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| Status |
Public on Mar 04, 2017 |
| Title |
Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans [skeletal muscle] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
We systematically analyzed genome-wide transcript expression profiles of subcutaneous adipose and skeletal muscle (insulin-responsive tissues) from a metabolically characterized cohort of unrelated and non-diabetic African Americans to idetify genes associated with gluco-metabolic phenotypes
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| Contributor(s) |
Sharma NK, Sajuthi SP, Chou JW, Calles-Escandon J, Rogers S, Ma L, Palmer ND, McWilliams DR, Beal J, Comeau ME, Cherry K, Hawkins GA, Menon L, Kouba E, Davis D, Burris M, Byerly SJ, Easter L, Bowden DW, Freedman BI, Langefeld CD, Das SK |
| Citation(s) |
26789776 |
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| Submission date |
Mar 03, 2017 |
| Last update date |
Jun 05, 2017 |
| Contact name |
Jeff Chou |
| E-mail(s) |
jchou@wakehealth.edu
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| Phone |
3367572617
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| Organization name |
Atrium Health Wake Forest Baptist
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| Street address |
Medical Center Blvd
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| City |
Winston-Salem |
| State/province |
NC |
| ZIP/Postal code |
27157 |
| Country |
USA |
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| Platforms (1) |
| GPL10904 |
Illumina HumanHT-12 V4.0 expression beadchip (gene symbol) |
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| Samples (255)
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| This SubSeries is part of SuperSeries: |
| GSE95676 |
Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans |
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| Relations |
| BioProject |
PRJNA377892 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE95675_non-normalized_muscle.txt.gz |
56.0 Mb |
(ftp)(http) |
TXT |
| GSE95675_normalized_matrix_muscle.txt.gz |
56.3 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
| Processed data are available on Series record |
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