Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans

Neeraj K Sharma, Satria P Sajuthi, Jeff W Chou, Jorge Calles-Escandon, Jamehl Demons, Samantha Rogers, Lijun Ma, Nicholette D Palmer, David R McWilliams, John Beal, Mary E Comeau, Kristina Cherry, Gregory A Hawkins, Lata Menon, Ethel Kouba, Donna Davis, Marcie Burris, Sara J Byerly, Linda Easter, Donald W Bowden, Barry I Freedman, Carl D Langefeld, Swapan K Das

Compared with European Americans, African Americans (AAs) are more insulin-resistant, have a higher insulin secretion response to glucose, and more often develop type 2 diabetes. Molecular processes and/or genetic variations contributing to altered glucose homeostasis in high-risk AAs remain uncharacterized. 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. Clinical research unit-based cross-sectional study. Unrelated non-diabetic AAs. SI measured by FSIGT. The expression levels of 2,212 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-eQTL results with data from transcript-SI association analysis identified cis-regulatory SNPs 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. 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 appear to be important in insulin resistance. Identification of SNPs associated with SI and with modulation of expression of SI-associated transcripts, including NINJ1, reveals novel genetic regulatory mechanisms of insulin resistance in AAs.