A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEXReport as inadecuate




A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX - Download this document for free, or read online. Document in PDF available to download.

BMC Genomics

, 14:136

Multicellular invertebrate genomics

Abstract

BackgroundGenome-wide association studies GWAS identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes T2D and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.

ResultsDisrupting orthologs of certain T2D candidate genes HHEX, THADA, PPARG, KCNJ11 led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX CG7056 directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity.

ConclusionCandidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.

KeywordsGenome-wide association study Drosophila melanogaster Diabetes mellitus, type 2 Hyperglycemia Dyslipidemias Phylogeny Reverse genetics High-throughput screening assays HHEX protein, Human AbbreviationsGWASGenome-wide association study

HBPHexosamine biosynthesis pathway

HDLHigh-density lipoprotein

LDLLow-density lipoprotein

QTQuantitative trait

SNPSingle nucleotide polymorphism

T2DType 2 diabetes.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2164-14-136 contains supplementary material, which is available to authorized users.

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Author: Jay Pendse - Prasanna V Ramachandran - Jianbo Na - Narisu Narisu - Jill L Fink - Ross L Cagan - Francis S Collins - Tho

Source: https://link.springer.com/







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