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 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.

journal_name

Diabetes

journal_title

Diabetes

authors

Sharma NK,Chuang Key CC,Civelek M,Wabitsch M,Comeau ME,Langefeld CD,Parks JS,Das SK

doi

10.2337/db18-1229

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

1508-1522

issue

7

eissn

0012-1797

issn

1939-327X

pii

db18-1229

journal_volume

68

pub_type

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