsets by ELISA using plasma from each AA and CA participant. Results: Colon tumors from AA patients showed significant fold-change increase in gene expression when compared to CA for FOXP3 (6.97 vs. 3.15), IL1B (122 vs. 14) and IL8 (262 vs. 28) (p < 0.05). In contrast, among CA we observed statistically higher gene expression of markers associated with antitumor activity such as GZMB (Granzyme B), IFNG and immunotherapy targets PDL1 (CD274) and CTLA4 (p < 0.05). TCGA data validated our observed higher expression of GZMB and PDL1 in CA patients as well as showed a 50% higher 5-year survival rate in AA patients with high expression of GZMB. Notably, our observations on immune cell populations show that AA tumors have significantly higher number of exhausted CD8+ cells (p < 0.01), mast cells (p < 0.02) and increased T regulatory cells when compared to CA. AA colon cancer patients differed from CA in cytokine production patterns in plasma (i.e. reduced IL-12). Conclusions: Our study demonstrates significant differences of the immunological profiles of colon tumors from AA compared to CA that suggest a deficiency of appropriate immune defense mechanisms in terms of gene expression, recruitment of immune cells and systemic secretion of cytokines. As such, these immune differences could be mitigated through population-specific therapeutic approaches.
2020-09-23 | GSE146009 | GEO
Project description:Background: African Americans (AA) have increased burdens of cardiovascular disease and cancer compared to Caucasian Americans (CA). This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to this health disparity. Methods: From self-identified, healthy, 20-29 year old AA (n=21) and CA (n=17), we established cultures of blood outgrowth endothelial cells (BOEC) and applied microarray profiling. BOEC have never been exposed to in vivo influences, and their gene expression reflects culture conditions (meticulously controlled) and donor genetics. Analysis used two distinct approaches. Significance Analysis of Microarray, a FDR-based test, identified significant differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey each of nine biological systems relevant to endothelial cell biology. Results: At the highly stringent threshold of FDR=0, we identified 31 single genes that were differentially expressed, 4 higher and 27 lower in AA. “PSPH” exhibited the greatest fold-change (AA>CA), but this was entirely accounted for by a homolog (PSPHL) hidden within the PSPH probe set. Among other significantly different genes were: for AA>CA, SOS1, AMFR, FGFR3; and for AA<CA, ARVCF, BIN3, EIF4B. Many more (221 transcripts for 204 genes) were differentially expressed at the more customary, less stringent threshold of FDR<.05. Using the biological systems approach, we identified shear response biology as being significantly altered for AA versus CA. It detected an apparent tonic increase of expression (AA>CA) for 46/157 genes within that system. Conclusions: The most significant single gene changes detected for AA involved genes having substantial, known roles in endothelial biology. Biological systems analysis suggested that shear stress response, a critical regulator of endothelial function and vascular homeostasis, may be different between AA and CA. These results potentially have direct implications for the role of endothelial cells in both vascular disease (e.g., hypertension and stroke) and cancer (via angiogenesis). The present findings are consistent with our overarching hypothesis that genetic influences stemming from ancestral continent-of-origin could impact upon endothelial cell biology and thereby contribute to disparity of vascular-related disease burden amongst AA.
2010-07-03 | GSE22688 | GEO
Project description:African Americans (AAs) are disproportionately affected by metabolic diseases and adverse drug events, with limited publicly available genomic and transcriptomic data to advance the knowledge of the molecular underpinnings or genetic associations to these diseases or drug response phenotypes. To fill this gap, we obtained 60 primary hepatocyte cultures from AA liver donors for genome-wide mapping of expression quantitative trait loci (eQTL) using LAMatrix. We identified 277 eGenes and 19,770 eQTLs, of which 67 eGenes and 7,415 eQTLs are not observed in the Genotype-Tissue Expression Project (GTEx) liver eQTL analysis. Of the eGenes found in GTEx only 25 share the same lead eQTL. These AA-specific eQTLs are less correlated to GTEx eQTL in effect sizes and have larger Fst values compared to eQTLs found in both cohorts (overlapping eQTLs). We assessed the overlap between GWAS variants and their tagging variants with AA hepatocyte eQTLs and demonstrated that AA hepatocyte eQTLs can decrease the number of potential causal variants at GWAS loci. Additionally, we identified 75,002 exon QTLs of which 48.8% are not eQTLs in AA hepatocytes. Our analysis provides the first comprehensive characterization of AA hepatocyte eQTLs and highlights the unique discoveries that are made possible due to the increased genetic diversity within the African ancestry genome.
2020-03-27 | GSE147628 | GEO