Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans.
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ABSTRACT:
SUBMITTER: Sharma NK
PROVIDER: S-EPMC4880154 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
Publications
Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans.
Sharma Neeraj K NK Sajuthi Satria P SP Chou Jeff W JW Calles-Escandon Jorge J Demons Jamehl J Rogers Samantha S Ma Lijun L Palmer Nicholette D ND McWilliams David R DR Beal John J Comeau Mary E ME Cherry Kristina K Hawkins Gregory A GA Menon Lata L Kouba Ethel E Davis Donna D Burris Marcie M Byerly Sara J SJ Easter Linda L Bowden Donald W DW Freedman Barry I BI Langefeld Carl D CD Das Swapan K SK
The Journal of clinical endocrinology and metabolism 20160120 4
Integrative multiomics analyses of adipose and muscle tissue transcripts, S, and genotypes revealed novel genetic regulatory mechanisms of insulin resistance in African Americans. ...[more]
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Project description:This SuperSeries is composed of the SubSeries listed below.
2017-03-04 | GSE95676 | 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: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:Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans
| PRJNA377890 | ENA
Project description:Insulin resistance (IR) is a harbinger of type 2 diabetes (T2D) and partly determined by genetic factors. However, genetically regulated mechanisms of IR remain poorly understood. Using gene expression, genotype, and insulin sensitivity data from the African American Genetics of Metabolism and Expression (AAGMEx) cohort, we performed transcript-wide correlation and expression quantitative trait loci (eQTL) analyses to identify IR-correlated cis-regulated transcripts (cis-eGenes) in adipose tissue. These IR-correlated cis-eGenes were tested in the European ancestry individuals in the Metabolic Syndrome in Men (METSIM) cohort for trans-ethnic replication. Comparison of Matsuda index-correlated transcripts in AAGMEx with the METSIM study identified significant correlation of 3,849 transcripts, with concordant direction of effect for 97.5% of the transcripts. cis-eQTL for 587 Matsuda index-correlated genes were identified in both cohorts. Enoyl-CoA hydratase domain-containing 3 (ECHDC3) was the top-ranked Matsuda index-correlated cis-eGene. Expression levels of ECHDC3 were positively correlated with Matsuda index, and regulated by cis-eQTL, rs34844369 being the top cis-eSNP in AAGMEx. Silencing of ECHDC3 in adipocytes significantly reduced insulin-stimulated glucose uptake and Akt Ser473 phosphorylation. RNA sequencing analysis identified 691 differentially expressed genes in ECHDC3-knockdown adipocytes, which were enriched in γ-linolenate biosynthesis, and known IR genes. Thus, our studies elucidated genetic regulatory mechanisms of IR and identified genes and pathways in adipose tissue that are mechanistically involved in IR.
| S-EPMC6609988 | biostudies-literature
Project description:ObjectiveTo examine the ethnic differences in insulin sensitivity (SI) as measured by the minimal model approach (SI-MM) and the reference method, the euglycemic-hyperinsulinemic clamp (EHC).Research design and methodsIn a prospective study design, thirty black Americans (BA) were age, sex, and BMI matched with non-Hispanic whites (NHW). Participants underwent frequently sampled intravenous tolerance test (FSIVGTT) and EHC on 2 separate days during a single visit.ResultsSI-MM values were significantly lower in BA when compared with NHW (0.035 ± 0.025 vs. 0.058 ± 0.036 [dL/min]/[μU/mL]; P = 0.003). However, there were no ethnic differences in SI measured by EHC (0.028 ± 0.012 vs. 0.035 ± 0.019 [dL/min]/[μU/mL]; P = 0.18).ConclusionsSI-MM systematically underestimates SI in BA when compared with NHW. These findings suggest that studies inferring lower SI in BA based on FSIVGTT and SI-MM should be interpreted cautiously.
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Project description:African Americans have been understudied in genome wide association studies of diabetes and related traits. In the current study, we examined the joint association of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with fasting insulin and an index of insulin resistance (HOMA-IR) in the HyperGEN study, a family based study with proband ascertainment for hypertension. This analysis is restricted to 1,040 African Americans without diabetes. We generated allele specific CNV genotypes at 872,243 autosomal loci using Birdsuite, a freely available multi-stage program. Joint tests of association for SNPs and CNVs were performed using linear mixed models adjusting for covariates and familial relationships. Our results highlight SNPs associated with fasting insulin and HOMA-IR (rs6576507 and rs8026527, 3.7*10(-7)?P?1.1*10(-5)) near ATPase, class V, type 10A (ATP10A), and the L Type voltage dependent calcium channel (CACNA1D, rs1401492, P?5.2*10(-6)). ATP10A belongs to a family of aminophospholipid-transporting ATPases and has been associated with type 2 diabetes in mice. CACNA1D has been linked to pancreatic beta cell generation in mice. The two most significant copy variable markers (rs10277702 and rs361367; P<2.0*10(-4)) were in the beta variable region of the T-cell receptor gene (TCRVB). Human and mouse TCR has been shown to mimic insulin and its receptor and could contribute to insulin resistance. Our findings differ from genome wide association studies of fasting insulin and other diabetes related traits in European populations, highlighting the continued need to investigate unique genetic influences for understudied populations such as African Americans.
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Project description:We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities.
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