Genetic regulation of exosome biogenesis pathway in human adipose and muscle tissue and association with obesity and insulin resistance

BACKGROUND: Animal studies provide evidence of a link between exosome profile, obesity and insulin resistance (IR). Although it is known that exosomes mediate cell-cell communication via their macromolecular cargo, the factors regulating exosomes in humans are unknown. METHODS: Leveraging genome-wide expression and genotype data from the African American Genetics of expression and Metabolism (AAGMEx) cohort, we focused on 262 genes in “Exosome pathway”, curated by us, to examine the relationship of the expression of these genes with IR and obesity and tested the role of single nucleotide polymorphisms (SNPs) in determining the variability in the expression of these genes in adipose and muscle tissue. Publicly available gene expression data on European ancestry individuals, genome-wide association studies (GWAS), and bioinformatic approaches were used to validate the role of obesity-associated genetic variants in regulating exosome pathway genes. RESULTS: Transcript levels of 96 and 15 exosome pathway genes were associated with gluco-metabolic traits (BMI and insulin sensitivity) in adipose and muscle tissue, respectively. Data also suggests transancestral replication of association. The cis -expression quantitative trait (cis-eQTL) analysis of exosome pathway genes identified 45 and 65 cis -eGenes in adipose and muscle tissue, respectively. Expression of a subset of 26 cis -eGenes in adipose were also associated with gluco-metabolic traits. Based on combined SNP-to-gene-linking analysis 35 and 82 adipose expressed exosomal genes (e.g. AHNAK , RAP2A ) were identified as target genes for gluco-metabolic trait-associated SNPs in GWAS catalogue and UKBB GWAS datasets, respectively. CONCLUSIONS: In summary, expression of exosome pathway genes in adipose and muscle tissue are associated with obesity and IR, and expression of a subset of these genes are determined by SNPs. Furthermore, analysis of the target genes of GWAS identified gluco-metabolic trait-associated SNPs suggests that a subset of these SNPs is potentially involved in causing obesity and related gluco-metabolic diseases, likely by modulating exosome biogenesis.