Format

Send to

Choose Destination
Diabetes. 2019 Jul;68(7):1508-1522. doi: 10.2337/db18-1229. Epub 2019 Apr 22.

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

Author information

1
Section of Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
2
Section of Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
3
Center for Public Health Genomics, Department of Biomedical Engineering, University of Virginia, Charlottesville, VA.
4
Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
5
Division of Public Health Sciences, Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC.
6
Section of Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC sdas@wakehealth.edu.

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 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.

PMID:
31010960
PMCID:
PMC6609988
[Available on 2020-07-01]
DOI:
10.2337/db18-1229

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center