Genetic Regulation of Enoyl-CoA Hydratase Domain-Containing 3 in Adipose Tissue Determines Insulin Sensitivity in African Americans and Europeans.

Abstract

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 <i>cis</i>-regulated transcripts (<i>cis</i>-eGenes) in adipose tissue. These IR-correlated <i>cis</i>-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. <i>cis</i>-eQTL for 587 Matsuda index-correlated genes were identified in both cohorts. Enoyl-CoA hydratase domain-containing 3 (<i>ECHDC3</i>) was the top-ranked Matsuda index-correlated <i>cis</i>-eGene. Expression levels of <i>ECHDC3</i> were positively correlated with Matsuda index, and regulated by <i>cis</i>-eQTL, rs34844369 being the top <i>cis</i>-eSNP in AAGMEx. Silencing of <i>ECHDC3</i> in adipocytes significantly reduced insulin-stimulated glucose uptake and Akt Ser⁴⁷³ phosphorylation. RNA sequencing analysis identified 691 differentially expressed genes in <i>ECHDC3</i>-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.